Deadly Short Cuts

"It's so good. Don't even try it once."

intravenous heroin user

Heroin is named after the German word for powerful, heroic, heroisch. According to popular legend,
its substitute, methadone, was initially christened Dolophine in honour of Adolf Hitler. In reality, the
name comes from the Latin dolor, meaning "pain", and fin, meaning "end": hence "end of pain".

The consumption of heroin is marked by a euphoric rush, a warm feeling of relaxation, a sense
of security and protection, and a dissipation of pain, fear, hunger, tension and anxiety. When heroin
is snorted or smoked, the rush is intense and orgasmic. Subjectively, time may slow down. Any
sense of anger, frustration or aggression disappears. Users enjoy the feeling of "being wrapped in
God's warmest blanket".

Heroin is the most fast-acting of all the opiates. When injected, it reaches the brain in 15-30
seconds; smoked heroin reaches the brain in around 7 seconds. The peak experience via this route
lasts at most a few minutes. The surge of pleasure seems to start in the abdomen; a delicious
warmth then spreads throughout the body, or at least the somatosensory cortex. After the intense
euphoria, a period of tranquillity ("on the nod") follows, lasting up to an hour. Experienced users will
inject between 2-4 times per day. After taking heroin, some people feel cocooned and emotionally
self-contained. Others feel stimulated and sociable. Either way, there is a profound sense of control
and well-being. The euphoria gradually subsides into a dreamy and relaxed state of contentment.
Higher doses of heroin normally make a person feel sleepy. At higher doses still, the user will nod
off into a semi-conscious state. The effects usually wear off in 3-5 hours, depending on the dose.
Heroin is not inherently toxic to the organ systems of the body. Whereas a 200-400mg dose of
heroin could kill a novice, a chronic user may take 1800mg without ill-effects. But in prohibitionist
society the mortality of street users is high.

Diacetylmorphine, or heroin, was first synthesized from morphine in 1874. It is formed simply
by adding two acetyl groups. Heroin is around three times more potent than morphine. Its increased
lipid solubility allows heroin to cross the blood-brain barrier more quickly. The drug is reconverted
back to morphine before it binds to brain-tissue receptors. Pure heroin is a white, odourless powder
with a bitter taste. Most illicit heroin, however, varies in color from white, pink/beige to dark brown.
This is because of impurities left from the manufacturing process or the presence of additives.

In the late nineteenth century, it was fondly believed that if only one could filter out the
"addictive" properties of opium, then one would capture its therapeutic essence. Heinrich Dreser, in
charge of drug development at Bayer, tested the new semi-synthetic drug on animals, humans, and
most notably himself. Dreser was impressed. He pronounced heroin an effective treatment for a
variety of respiratory ailments, especially bronchitis, asthma and tuberculosis.

Commercial production of heroin began in 1898. Heroin was advertised under its well-known
trademark by German manufacturers Bayer as "the sedative for coughs". The new wonderdrug
enjoyed widespread acceptance in the medical profession. This was because heroin induces a
serene, un-manic euphoria with minimal interference with sensation, motor skills or intellect -
though chronic opioid use typically diminishes the inclination to abstract thought.

Bayer was soon enthusiastically selling heroin to dozens of countries. Free samples were
handed out to physicians. The medical profession remained largely unaware of the potential risk of
addiction for years. Eventually news filtered out. Doctors noticed that some of their patients were
consuming inordinate quantities of heroin-based cough remedies. It transpired that heroin was not
the miracle-cure for morphinism that some of its early boosters had supposed. In 1913, Bayer
halted production. They wrote the drug out of their official company history, and focused instead on
marketing their second blockbuster drug, aspirin.

Comprehensive control of opiates in the United States was first established in 1914 with the
Harrison Narcotic Act. In 1924, federal law made any use of heroin illegal. Within a decade, the
Bureau of Narcotics had arrested some 50,000 users and 25,000 physicians. Most of the problems
suffered by contemporary users derive, directly or indirectly, from the criminalisation of heroin use
and the draconian penalties inflicted on those who take it. Likewise, most of the needless pain
suffered by the physically ill today derives, directly or indirectly, from the demonisation of opioid
drugs and from the reluctance of physicians to prescribe stigmatised remedies for pain that really
work.

During World War One, newspaper editors, police forces, politicians and "patriots" whipped up
a climate of hysteria against seditious "dope fiends" enslaved by "the German invention". Heroin use
was associated with anarchy, violence, foreigners and Bolshevism. Prohibition led inexorably to
control of the heroin business by organised crime. Jewish gangsters such as Meyer Lansky
dominated distribution in the 1920s. In the 1930s, they were superseded by the Mafia: this was the
era of "Lucky" Luciano, the celebrated Sicilian mobster.

Drug law was widely flouted. In explaining the failure of decades of prohibitionist legislation,
former chief of police of the USA, Joseph D McNamara, wrote in National Review...

"It's the money, stupid. After 33 years as a police officer in three of the country's largest cities, that
is my message to the righteous politicians who obstinately proclaim that a war on drugs will lead to
a drug-free America. About $500 of heroin or cocaine in a source country will bring in as much as
$100,000 on the streets of an American city. All the cops, armies, prisons and executions in the
world cannot impede a market with that kind of tax-free profit-margin. It is the illegality that
permits the obscene mark-up, enriching drug-traffickers, distributors, dealers, crooked cops,
lawyers, judges, politicians, bankers, businessmen..."
Choking off the supply of narcotics at source isn't a realistic prospect either. Myles Ambrose, one of
President Nixon's closest advisers in the War on Drugs, was scathing in his judgement of some of
his fellow drug-warriors...
"...The basic fact that eluded these great geniuses was that it takes only ten square miles of poppy
to feed the entire American heroin market, and they grow everywhere...."
Traditionally, the purity of heroin in a bag has ranged from 1% to 10%; more recently, heroin
purity has ranged from 1% to 98%, with a US national average of 35 percent. Pure heroin is rarely
sold on the street. A bag may contain 100 mg of powder, only a portion of which is heroin; the
remainder could be sugars, starch, powdered milk, or quinine. Until recently, heroin in the United
States was almost exclusively injected, either intravenously, subcutaneously ("skin-popping"), or
intramuscularly. Injection is the most practical and efficient way to administer low-purity heroin.
The availability of higher-purity heroin, however, allows users to snort or smoke ("chasing the
dragon"). Snorting is most widespread in those areas where high-purity heroin is easy to obtain.
 When injected, heroin provides an extremely powerful rush. After 4 to 8 hours, the effects
start to wear off. Tolerance develops to the respiratory depressant, sedative, analgesic, emetic and
euphorigenic effect. So users tend to increase their daily dose - sometimes as much as a
hundredfold or more - if financial resources permit. Financial resources frequently don't: the term
"junkie" derives from addicts who stole junk metal to support their habit.

Injecting drugs can be a risky business in prohibitionist society. This is because hygiene is
difficult, education is minimal, and fluctuations in quality can lead to accidental overdose. US
opposition to needle-exchange programs at home and abroad has massively promoted the spread of
HIV and hepatitis in users - and non-users - alike. Noxious tobacco-smoking aside, the Supreme
Court of the United States has never been sympathetic to a drug-based lifestyle....

"To be a confirmed drug addict is to be one of the walking dead....The teeth have rotted out, the
appetite is lost, and the stomach and intestines don't function properly. The gall bladder becomes
inflamed; eyes and skin turn a bilious yellow; in some cases membranes of the nose turn a flaming
red; the partition separating the nostrils is eaten away-breathing is difficult. Oxygen in the blood
decreases; bronchitis and tuberculosis develop. Good traits of character disappear and bad ones
emerge. Sex organs become affected. Veins collapse and livid purplish scars remain. Boils and
abscesses plague the skin; gnawing pain racks the body. Nerves snap; vicious twitching develops.
Imaginary and fantastic fears blight the mind and sometimes complete insanity results. Often times,
too, death comes-much too early in life....Such is the torment of being a drug addict; such is the
plague of being one of the walking dead..." (1962)

Heroin is sometimes smoked with crack cocaine. This combination delivers an even more
intensely rewarding experience than taking either drug alone. "Speedballs" are hugely addictive and
ruinously expensive. Yet in a clinical setting and among the terminally ill, the simultaneous use of
cocaine, methylphenidate or amphetamines with heroin or morphine can augment the opioid's
analgesic and anxiolytic effect while allowing its dosage to be lowered. The risks of respiratory
depression are thus diminished.

Why do we like opium and its derivatives so much?

Heroin mimics the action of natural chemicals, endorphins, produced by the body in response
to pain. Endorphins are small-chain peptides that activate our endogenous opioid receptors. Opioid
receptors are proteins embedded in the cell membrane; opioid agonists bind to the receptors to
initiate their effects. The highest density of opioid receptors is found in the limbic system. Their
activation produces feelings of happiness, relaxation, fearlessness and tolerance to pain. Endorphins
are hundreds or even thousands of times more potent than morphine on a molar basis. Their
potency means their concentrations in vivo are low. Endorphins are also involved in respiration,
nausea, vomiting, pain modulation, hormonal regulation and itching.
 Opioid drugs also act in these limbic brain regions. Yet except at very high doses, the
opioids don't block the pain messages themselves. Rather, they change the subjective
experience of the pain. This is why people receiving morphine for pain-relief may say
that they still feel the pain - but that it doesn't bother them any more. Many users
self-medicate: opioids are powerful antidepressants and antianxiety agents. Response
and remission rates are high; but so are tolerance, dependence and addiction. In
Search
Of The Big Bang
What is Crack Cocaine?
Cocaine is an alkaloid found in leaves of the South American shrub Erythroxylon coca. It is a
powerfully reinforcing psychostimulant. The drug induces a sense of exhilaration in the user
primarily by blocking the reuptake of the neurotransmitter dopamine in the midbrain. If the
predictions of The Hedonistic Imperative are vindicated, then future millennia will witness what
Robert Anton Wilson once called "hedonic engineering". Mature enhancements of currently drug-
induced states of euphoria will be transformed into a absolute presupposition of sentient existence.
Gradients of life-long happiness will be genetically pre-programmed. "Peak experiences" will become
a natural part of everyday mental health. Cocaine, alas, offers only a tragically delusive short-cut.

In pre-Columbian times, the coca leaf was officially reserved for Inca royalty. The natives used
coca for mystical, religious, social, nutritional and medicinal purposes. Coqueros exploited its
stimulant properties to ward off fatigue and hunger, enhance endurance, and to promote a benign
sense of well-being. Coca was initially banned by the Spanish. In 1551 the Bishop of Cuzco
outlawed coca use on pain of death because it was "an evil agent of the Devil". The noted 16th
century orthodox Catholic artist Don Diego De Robles declared that "coca is a plant that the devil
invented for the total destruction of the natives." But the invaders discovered that without the Incan
"gift of the gods", the natives could barely work the fields - or mine gold. So it came to be cultivated
even by the Catholic Church. Coca leaves were distributed three or four times a day to the workers
during brief rest-breaks.

Returning Spanish conquistadores introduced coca to Europe. Even Shakespeare may have
smoked it - and inhaled. The coca plant is perishable and travels poorly. Yet coca was touted as "an
elixir of life". In 1814, an editorial in Gentleman's Magazine urged researchers to begin
experimentation so that coca could be used as "a substitute for food so that people could live a
month, now and then, without eating..."

The active ingredient of the coca plant was first isolated in the West by the German chemist
Friedrich Gaedcke in 1855; he named it "Erythroxyline". Albert Niemann described an improved
purification process for his PhD; he named the product "cocaine". The name stuck. Sigmund Freud,
an early enthusiast, described cocaine as a magical drug. Freud wrote a song of praise in its honour;
and he practised extensive self-experimentation. To Sherlock Holmes, cocaine was "so
transcendentally stimulating and clarifying to the mind that its secondary action is a matter of small
moment". Robert Louis Stephenson wrote The Strange Case of Dr Jekyll and Mr Hyde during a six-
day cocaine-binge. Intrepid polar adventurer Ernest Shackleton explored Antarctica propelled by
tablets of Forced March.

Doctors dispensed cocaine as an antidote to morphine addiction. Unfortunately, some of their

patients made a habit of combining both.
 Cocaine was soon sold over-the-counter. Until 1916, one could buy it at Harrods: a kit labelled
"A Welcome Present for Friends at the Front" contained cocaine, morphine, syringes and spare
needles. Cocaine was widely used in tonics, toothache cures and patent medicines; in coca
cigarettes "guaranteed to lift depression"; and in chocolate cocaine tablets. One fast-selling product,
Ryno's HayFever and Catarrh Remedy ("for when the nose is stuffed up, red and sore") consisted of
99.9 per cent pure cocaine. Prospective buyers were advised - in the words of pharmaceutical firm
Parke-Davis - that cocaine "could make the coward brave, the silent eloquent, and render the
sufferer insensitive to pain".

When combined with alcohol, the cocaine alkaloid yields a further potently reinforcing
compound, now known to be cocaethylene. Thus cocaine was a popular ingredient in wines, notably
Vin Mariani.Coca wine received endorsement from prime-ministers, royalty and even the Pope.
Architect Frédérick-Auguste Bartholdi remarked that if only he had used Vin Mariani earlier in his
life, then he would have engineered the Statue of Liberty a few hundred meters higher.

Coca-cola was introduced in 1886 as "a valuable brain-tonic and cure for all nervous
afflictions". It was promoted as a temperance drink "offering the virtues of coca without the vices of
alcohol". The new beverage was invigorating and popular. Until 1903, a typical serving contained
around 60mg of cocaine. Sold today, the drink still contains an extract of coca-leaves. The Coca-
Cola Company imports eight tons from South America each year. Nowadays the leaves are used
only for flavouring since the drug has been removed - though molecular traces of cocaine remain.
What happens to the discarded cocaine is obscure.

A coca leaf typically contains between 0.1 and 0.9 percent cocaine. If chewed in such form, it
rarely presents the user with any social or medical problems. Indeed coca-chewing may be
therapeutic. When the leaves are soaked and mashed, however, cocaine is then extracted as a
coca-paste. After the organic solvent used has evaporated, the coca-paste is 60 to 80 per cent pure.
It is usually exported in the form of the salt, cocaine hydrochloride. This is the powdered cocaine
most common, until recently, in the West. Drug testing for cocaine aims to detect the presence of
its major metabolite, the inactive benzoylecgonine. Benzoylecgonine can be detected for up to five
days in casual users. In chronic users, urinary detection is possible for as long as three weeks.

Yet old-fashioned cocaine hydrochloride still wasn't good enough. Sensation-hungry thrill-
seekers have long sought the ultimate high from the ultimate "rush". They haven't been satisfied
with the enhanced mood, sexual interest, self-confidence, conversational prowess and intensified
consciousness to be derived from just snorting cocaine. Normally, only the intravenous route of
administration could be expected to deliver the more potent and rapid hit they have been seeking.
Yet there are very strong cultural prejudices against injecting recreational drugs. So a smokeable
form was developed.

Since the hydrochloride salt decomposes at the temperature required to vaporise it, cocaine is
instead converted to the liberated base form. Initially, "free-base" cocaine was typically produced
using volatile solvents, usually ether. Unfortunately, this technique is physically dangerous. The
solvent tends to ignite. Hence a more convenient method of producing smokeable free-base became
popular. Its product is crack. To obtain crack-cocaine, ordinary cocaine hydrochloride is
concentrated by heating the drug in a solution of baking soda until the water evaporates. This type
of base-cocaine makes a cracking sound when heated; hence the name "crack". Base-cocaine
vaporises at a low temperature, so it can be easily inhaled via a heated pipe.

Crack-cocaine delivers an intensity of pleasure completely outside the normal range of human
experience. It offers the most wonderful state of consciousness, and the most intense sense of
being alive, the user will ever enjoy. (S)he will access heightened states of being whose modes are
unknown to chemically-naïve contemporaries. Groping for adequate words, crack-takers sometimes
speak of the rush in terms of a "whole-body orgasm". Drug-naive virgins - slightly shop-soiled or
otherwise - cannot be confident (unless in thrall to ill-conceived logical behaviourist theories of
meaning) that they have grasped the significance of such an expression. For to do so, it would be
necessary to take the drug via its distinctive delivery-mechanism oneself. This is at best very
imprudent.

Ultimately, the emotional baseline, and affective analogue of Absolute Zero, characteristic of
post-humanity in its hedonically enriched modes of awareness may be greater than anything we can
now grasp. It may be higher than the rapturous transports of the most euphoric coke-binge in
paleo-human history. In the meantime, a drug which induces a secular parody of Heaven commonly
leads the user into a biological counterpart of Hell.

When Is It Best To Take Crack Cocaine?

As a rule of thumb, it is profoundly unwise to take crack-cocaine. The brain has
evolved a truly vicious set of negative feedback mechanisms. Their functional effect
is to stop us from being truly happy for long. Nature is cruelly parsimonious with
pleasure. The initial short-lived euphoria of a reinforcer as uniquely powerful as
crack will be followed by a "crash". This involves anxiety, anhedonia, depression,
irritability, extreme fatigue and possibly paranoia. Physical health may deteriorate.
An intense craving for more cocaine develops. In heavy users, stereotyped compulsive and
repetitive patterns of behaviour may occur. So may tactile hallucinations of insects crawling
underneath the skin ("formication"). Severe depressive conditions may follow; agitated delirium;
and also a syndrome sometimes known as toxic paranoid psychosis. The neural after-effects of
chronic cocaine use include changes in monoamine metabolites and uptake transporters. There is
down-regulation of dopamine D2 receptors to compensate for their drug-induced overstimulation.
Thus the brain's capacity to experience pleasure is diminished.

The social consequences of heavy cocaine use can be equally unpleasant. Non-recreational
users are likely eventually to alienate family and friends. They tend to become isolated and
suspicious. Most of their money and time is spent thinking about how to get more of the drug. The
compulsion may become utterly obsessive. The illusion of free-will is likely to disappear. During a
"mission", essentially a 3-4 day crack-binge, users may consume up to 50 rocks a day. To obtain
more, crack addicts will often lie, cheat, steal and commit crimes of violence. Once-loved partners
and children may be callously cast aside. Whole communities can be disrupted by crack-abuse.
Whereas "empathogens" such as MDMA / Ecstasy - which trigger the release of more serotonin than
dopamine - will typically promote empathy, trust, compassionate love and sociability,
"dopaminergic" drugs such as cocaine or amphetamines, if taken on their own and to excess, can
easily have the reverse effect. This story has complications - cocaine's affinity for the serotonin
transporter is actually greater than for the dopamine transporter. But simplistically, cocaine tends to
be a "selfish" drug.

There is perhaps a single predictable time of life when taking crack-cocaine is sensible,
harmless and both emotionally and intellectually satisfying. Indeed, for such an occasion it may be
commended. Certain estimable English doctors were once in the habit of administering to
terminally-ill cancer patients an elixir known as the "Brompton cocktail". This was a judiciously-
blended mixture of cocaine, heroin and alcohol. The results were gratifying not just to the recipient.
Relatives of the stricken patient were pleased, too, at the new-found look of spiritual peace and
happiness suffusing the features of a loved one as (s)he prepared to meet his or her Maker.
 Drawing life to a close with a transcendentally orgasmic bang, and not a pathetic and god-
forsaken whimper, can turn dying into the culmination of one's existence rather than its present
messy and protracted anti-climax.

There is another good reason to finish life on a high note. In a predominantly secular society,
adopting a hedonistic death-style is much more responsible from an ethical utilitarian perspective.
For it promises to spare friends and relations the miseries of vicarious suffering and distress they
are liable to undergo at present as they witness one's decline.

A few generations hence, the elimination of primitive evolutionary holdovers such as the
ageing process and suffering will make the hedonistic death advocated here redundant. In the
meanwhile, one is conceived in pleasure and may reasonably hope to die in it.

BUILT FOR SPEED?

Methamphetamine has reclaimed a place in the lexicon of "party" drugs. Hailed by nocturnal adventurers, condemned
by raver idealists, is speed a sleepless dream or an addictive nightmare?

by
Todd C. Roberts

Here at the end of the millennium, the pace of modern life seems fleeting -- a whirl of
minutes, hours and days. In dealing with the changes, humans have equipped themselves with the
tools to move faster, more efficiently. At the same time a dependence for the marketing, high-speed
transportation and pharmacology of this modern age has evolved. In a race to outdo ourselves, we
have moved dangerously toward the fine line between extinction and evolution. Therefore, the
human capacity to handle the velocity becomes a fragile balance.

Our generation (see Gen X, 20-somethings) could be considered the sleepless generation. An age of
society's children weaned on the ideals of high-speed communication and accelerated culture has
prided itself in mastering many of the facets of human existence -- doing more, sleeping less. The
machines of this age have in a way enabled us to create a 24-hour lifestyle. We have pushed the
limits of the modern world further -- ATMs, high-speed modems, smart bombs and bullet trains.
However, the limitations of human existence, like sleep, may still provide the stumbling block for
infinite realization. That is, without chemical aid.

In many ways, capitalism fuels the idea. Our society is based upon the mass consumption of
these substances. Cultural ideals, while seemingly benevolent as "Have a Coke and a smile" have
sold the link to chemical substances like caffeine and nicotine to "the good life." Today, stimulants
are the bedrock for consumer culture. For our generation, this appeal was heightened by raising the
stakes in the '80s on what it meant to have fun.

Late night clubs, high speed music and 24-hour lifestyles brought the specter of drugs to the fold as
a necessity for being able to attain more. Leaps away from the psychedelics of the '60s, in the '80s
these stimulant drugs became tools -- utilitarian devices to gain wealth, intelligence and prestige.
Sleep became a barrier for success. Dreams were the frivolous luxuries of childhood.

Raves, founded equally in the post-conservative underground late-'80s and the chaotic early-'90s,
are part of the pastiche that has consequently become more dream-like, more unreal and still
somehow manageable. The hyperreality of today goes hand in hand with the drugs being
administered.
It's 6 a.m. Around the speaker bins are small packs of animated dancers grinding their feet
into the floor and shaking their hands in front of them. The lookie-loos and weekend warriors have
long since gone home. Absent from their faces are the smiles of midnight, replaced by the blank,
vacant stare of sleepless dreams. They have a name in the rave community, they are "tweakers."
"Tweaking," the common name for sniffing lines of speed, the drug methamphetamine, (popular for
its availability and price) has somehow replaced MDMA and LSD as the perfect rave drug, allowing
users the clear head and stamina to keep dancing long after their bodies have gone to sleep.

A prominent opinion during the aftermath of the Los Angeles Summer of Love was that speed killed
the rave scene. Where speed had been seen in every scene from metal to the punk scene, for some
reason it was shocking for some to see methamphetamine take hold, even though MDMA (an
amphetamine-like substance) had been circulating for years. Some likened the rise to the quash of
young newcomers, some equated it with the greed of drug dealers. Judging from today's roster of
events throughout the nation, raves are still alive and well. However, many old-schoolers have been
turned off by the newbie vibe that came with speed's rise in popularity. Some were casualties
themselves of the drug's addictive nature. Others say that speed alone is what fuels the rave scene,
keeping it from dying.

Amphetamine was first synthesized in 1887. First popularized by pharmaceutical company

Smith Kline & French as the nasal inhaler, Benzedrine, in 1932. (Amphetamine is widely known as a
bronchio dialator, allowing asthmatics to breathe more freely.) A probable direct reaction to the
Depression and Prohibition, the drug was used and abused by non-asthmatics looking for a buzz.
Jazz great Charlie "Bird" Parker would remove the inhaler's Benzedrine strip and soak it in his
coffee.

Methamphetamine, more potent and easy to make, was discovered in Japan in 1919. The crystalline
powder was soluble in water, making it a perfect candidate for injection. Also smoking the drug
creates a similar rush. It is still legally produced in the U.S., most often prescribed for weight loss,
sold under the trade name Desoxyn. As the name "speed" suggests, amphetamines elevate mood,
heighten endurance and eliminate fatigue, explaining the drug's popularity with the military. Hitler
was supposedly injected with methamphetamine.

Speed rose to popularity in California, home of many of the largest meth labs in the country, riding
on the back of biker gangs. Bikers have been historically blamed for introducing the drug into the
psychedelic '60s, subsequently bringing down a whole Summer of Love with violence and angst.
Since then, speed has been given a bad rap. It has been called a trailer park drug for decades, due
to the fact that it can be cooked up so cheaply and easily. It's the drug of choice for long-distance
truckers and college students pulling all-nighters. Over the counter ephedrine, or "white crosses,"
has taken the place of pharmaceutical amphetamine as an easy-to-get alternative.

What is often misunderstood is the relationship between speed and crystal meth. The common
reference to speed in the rave scene is the methamphetamine salt (HCl powder), whereas "crystal"
usually refers to the free-base form of methamphetamine. Another form "Ice," a higher-grade,
purer form of crystal meth is smoked, a single hit creates a high that lasts for hours and several hits
can wire a user for days. However, its high price prevents it from taking hold. A gram of "ice"
commands about $5,000 on the street.

Speed came to the rave scene in 1992. Theory: when the parties in '92 started to get really
good, the police were cracking down more on the prime-time parties -- partiers needed to find late-
night/early morning activities like after-hours. Consequently, the price of taking 3-4 pills of ecstasy
became too expensive an option, speed took over as an easier to get and cheaper alternative. Now,
the standard street price in Los Angeles for a gram of speed is approximately $100, where ecstasy
sells for approx. $150 or more.

One major misconception is the link between methamphetamine and ecstasy [MDMA]. Ecstasy does
not necessarily contain speed, yet both contain the methamphetamine structure. However, each
affects a far different region of the brain resulting in different psychological effects. Ecstasy
primarily effects serotonin in the brain -- the center for self-satisfaction and emotional systems.
Speed affects dopamine primarily, a neurotransmitter linked to pleasure and reward. (Oddly, alcohol
also affects a dopamine center.) Often, MDMA is "cut" with speed to lower the street price of the
drug, thus changing the overall effect. The two are similar in chemical makeup but one cannot be
made from the other. Slightly changing the chemical makeup produces a wholly different effect in
the human brain. While both have addictive potential, speed, because of its dopamine ties, is much
more profoundly addicting. Qualitatively, speed and ecstasy supposedly give off "glows" that are far
different.

Ecstasy has a definite link to the rave scene. In some places it is synonymous. Speed too has been
linked to the rave scene -- some say it was the death of the ideal. What's unusual, given the
qualitative similarities between the two, are the differing opinions about speed. While many admit
openly to taking MDMA, they will not condone or even accept speed as a "valid" recreational drug.
The stigma that goes with "tweaking" can be quite severe.

"Speed is evil," says Dominic. "I have seen more people's lives twisted up off that drug than
anything else in the world. I was first introduced to it about five years ago by a girl I was dating. I
basically watched her use of it turn from an occasional party thing to basically the sustenance of her
life. Her body withered way, and everything she did revolved around speed."

"Speed does not belong in the underground scene," he continues. "Something that is so damn
negative could never co-exist with the positive ideals that we try to promote. If you want to get
amped, feel energy and stay up all night, try alternatives -- using speed just to stay up is a total
cop out." However, his opinion is that ecstasy has opposite effects and could actually save the rave
scene. "[MDMA] induces a sense of spiritual enlightenment, happiness, and sometimes social
understanding, something that could never be achieved by shoving a few rails of driveway cleaner
up your nose."

"I'm all for consciousness expansion, even if by chemical means," says another critic, Michael.
"Preferably organic chemistry. The problem is major parts of the scene moved away from
enlightenment, transcendence and betterment of the self through involvement in community"

A regular user of the drug is DJ Velour, 19, also finds some criticism for it. "I believe that
speed/crystal is one of the most psychologically addictive drugs around," he says "Whenever I get
tired or wish I had more energy, I always think how nice it would be to have some speed. In that
respect, I am addicted, because it is definitely a part of my thought pattern now. And I haven't
done speed for over 3 weeks now." Even though his experiences have not all been good, he is still
connected to the drug.

"Amphetamines, in my mind are not evil," says Velour, hoping to defend the drug against his critical
peers. "They are simple chemicals, if there is anything evil it is the society we live in which dictates
that they are illegal and thus makes them harder to get."

"I will admit one thing, it is very addictive," he goes on. "Once you take it a few times, you will
continue to think about it after you stop. I haven't done speed for a month now and still some days
will go by where I have only had 3 or 4 hours sleep, and I think to myself, 'You know, speed would
really help out right now.' However, that is what makes me a more responsible user. I not only
realize my desire for speed and other amphetamines and I curb the habit." He feels that his ability
to control his habit is more powerful than his lust for it. "Many of my friends are long time users of
speed. However, by no means have they ruined their lives."

DJ Velour believes that the rave community can co-exist with a drug like methamphetamine. He
also, among others, mentions speed's many different appearances that make for different
psychological outcomes. "Speed and other stimulants can be a positive part of a raving community.
However, just like any other drug it depends upon the person taking it and the purity/mixture of the
drug. As strange as this may sound, different speeds can evoke different emotions. They not only
stimulate latent emotions, increasing their strength, but they can also enforce emotions much in the
way ecstasy can. I have had some very "happy" speed that made me feel as happy as when I was
on X. On the flip side I have had some lower grade speed that made me feel depressed."

Speedlore and Methology: Part I

"Of all the separate realities, legal landscapes, and metabolic metropolis that thrive beneath the
surface of the Cleaver's USA, no subculture seems as pervasive or uniform as the nationwide-eyed,
high dosage methamphetamine club.

This group is a tribute to the idea that some things stay the same across time or space... the
members come and go, some leave quietly, some go snitch, croak, or disappear, some hang in
there after their lights have gone out, and quite a few are dragged off at 6:00 a.m. Friday morning
by blue windbreakers with yellow writing.

Getting in too deep is what we do, it's who we are.

But despite all this, there are a few of us who have managed to hang around the periphery for
decades, avoiding the felonies, gunshots, big ripoffs, and crippling motorcycle accidents. Other than
luck, the key to staying alive is knowing when to take a step back, on your own, and avoid the
biggest bear-trap in the speed circus: taking yourself too seriously...

Truly not giving a fuck is the only way to maintain perspective. In other words, there are worse
things that can happen, than having to lay down and go to sleep for a week... no drug or state of
mind is worth dying for, killing for, or doing hard time for..." (Speed Phreak)

"My experience with speed-like substances really begins with coffee," says Mark, an addict that
relates his experiences back to an early age. "I've been drinking the stuff since Jr. High School as
my get me up and go thing. But the relationship with amphetamines starts six or seven years ago
with poppers (ephedrine, mini-thins). I started taking them to stay awake in college to finish papers
and the like."

"Things got really serious when I started doing CAT, a local low-grade speed that was in vogue
about six years ago." CAT, or methacathinone, is a popular substance made from common
household chemicals like drain-cleaner, Epsom salts and battery acid. "I realized how bad my
problem was when right around the time the land war in Iraq began. I had stayed up for days on
end, watching the planes bomb the Iraqis. It's the only drug I've done at work. To this day what
was a six month period still seems to me to be several weeks. It's also the only drug I've done
where my peers at work noticed mood swings, irritability, and sleeplessness. The CAT I knew dearly
also tweaked me on methamphetamine when the CAT seemed to loose its luster." CAT is notorious
for its hardcore addictive potential, apparently strong enough to hook users after just one sample.
[Editorial Note: Methcathinone is related to ephedrine similarly to how speed is related to
ephedrine. If you take ephedrine and reduce it you get methamphetamine, if you take ephedrine
and oxidize it then you've got methcathinone. The reference to "drain-cleaner and battery acid" is to
common sources of the chemicals sodium hydroxide and H2SO4 which are used in chemical
synthesis. Methcathinone is not "made from" those substances but can be "made using" those
substances. -- lamont@hyperreal.org ]

"Even after I kicked the CAT habit, I would usually indulge my speed addiction by crushing up mini-
thins and snorting them. This continued for about another year. Most recently (for about a year) I
moved to MDMA as the speed kick. At first I did it about once a month, but that has fallen off to a
much less frequent, but still regular usage."

"What caught me about speed, and what catches me now, is the feeling of invulnerability. I think I
get from speed what most cocaine users get from coke. The feeling of being on top of the world. As
a raver, speed is also a convenient way to keep dancing long after your body has gone to sleep."

Asked if the drug has improved his life, he answers, "What a joke. Improve? Beyond the nominal
gain of being able to dance until the wee hours of the morning, it doesn't. And productivity? Any
gains are ephemeral and short-lasted."

"I do in fact know some people who skate through life without problems with drugs. But I think
more people than not overestimate their ability to handle drugs. Drugs can be fun, but they also
tend to get in the way of being a functional human being with multi-dimensional interests, as
opposed to being a full-time club kid, which gets you nowhere fast."

For "Pat," the drug poses a serious paradox. He was prescribed methamphetamine for a learning
disability and consequently produced a problem through abuse. "I'm able to work with concentration
on something far longer than a few hours," he says of meth. "I have Attention Deficit Disorder [and]
speed seems to improve my attention span."

"It can be a transcendental drug if you do enough. I've had really intense thought about
observations of myself, or new ideas about what I'd like to do with my music, or other creative
thoughts. This occurs with other psychedelic drugs that I've done." Still, he describes the typical
problem with drugs like speed. "Speed is funny. You think you've got it under control when you first
do it because it's usually so nasty on the sinuses and your body that you don't ever think you could
get used to the feeling... [However], you do."

Other users bring up the fact that MDMA also has an addiction factor, that many only attribute to
meth. "I like speed just fine," says Benboy. "But I have seen many speed freaks go out like that.
And I've seen a few 'E' freaks buy the farm too, even though I do think E is much safer). But a
drug, whether it's strychnine, THC, caffeine or Prozac, is nothing more than an inert substance; as
dangerous as a head of lettuce in itself. It's what you do with it that makes a difference. But the
difference between jonesing for a sugar fix and a speed fix is only partially chemical and
physiological. Most of it is social." The drug itself is not the problem, it's the setting involved. The
availability and the motive to remain awake for long hours may compound the addiction of speed.

Still others attribute a great deal of positive qualities to methamphetamine. "My brain was so clear
when I used this, that I came up with answers to problems that had been bugging me for months,"
says an anonymous post to one of the world wide web's drug archives. "This stuff makes your brain
work at 100% efficiency and doubles processor speed. It makes you feel (and probably actually
does) like your IQ jumped quite a bit." According to some medical journals, methamphetamine does
produce slight improvements in mental acuity, though performance of only "simple mental tasks" is
improved, although the amount of errors is not necessarily decreased.

Still many would attribute "wonder drug" status to meth, enabling them to get more done without
sleep. Students, hackers and late-night workers rely on the drug to keep them awake. "Sleep will
never even occur to you," the post continues. "Do two hits in the morning before work, and you will
never miss the sleep from the night before. As a matter of fact, you will feel better than if you had
skipped the drug and slept all night!"

Speedlore and Methology: Part II

"The American Speedfreak is not a lost soul. We know how to have fun between the first ether gasp
and locking ourselves in the closet. A twisted wisdom creeps into those of us who manage to
survive, a sort of collective unconsciousness, an unspoken Crankster ideology:

It's time to get some sleep when:

You're out of crank

Your face is bouncing off the table

Your veins have completely disappeared beneath pasty goose flesh

Your shoes don't fit anymore

24 simultaneous projects have stalled for lack of floor space suddenly

everyone is a cop

You've just set yourself on fire, again

You're nodding out...

into glassware

15 minutes after shooting a 1/4g

at stoplights

in mid-sentence

in mid-shot

in mid-fuck"

(Speed Phreak)

Speed was created for a future world where everything moves at a faster clip, an
unsettling velocity. Seemingly synthesized as an accessory to a fast car, high speed lifestyle, it has
made mutations over the years to evolve for a new race. The punk, cyber, industrial and rave
scenes has exemplified their fetish for speed. The desire for future frontiers -- high gloss veneers
and space travel-- is not inhuman, but the problem comes with the human limitation to handle the
extremes of rocket travel or the side-effects of re-entry. Like a space capsule falling to earth, the
destruction that comes from the come-down can be severe.

The come-down is what many users refer to as "the crash." Usually symptoms like chills, nervous
twitching, sweats and exhaustion are prevalent. The "high" produced is a result of extra activation
chemicals in the brain. "The so-called stereotypic behavior in animals (compulsive gnawing, sniffing)
is associated with dopamine release from reservoirs in neurons in the brain," says Matt Plunkett, an
Organic Chemistry graduate student at U.C. Berkeley. "The increase in motor activity involves the
noradrenaline system. [The drug] mimics the molecule noradrenaline (norepinephrine) at the
receptors for this neurotransmitter. Hence your body acts as if there were more of it around."

Simply put, stimulants cause their effects by blocking re-uptake of neurotransmitters at a pre-
synaptic membrane. The cell secretes activation chemicals, but cannot re-absorb them in the
presence of cocaine or speed. The user feels "wired," full of energy, because their cells are receiving
massive stimulation. The more concentrated the drug is, the more intense the rush is, and the more
damaging the effects. In worst case scenarios, heart attacks occur from over stimulation and energy
depletion.

The come down is a result of the chemical being released all at once, making you high, but then is
subsequently degraded in the synapse. So once you come down, there's not as much as there
normally should be, creating the "come-down blues."

Prevalent discussion between users on either side of the methamphetamine argument

involves addiction. According to several studies, criteria for addiction includes: unsuccessful
attempts to quit, persistent desire and craving, continued use despite knowledge of harm to oneself
or others, taking the drug to avoid or relieve withdrawal. While the social definition for addiction is
debatable, the chemical and physical activity in the body is founded in one of several compounds in
the brain. "Many drugs that are addictive, have primary or major effects on the dopamine system
(nicotine, amphetamine, cocaine, alcohol, heroine)," says Plunkett. "Drugs that don't have a major
effect on dopamine generally aren't 'addictive' in the same way -- Marijuana, MDMA, LSD,
psilocybin, etc. Although abuse potential is there, it doesn't generate the same kind of craving.
Dopamine is normally involved with pleasure and reward, among many other biochemical roles."

With long-term abuse, the effects of methamphetamine become much more severe. Tolerance is an
issue, like in most drugs, where more of the drug is needed to get "high." Psychosis, specific to
methamphetamines usually sets in after a time which is said to include "suspicion, anxiety and
auditory hallucination." Though reportedly, much more acute are the changes in lifestyle and
eventually in personality that manifest. Users exhibit an affective disorder and subtle change in
psychological temperament. Apparently, these symptoms can last up to five years. Many who have
witnessed the changes in habitual users report the shift to aggressive or non-affectionate behavior
which may also be attributed to methamphetamine. Also apparent is some nerve damage in
habitual users (primarily crystal smokers) -- jaw clenching and facial ticks.However, how much can
be attributed tot the drug and how much to sleep deprivation is unclear.

Meth is one of the most addictive drugs of today's commonly used drugs. According to one study
that appeared in In Health magazine (Dec. 1990), the addictive potential inherent in the drug,
methamphetamine, taken nasally ranks over cocaine, caffeine and PCP (angel dust) in addictive
qualities. MDMA, marijuana, psilocybin and LSD ranked at least 50 points lower than meth on a 100
point scale, nicotine being the highest above both crack and crystal meth. Talk of "addictive
personalities" have recently been founded valid, involving individual physiology, psychology, social
and economic pressures to suggest a person's vulnerability to drug dependency. Therefore, it does
rely greatly on the person when talking about their potential for abuse. Still, many theorists contend
that stimulants -- lumping in caffeine, nicotine and amphetamines -- by their nature are addictive
and must be reconsidered by society.

Ethnobotanist, drug theorist and author Terence McKenna calls the "dominator" drugs --
synthetic drugs that have been refined and concentrated, therefore losing their natural link to the
planet and to human-kind. He equates them with the religious fundamentalism and beige fascism of
the post-industrial, Western world -- the center for ego-dominator culture. McKenna considers the
natural psychedelics, psilocybin and even LSD, to be more intuitive and based upon the natural
human spirit.

"Dominator" drugs have been established and validated by "dominator culture," a culture interested
in the mass consumerism of these legitimate substances -- sugar, nicotine, caffeine. He relates the
emergence of drugs like methamphetamine back to the institutionalized abuse of these substances.
"The history of commercial drug synergies -- the way in which one drug has been cynically
encouraged and used to support the introduction of others -- over the past five hundred years is not
easy to contemplate," he writes in his book Food of the Gods.

"The hypocrisy of dominator culture as it picks and chooses the truths and realities that it finds
comfortable," he continues. Some drugs like alcohol and nicotine have long been legal and
subsidized by dominator culture, however their qualitative separation from drugs like cocaine or
speed is still unclear. "[These drugs] are still at the depths of drug depravity especially considering
the violent or illegal acts that the craving may induce [because of their illegal status], however
tobacco addicts (smokers) might kill for their fix too if they had to, but instead they simply walk out
to a 7-Eleven and buy cigarettes."

While I am no proponent of speed or drug abuse, I have become glaringly aware of the
hypocrisy prevalent in mainstream and underground culture regarding the legitimation of certain
drugs. When finger-pointing, it is important to remember the glass houses we all live in. Addiction is
a problem, but the bigger problem is sweeping it into a closet, pretending it isn't real, pretending
that our own addictions are more manageable.

Speed is a potentially dangerous substance. It can be used as a tool, like late-night coffee drinkers.
It can also be used as a recreational drug. However, it can also be abused and exploited to the point
where the need for it besides soothing a craving is the only point. And then, there is no point. Some
may argue that there is an aesthetic, a qualitative high, however, by methamphetamine's nature --
as a refined, concentrated addictive substance -- it only perpetuates the cycle for needing more.

There is very little factual information about amphetamines and their dangers available to the lay
person. Research on the subject, aside from medical journals, is virtually nill. There is however a
great deal of dangerous propaganda -- hear-say, lies, rumors. Misinformation sometimes is more
dangerous than no information and real answers are only found through communication.

Many other drugs have been part of the rave community over the years -- nitrous oxide, Special K
(ketamine) and especially ecstasy (MDMA) but none have exhibited the burn-out or addiction rate
associated with methamphetamine. While meth (or any drug) is an inert substance that we cannot
attribute blame to, by its nature it has raised the question "Are we really built for speed?" It seems
that the human body, while naturally resilient to much self-inflicted abuse, may not be a reliable
container for the soul at high speeds. Methamphetamine may have the ability to chemically fuel the
ride, physically it may just prove the limitations for human society.
Control drugs. Don't let them control you.

Article originally appeared in URB Magazine, October 1995

Methamphetamine
Frequently Asked Questions

deadlock@paranoia.com

April 15, 1996

Abstract
Surprisingly, there does not appear to be a comprehensive source of information relating to
methamphetamine. While no list is ever complete, this one attempts to answer technical questions
related to the chemical methamphetamine. Unfortunately, there tends to be a great deal of street
lore that is blatantly wrong about methamphetamine and similar compounds. This document also
attempts to point out some of the more common myths, and provide rational explanations.

Disclaimer
Do not use this information. I am not a chemist. This is for informational purposes only. Use of this
information for illegal purposes is not condoned. The author makes no warranty, expressed or
implied, of the suitability of this information for any particular purpose. The author does not endorse
the abuse of any drugs, legal or otherwise.

This information has been gathered from openly available sources.

This is a preliminary document and should be considered fictitious until proven otherwise.

Overview
Methamphetamine (also known as speed, meth, crystal, crank, and sometimes confusingly called
ice) is a chemical widely known for its stimulant properties on the human body. It is frequently
confused with other drugs that share similar symptoms, including amphetamine, 4-methyl-
aminorex, ephedrine, caffeine, and other chemicals, both legal and illegal.

Terminology

In this document, we shall refer to the drugs by their common chemical names, rather than by
"street names", since the street names do not have a one-to-one correspondence to actual
chemicals. For example, the term "speed" can mean methamphetamine or amphetamine. The term
"ice" is generally considered to apply to 4-methyl-aminorex, but is often used to refer to relatively
pure (and in some cases, not so pure) forms of methamphetamine.

We shall use the term "methamphetamine" to refer to the substance in either its free base (i.e.
simple, unadorned) or salt (usually hydrochloride) form. When precision is needed, we shall
explicitly state one form or the other.
Pharmacology
This is one of the most difficult sections to write, partially because there is very little "science"
involved. The literature gives conflicting reports, due to the fact that many criterion are subjective,
and probably also due to confusion over terminology.

The pharmacological effects of methamphetamine are very similar to those of similarly structured
molecules.

Administration

Methamphetamine can be taken orally, snorted, smoked or injected, in approximately increasing

order of immediacy of onset.

Onset

Onset can be immediate (in the case of injection), or can take as long as 30-40 minutes if ingested
orally.

Duration

Duration is subjective, but is probably on the order of 4 - 8 hours. Delayed absorption (for example,
due to oral ingestion) can prolong the effects relative to time of administration. Of course, larger
doses last longer due to the fact that it is removed from the blood at a finite rate.

Plasma Life

The length of time that methamphetamine will stay in the plasma (blood) is between 4 to 6 hours.
It can be detected in the urine one hour after use and up to 48 hours after use.

Dosage

A toxic reaction (or overdose) can occur at relatively low levels, 50 milligrams of pure drug for a
non-tolerant user. Different peoples' metabolisms work at different rates, and drug strengths vary,
so there is no way of stating a "safe" or "unsafe" level of use.

Effects

These include euphoria, hyperexcitability, extreme nervousness, accelerated heartbeat, sweating,

dizziness, restlessness, insomnia, tooth grinding, incessant talking, and other effects.

Methamphetamine and other CNS stimulants have strong bronchodilation effects. Vasoconstriction
(tightening of blood vessels) and pupil dilation are also common. Elevated blood pressure, heart
rate, and other general symptoms of increased sympathetic nervous activity.

The physical effects are almost assuredly due to interactions between the amphetamine structure
and human physiology, probably due to the similarity to adrenaline (epinephrine).

Mental capacity is not diminished directly by the drug. In fact, some studies have shown slight
increases in mental capacity on simple tasks. It has been prescribed for attention deficit disorder,
among other things.
Confusing reports here tend to center around the effects of fatigue on mental capacity.

Emotional responses may range from euphoria to anger and paranoia. Preliminary doses tend to
produce the former, while continued use (e.g. for three or more days) tends to produce the latter.

It appears that these feelings may be linked to the neurotransmitters dopamine and/or serotonin,
although I have not seen a good reference on this yet.

For More Information

Add references for pharmacological data here

Chemistry
This is the easiest section to write, and the most fun, since I can be relatively sure of the facts.

Molecular Information

All information is on free base unless otherwise noted.

Naming
Methamphetamine Free Base:
Chem Abstract Service (9th+ CIP) uninverted name:
N,alpha-Dimethylbenzeneethanamine
Previous name:
d-N,alpha-dimethylphenethylamine
Alternate Names:

• d-N-methylamphetamine
• d-deoxyephedrine (e.g. right-handed ephedrine, minus an oxygen)
• d-desoxyephedrine
• 1-phenyl-2-methylaminopropane
• d-phenylisopropylmethane
• methyl-beta-phenylisopropylamine

Trademarks:
Norodin
Methamphetamine Hydrochloride:

What we mean by hydrochloride is that it has formed a "salt". The basic structure is unchanged, but
an HCl molecule has become attracted to the free base. In this case, the hydrogen from the HCl has
become attracted to the nitrogen in the free base.

You will notice that the salt form is much more common. This is for physiological reasons. The same
reaction which attracts the free base to HCl could also attract it to other molecules, causing
irritation and other symptoms.

Trademarks:

• Amphedroxyn
• Desfedrin
 • Methedrine
• (many others)

Structure

Formula
Methamphetamine Free Base:
C6H6CH2CH(NHCH3)CH3
Hill Convention:
C10H15N

Molecular Weight
149.24

Percent Composition
C 80.48% H 10.13% N 9.39%

Melting Point
170-175 degrees C

Chirality
Explain isomers in chemical terms.

The human terms:

The d- is cool, the l- is shit, remember. If you have time, energy, and equipment, you can separate
the two and reprocess the l- into d- by oxidizing it and reaminating it as described in the "critique"
of the Phrack synthesis.

Discuss other opinions (some say chirality does not matter, etc.)

For More Information

The Merck Index

Synthesis

Industrial Methods

(add references)

• Reduction of ephedrine or pseudoephedrine

 • Reducing condensation product of BMK and methylamine
• Synthesis from D-phenylalanine

Field Methods

General
Add a lot here on different methods.
From: lamontg@u.washington.edu (Lamont Granquist)
jkenner@cello.gina.calstate.edu (Jason Kennerly) writes:
Manufacturing methamphetamine, on the other hand, requires the use of not just ether, but
reducing agents such as LiAlH4. BAD STUFF! There are other recipes, but none to practical to
attempt. Apartment manufacture of meth is not possible.
Reduction of ephedrine with HI is a little better than LAH reduction.

Condensation Product of Phenylacetone and Methylamine

From: ez026264@dale.ucdavis.edu (Speed Raver)

Assuming you don't have amphetamine lying around, an easy synthesis with a very high yield is to
reduce the condensation product of phenylacetone and methylamine. The benefit of this method is
that different amines can be used to produce novel N-alkyl amphetamines (ethamphetamine, tert-
butylamphetamine, etc.)

From Ephedrine or Pseudoephedrine

From: ez026264@dale.ucdavis.edu (Speed Raver)

Making it from ephedrine or pseudoephedrine is possible. The only difference between

methamphetamine and (pseudo)ephedrine is that damn alpha-hydroxy group. Reacting your
ephedrine with thionyl chloride replaces the OH with Cl to produce N-methyl-alpha-
chloroamphetamine as an intermediate. Hydrogenating this product is easy: use lithium aluminum
hydride, sodium borohydride, or even hydrogen gas with nickel or platinum metal as a catalyst. The
product of this step is N-methylamphetamine and HCl. Evaporate off the water and you have
methamphetamine hydrochloride.

From: yshan@bcarh697.bnr.ca (Yogi Shan)

Hydrogenation starting with (-) ephedrine, whether direct or via the halide, will give d-meth. If you
start with dl-ephedrine, you get dl-meth.

Reduction With Hydroiodic Acid and Red Phosphorus

From: lamontg@u.washington.edu (Lamont Granquist)

From Fester, Secrets of Meth Manufacturing:

METHOD 4: REDUCTION WITH HYDROIODIC ACID AND RED PHOSPHORUS

In this procedure, the alcohol grouping of ephedrine, pseudoephedrine, or PPA is reduced by boiling
one of these compounds in a mixture of hydroiodic acid and red phosphorus. Hydroiodic acid works
as a reducing agent because its dissociates at higher temperatures to iodine and hydrogen, which
does the reducing. The dissociation is reversible. The equilibrium is shifted in favor of dissociation
by adding red phosphorus to the mixture. The red phosphorus reacts with the iodine to produce PI3,
which then further reacts with water to form phosphorus acid and more hydroiodic acid. Since the
hydrogen atom of the HI is being absorbed by the ephedrine, the red phosphorus acts as a recycler.

In some reductions, the need for HI is dispensed with just by mixing red phosphorus and iodine
crystals in a water solution. The red phosphorus then goes on to make HI by the above mentioned
process. With a small amount of due care, this is an excellent alternative to either purchasing,
stealing, or making your own pure hydroiodic acid.

This method has the advantage of being easy to do. It was formerly the most popular method of
making meth from ephedrine. Now red phosphorus is on the California list of less restricted
chemicals, so an increased level of subterfuge is called for to obtain significant amounts. One might
think that this is easily gotten around by making your own red phosphorus, but this is a process I
would not want to undertake. Ever hear of phosphorus shells? I would much rather face the danger
of exploding champagne bottles. Those who insist on finding out for themselves, will see Journal of
the American Chemical Society, volume 68, page 2305. As I recall, the Poor Man's James Bond also
has a formula for making red phosphorus. Those with a knack for scrounging from industrial sources
will profit from knowing that red phosphorus is used in large quantities in the fireworks and
matchmaking industries. The striking pad on books of matches is about 50% red phosphorus.

The determined experimenter could obtain a pile of red phosphorus by scraping off the striking pads
of matchbooks with a sharp knife. A typical composition of the striking pad is about 40% red
phosphorus, along with about 30% antimony sulfide, and lesser amounts of glue, iron oxide, MnO2,
and glass powder. I don't think these contaminants will seriously interfere with the reaction.
Naturally, it is a tedious process to get large amounts of red phosphorus by scraping the striking
pads off matchbooks.

Another problem with this method is that it can produce a pretty crude product if some simple
precautions are not followed. From checking out typical samples of street meth, it seems basic
precautions are routinely ignored. I believe that the by-products in the garbage meth are
iodoephedrine, and the previously mentioned azirine. If a careful fractional distillation is done, these
products can be removed. They can be avoided in the first place if, when making hydroiodic acid
from iodine and red phosphorus, the acid is prepared first, and allowed to come to complete
reaction for 20 minutes before adding the ephedrine to it. This will be a hassle for some, because
the obvious procedure to follow is to use the water extract of the ephedrine pills to make the HI in.
The way around the roadblock here is to just boil off some more of the water from the ephedrine pill
extract, and make the acid mixture in fresh pure water. Since the production of HI from iodine and
red phosphorus gives off a good deal of heat, it is wise to chill the mixture in ice, and slowly add the
iodine crystals to the red phosphorus-water mixture.

To do the reaction, a 1000 ml round bottom flask is filled with 150 grams of ephedrine
hydrochloride (or PPA-HCl). The use of the sulfate salt is unacceptable because HI reduces the
sulfate ion, so this interferes with the reaction. Also added to the flask are 40 grams of red
phosphorus and 340 ml of 47% hydroiodic acid. This same acid and red phosphorus mixture can be
prepared from adding 150 grams of iodine crystals to 150 grams of red phosphorus in 300 ml of
water. This should produce the strong hydroiodic acid solution needed. Exactly how strong the acid
needs to be, I can't say . I can tell you that experiments have shown that one molar HI is ineffective
at reducing ephedrine to meth. The 47% acid mentioned above is a little over 3.5 molar. I would
think that so long as one is over 3 molar acid, the reaction will work.

With the ingredients mixed together in the flask, a condenser is attached to the flask, and the
mixture is boiled for one day. This length of time is needed for best yields and highest octane
numbers on the product. While it is cooking, the mixture is quite red and messy looking from the
red phosphorus floating around in it.

When one day of boiling under reflux is up, the flask is allowed to cool, then it is diluted with an
equal volume of water. Next, the red phosphorus is filtered out. A series of doubled up coffee filters
will work to get out all the red phosphorus, but real filter paper is better. The filtered solution should
look a golden color. A red color may indicate that all the phosphorus is not yet out. If so, it is
filtered again. The filtered-out phosphorus can be saved for use in the next batch. If filtering does
not remove the red color, there may be iodine floating around the solution. It can be removed by
adding a few dashes of sodium bisulfate or sodium thiosulfate.

The next step in processing the batch is to neutralize the acid. A strong lye solution is mixed up and
added to the batch with shaking until the batch is strongly basic. This brings the meth out as liquid
free base floating on top of the water. The strongly basic solution is shaken vigorously to ensure
that all the meth has been converted to the free base.

With free base meth now obtained, the next step, as usual, is to form the crystalline hydrochloride
salt of meth. To do this, a few hundred mls of toluene is added to the batch, and the meth free base
extracted out as usual. If the chemist's cooking has been careful, the color of the toluene extract
will be clear to pale yellow. If this is the case, the product is sufficiently pure to make nice white
crystals just by bubbling dry HCl gas through the toluene extract as described in Chapter 5. If the
toluene extract is darker colored, a distillation is called for to get pure meth free base. The
procedure for that is also described in Chapter 5. The yield of pure methamphetamine hydrochloride
should be from 100 to 110 grams.

Lithium-Ammonia Reduction
Reference: Ely, R. A. and McGrath, D.C., "Lithium-Ammonia Reduction of Ephedrine to
Methamphetamine: An Unusual Clandestine Synthesis," Journal of Forensic Sciences, JFSCA, Vol.
35, No. 3, May 1990, pp. 720-723

Procedure:

All the chemicals were reagent grade, with no special treatment of the tetrahydrofuran (THF), and
the atmosphere above the condensed ammonia was not flushed with nitrogen gas.

A three-neck flask was cooled in a dry ice/acetone bath. A condenser was fitted in the center neck,
an additional funnel containing l-ephedrine base in THF was fitted into one side neck, and a rubber
stopper fitted with a glass tube extending to the bottom of the flask was fitted in the third neck.
Anhydrous ammonia gas was condensed and collected in the flask. Small pieces of lithium metal
were rinsed in petroleum ether, patted dry, and added to the condensed ammonia. A deep royal
blue color was noted as the lithium metal dissolved in the condensed ammonia.

The l-ephedrine was added drop wise to the lithium ammonia solution over a period of
approximately 10 minutes with stirring. When all of the l-ephedrine had been added, ammonium
chloride was added slowly to the solution. The flask was removed from the cooling bath, and the
condensed ammonia was allowed to warm to room temperature and evaporate from the flask
through the side necks.

When most of the ammonia had evaporated, water was added to the remaining solution until it
cleared and any remaining lithium metal was decomposed. The remaining solution was removed
from the flask to a separatory funnel, where the aqueous layer was discarded. The THF layer was
dried with magnesium sulfate, and the hydrochloride salt of the methamphetamine was made by
bubbling hydrogen chloride through the THF.

The same procedure was used, substituting phenylproponolamine and methylephedrine as the
starting materials. A second synthesis was conducted with l-ephedrine, using the same procedure
except that the reaction was not quenched with ammonium chloride.

Results:

The reaction was found to reduce l-ephedrine to d-methamphetamine quickly and easily .
Furthermore, it was found that the reaction converted phenylpropanolamine to amphetamine and
methylephedrine to dimethylamphetamine. The time required for the reaction to proceed from the
condensing of the ammonia gas in the reaction flask until the excess lithium was decomposed was
approximately one hour. The majority of this time was spent waiting for the condensed ammonia to
evaporate from the reaction flask.

It was also found that the ephedrine would reduce to methamphetamine without the addition of
ammonium chloride as a quenching agent.

From: eleusis@netcom.com (Eleusis)

According to the infamous J.For.Sci. article describing a "novel method of amphetamine production",
the researchers concluded that with or without an ammonium chloride quench yields were good. I
like this article especially because the rinky-dink DEA chemists that wrote it didn't seem to entirely
grasp the concept of the procedure they were doing (in fact, a slightly modified Birch reduction
known by some other name I can't recall). All in all, quite an entertaining and educational
article ;-).

From: dmurphy3@aol.com (DMurphy3)

This may be so (in fact I read the same article), but typically a water quench leads to the alcohol,
which is what we were trying to get rid of to start with. Also, if one were using Na rather than Li (Na
is the Birch, I too forget the Li named reduction), adding water to quench will *definitely* be
exciting, particularly considering the flammability of THF or ether.

Apparently they were following the guys handwritten notes. It would have been even more
interesting had they used the real Birch method, using Na, especially when they tried the water
quench ;>)

From: eleusis@netcom.com (Eleusis)

Yep - apparently that would be the case. As well, any extra Li (or Na if doing the straight Birch
method) would convert to the Hydroxide, which might fuck the product up a bit.

I bet you they *did* do that the first time, and then, after they replaced that wing of the lab, they
decided not to "publish" those results ;-).

From Phenylalanine
From: ez026264@dale.ucdavis.edu (Speed Raver)
A surprisingly simple synthesis is possible from the amino acid phenylalanine, which is available at
health food stores for about $14 for 100 tablets. Phenylalanine is 2-amino-3-phenylpropanoic acid,
which is more or less amphetamine with a COOH where the CH3 should be at the end of the chain.
Thionyl chloride will replace the OH with a Cl, which falls off and is replaced by H when you give it
lithium aluminum hydride, sodium borohydride, or hydrogen gas and nickel/platinum. If you use
hydrogen and metal for that step, you'll ha v e to reduce the carbonyl group with one of the
hydrides, so best save time + effort and use them and do both reductions at once. When that
carbonyl is reduced, you now have amphetamine. Go back up to that first one I mentioned for
upgrading amphetamine into methamphetamine.

Incomplete Syntheses

These are methods that are subjectively evaluated to be less useful, but still may serve as
interesting lessons in applied chemistry.

Synthesis from Amphetamine

From: ez026264@dale.ucdavis.edu (Speed Raver)

One of the easiest ways to make methamphetamine is from amphetamine. Of course, this assumes
you have amphetamine in the first place, but let's just pretend you have some and you want to
spice it up a bit. The difference between amphetamine and methamphetamine is the addition of a
single methyl group (CH3) to the amino group sticking off the middle carbon atom in the chain.
Fortunately, substituting amines is really simple. Vaporize your amine (your amphetamine) with a
bunch of vaporized chloromethane (CH3Cl, a solvent) and some gaseous pyridine... voila, the amino
group takes the methyl from the chloromethane and lets a hydrogen go. The hydrogen joins the
liberated chlorine, and the resulting HCl is soaked up by the pyridine. The pyridine is optional.
Adding it drives the reaction a bit by pulling the excess HCl out of the equation, but it's not
necessary.

Methylamine
From: dnaugler@sfu.ca (David Naugler)
jkenner@cello.gina.calstate.edu (Jason Kennerly) writes:
Does the P2P method [reductive amination] ever end up attaching TWO chains to the same
methylamine, producing a crazy looking monster with two "wings"
This last question is solved be reference to a principle called the law of mass action. An excess of
methylamine will inhibit the secondary reactions.

Typically, a reductive amination done in a parr bomb or using sodium cyanoborohydride is done with
a five times molar excess of methylamine (or methylamine hydrochloride.)

Phenylacetone
From: jkenner@cello.gina.calstate.edu (Jason Kennerly)

Let me know how bromobenzene + acetone + NaOH turns out. I'm interested in this since I haven't
seen it anywhere else (unlike some people, I don't have the Abstracts in my closet :)

Make sure to use an EXCESS of acetone, because 1 its more readily available and 2 it will prevent
any diphenyl/triphenyl/xphenyl acetone from forming.

Hell, if your making straight amphetamine, you could even just go with acetone as the solvent too,
if you could come up with a good way to separate the 2-aminopropane you'd make with the
amphetamine. Given that this gunk has a bp of 33 or 34 degrees at standard pressure, it shouldn't
be too hard. Smells like ammonia though... maybe you should "catch" it in HCl water when you
distill.

As with any distillation there will be some left over. Never fear, 2aminopropane (or
"isopropylamine") is water MISCIBLE. Yes, the BASE form is miscible w/ H2O! Amphetamine BASE is
only "slightly" soluble in water, so if your really a purist you can dissolve your "mostly amphetamine
some 2aminopropane" in ether and backwash with water maybe ONCE. Then precipitate the crystals
with dry HCl or H2SO4?

Question is, how much ammonia and reducing agent are you willing to waste on making
2aminopropane?

Purification by Crystallization
From: csc@pilot.njin.net (Sean Casey)

For a purification by crystallization of any of the HCL salts of ephedrine and related illegals, I'd
suggest a two solvent system with methanol and methylethylketone. This tends to occlude a slight
amount of solvent so keep your crystal size small and grind and dry the result. Both these solvents
are easily available if you know where to look.

I wouldn't suggest ethanol or acetone as they tend to easily collect H2O; this can happen
unexpectedly and when it does, their solvency power will greatly increase, redissolving your
crystals. Be careful as methanol is toxic; don't get it on you or breathe the fumes.

Read a lab handbook about two-solvent purification by crystallization. Fascinating stuff.

Related Chemistry
amphetamine
ephedrine
pseudoephedrine
phenylalanine

Street Knowledge
Very scientifically unsound, but interesting nonetheless.

Street Doses

An average wrap of speed contains less than 10% Amphetamines, (often as low as 2%) and over
90% of adulterants.

Coloration

From: jkenner@cello.gina.calstate.edu (Jason Kennerly)

Methamphetamine in its pure hydrochloride salt form is colorless. However, products on the market
today are often not colorless. The following is a table of some common impurities and the colors
associated with them. Note: There is no doubt a segment of the dealers who will add food coloring
or some other such color to their drug to make it more appealing, with the philosophy that a
brightly-colored product may sell better than an off color product. This is relatively uncommon
however.

• RED: The product was made from pseudoephedrine, and the red coloring of the tablet was
not adequately washed away (it is difficult)
• ORANGE: Ephedrine sulfate was used, and some of the sulfate was reduced to sulfur.
• PURPLE: Iodine from a phosphorus-iodine reaction was not washed out.
• GREEN: Copper (or other metallic) salts somehow made their way in to the mixture,
probably due to the reaction vessel used in the manufacture.
• BROWN: Oxidized red coloring (see above), or tablating agent was present in the reduction.

Sometimes "speed" is present as waxy rocks that almost seem wet, but do not dry out properly. I
am not sure what the cause of this is, but its most likely some form of oil, either formed in the
reaction or left over from a very poor solvent. It may or may not be harmless depending upon what
it is. This oil is often removed with acetone, but ethyl-ether would be better suited for this as it dries
faster.

Pure methamphetamine HCl melts at around 170c (338f ). The crystals can be carefully chopped
and mixed with sodium carbonate, and when the resulting powder is heated (and the
methamphetamine HCl melts) CO2 and methamphetamine base vapor is given off. This is probably
one of the more effective ways of smoking meth if you are careful, however the hydrochloride salt is
often the form smoked as the base form is often an oil and is difficult to store, transport, and work
with. Smoking the HCl form is OK if you don't mind a small quantity of pyrolysed drug.

d-methamphetamine is, by nature, optically active. l-methamphetamine is also optically active, but
in the "opposite" direction. You can test methamphetamine HCl for optical activity with the greyish-
clear plastic pieces from a pocket video game. Dissolve the methamphetamine in distilled water,
then place one of the optical filters (the grayish clear things from the games LCD display) in front,
and one in behind of the solution. Rotate one filter, and note the angle that is brightest and the
angle that is darkest. If many "swirlies" appear, either use a different vessel to hold the solution in,
or make sure the solution is well stirred. After you have done this, repeat the procedure with
distilled water. A handy thing to use as a "calibration" of sorts is to extract the l-desoxyephedrine
from a Vicks Inhaler (which is l-methamphetamine), and run this test on it as well.

RESULT:

• Same as water: DL-methamphetamine (or other inactive) Most likely made from P2P
(methamphetamine) or DLPA (phenylalanine). The DLPA-crank may in fact only be dl-
amphetamine. Might be 100% cut [read: nothing] also...
• Same as Vicks: You've been ripped off ! -or- there's so much unchanged ephedrine as to
cancel the dextrorotary effects of the meth (l-ephedrine, when reduced, is dextrorotary (see
explanation elsewhere)
• Opposite of vicks compared to water: DL-methamphetamine. Dextrorotary product is almost
certainly methamphetamine (or extracted dexedrines?) as its is not worth the trouble to get
other dextrorotary precursors or resolve dl-amphetamine...
• Worth Noting: Cathinone and Methcathinone, when dissolved in methanol, will become
racemic due to the nature of the molecule (keytone). I'm not sure what other conditions
cause this but I am aware that it happens easily, so methcathinone from the black market is
almost definitely racemic...
The EPHEDRINE/CAT TEST
Its probably not too uncommon that some guy screws up a synthesis, but by some chance gets a
partial yield. Or a dealer uses Ephedrine as cut. The problem with Ephedrine (far more so than
pseudephedrine) is its beta-agonist properties - it raises blood pressure and pulse far more per "unit
of high" than methamphetamine.

It is advisable to become familiar with the many ways of synthesizing methcathinone from
(pseudo)ephedrine, as just such a procedure can be used on freshly produced methamphetamine to
verify that the (pseudo)ephedrine was in fact reduced.

The smell of basic methcathinone has been reported to resemble that of "pistachio ice cream".
Suffice to say that it is sweet, pleasant, and to a cat-head, nirvana. You should become familiar with
this as well, in order to be able to know if suspected methamphetamine is in fact actually
methcathinone.

The "BURN TEST" [residue test]

Methamphetamine HCl is heated on a piece of foil over a flame. It should first melt (at over 170c)
then begin to fume. Often the fumes will ignite. All amphetamines will pass this test that I am aware
off, including the over-the-counter l-isomer present in vicks inhalers (the *only* way to check this is
to check optical activity , either by resolution or by actually measuring it with optical filters).
Methcathinone HCl has a higher melting point than methamphetamine HCl (like over 190c at least)
and a characteristic smell, giving it away in an instant. Residue left behind may be by-product or
"cut", there's no good way to tell which... Suffice to say that if there is more than a very small
amount left afterwards, there is either cut or by-products present.

The TASTE TEST [illegal without prescription snicker snicker]

Methamphetamine has a very bitter taste. Amphetamine has a bitter taste, followed by some
degree of numbness. This isn't the most useful test in the world, especially considering it relies upon
subjective senses too much IMHO, but it may help discern the product. Methamphetamine is also
more active on serotonin that amphetamine according to net resources.

From: dmurphy3@aol.com (DMurphy3)

Sometimes 'speed' is present as waxy rocks that almost seem wet, but do not dry out properly. I
am not sure what the cause of this is, but its most likely some form of oil, either formed in the
reaction or left over from a very poor solvent. It may or may not be harmless depending upon what
it is.
It is more than likely the "didesoxyephedrine" referred to by Emde, a product of the coupling of two
radicals of the reduced ephedrine or pseudoephedrine. It appears to some extent in almost all
syntheses relying on reduction and typically appears at the very end of the process of forming the
HCl salt by bubbling HCl through the mixture. And no, I haven't forgotten my promise to post this
paper. The scans just sucked when I tried to scan as text (5 pages magically became 10-15 of
scrambled text). I am currently trying gif type scans. The *oil* may be removed, as you stated, by
washing with ether. However, it will never dry out as completely one might suspect. Even drying
under heavy vacuum leads to only a temporary solution. Once it is exposed to air it quickly becomes
an oil again. Often this is a brown color as you stated for other by-products. As far as the rest of the
post, I find it very useful and agree with it completely.

Myths and Rumors

"Smelling meth on a person"
Fatigue causes secretion of different chemicals, including ammonia, from the body. Thus you
are smelling fatigue, not meth.
"Made from poison"
Made from several toxic chemicals; this does not mean it is itself poisonous. For example,
drinkable salt water can be made from lye and muriatic acid.
"Used to cut other drugs"
Overstated in this role. Usually something much cheaper (and less clean) is used.
"Meth Oil" ??
"Speed Bumps"

Incorrect Syntheses

Phrack Magazine

Volume One, Issue Four, Phile / 8 of 11

THE TRIED AND TRUE
HOME PRODUCTION METHOD FOR
"METHAMPHETAMINE"
Written and tested by: The Leftist.

What to do with it once you have made it.

Take a ball about the size of a lead pellet, and wrap it in tissue, and swallow, or you can put it in
capsules and use it. You can smoke it, mix it with vitamin B-12, and snort it like cocaine. You can
also sell it, for about $65-70.00 a gram, and don't forget to cut it. Remember, this is pure stuff!!

List of chemicals and materials

• Dilute Hydrochloric acid--> This may be purchased at the hardware store. It sold as a brick
and driveway cleaner. They call it muriatic acid.
• Sodium Hydroxide--> This, you probably already have. It's called "lye" at most places; it's
drain cleaner.
• Ethyl Ether--> You'll probably have to make this. Don't worry, it's a breez Just go to your
local K-mart or Auto parts store, and get a can of that "STARTING FLUID" it comes in a spray
can. It's used for cold weather starting of gasoline engines.
• "VICKS" nasal inhalers--> USE ONLY VICKS!! No other kind will work that I know of. These
are at any drug store or grocery, etc.. You need 12 of em, but don't buy em' by the dozen,
unless its winter time, then you can just say yer from some nursing home, and you're
stockin up for the patients. Otherwise buy em' 2 at a time, if possible. Get a friend to help
you. The druggists at the drug store usually will know what's goin on if you buy quantity.

LIST OF EQUIPMENT
• Two large eyedroppers
• ten small glass bottles
• one large glass or porcelain bowl
• coffee filters
• one small jar with a top
• one Pyrex baking dish
• one glass test tube.
 -==*(> N O T I C E <)*==-
PLEASE! DON'T SMOKE IN THE SAME ROOM WHEN YOU DO THIS. OPEN A WINDOW IN THE ROOM
IF POSSIBLE. FOLLOW THESE INSTRUCTIONS EXACTLY. THIS RECIPE HAS BEEN TESTED AND THIS
IS T BEST WAY TO DO IT. DON'T TAKE SHORTCUTS, AND DON'T EVEN START TO DO THIS UNLESS
YOU HAVE ABOUT 3 HOURS SPARE.

PREPARING ETHER!
(DO THIS FIRST)

Take one of the small bottles and spray starter fluid in it till it looks half-full. Then fill the rest of the
way with water, cap the bottle and shake for 5 minutes. Then, draw off the top layer with the
eyedropper, and throw away the water layer. Repeat this until you have about 3 oz. of ether. Put
the cap on it, and put it in the refrigerator if you can. (If you can't, don worry about it) You'll use
this in the procedure below.

THE TRIED AND TRUE HOME PRODUCTION METHOD

1. Break open the inhalers, a pair of real sharp scissors does this good. Place the cottons that
were inside in a jar and close the lid. (Remember you use all 12 cottons.)
2. In the bowl, combine 1- 1/3 oz. water and 2/3 oz. muriatic acid. Shred cottons in this
solution, and knead for 5 minutes with hands. (ALWAYS BE SURE THERE'S CLEAN RUBBER
GLOVES on your hands.) You can do it bare-handed if you' got tough skin. Squeeze all juice
out of filters after you knead, and throw em away.
3. Filter the remaining liquid into the quart jar. It will be necessary to this several times to get
that awful smelling oil out. The chemicals in the inhalers have been bonded to the HCl, and
the oils have been filtered off. Throw the filters away.
4. Pour enough of the solution into a small bottle to fill it 1/3 full. Save any leftover juice for the
second batch.
5. Pour 1/4 teaspoon of the lye crystals into the bottle and agitate. Do this carefully, as the
mixture will become hot, and give off a gas. Repeat this step until the mixture remains
cloudy.
6. Fill the bottle from step (5) up the rest of the way with ether. Cap the bottle, and agitate for
about 8 minutes. It is very important to expose ever molecule of the free-base to the ether
for as long as possible.
7. Let the mixture settle. There will be a middle layer that is very thick. Tap the side of the
bottle to get this layer as thin as possible.
8. Remove the top layer with the eyedropper, being careful not to get any of the middle layer in
it. Save the top layer, and throw the rest away.
9. Fill a bottle half-way with water, and about 10 drops of acid. Pour the top layer from step (8)
into the bottle, and cap it. Shake the bottle for 2 minutes. When it settles, remove the top
layer and throw it away. The free base has now been bonded to the HCl/water mixture.
10. If there is anything left from step (3), repeat the procedure with it.
11. Evaporate the solution in the Pyrex dish on low heat. You can do this o the stove, but I have
found that if you leave it on top of a hot-water heater (like the one that supplies hot water to
your house) for about 2-3 days, the remaining crystals will be Methamphetamine.

Some notes:

Police are now calling this the "New Cocaine".

It is very easy to become delirious off the ether fumes, so be sure you are well ventilated, I mean
it!!!

Small, aspirin, or experiment bottles seem to work the best for smaller batches. The measurements
are not exact, so you don't have to be either.

In step 9, be sure you don't use too much water. Remember, this is the water you have to use to
evaporate.

==Phrack Inc.==
From: rkhunter@hale.cts.com (Admiral Hunter)

(WARNING!) This recipe is bogus! YOU WILL NOT HAVE METHAMPHETAMINE! You have simple
extracted pseudoephedrine! All this stuff will give you is engziety(sp?)...

There are better recipes out there but if you cant get your hands on sodium borohydride and a
reflux condenser then don't even mess with this recipe!

But the ETHER extraction method is as true today as it was then!

From: ez026264@dale.ucdavis.edu (Speed Raver)

One, from Phrack magazine, is the "tried and true method" for prepping meth from Vick's nasal
inhalers. Vick's nasal inhalers contain "l-desoxyephedrine," another name for "l-methamphetamine."
The l- isomer of methamphetamine is the relatively inactive one, usable as a (mild) nasal
decongestant. The d- isomer is the one that every one wants and that Uncle Sam has declared is
just too cool for any one except doctors.

The procedure described would extract the l-meth from the inhalers and collect it and that's it. I'm
sorry, but the Isomer Fairy can't wave her magick wand and reverse the chirality of the molecule.
The only way to change between the two isomers is to oxidize the l-meth into phenylacetone,
condense it with methylamine, then reduce it. Sorry, but soaking inhalers in HCl then separating the
"juice" with Et2OH just won't do it. You'll get l-meth and that's that.

The same recipe (for extraction of l-isomer), reformulated:

List of chemicals and materials

• Dilute HCl - also called Muriatic acid - can be obtained from hardware stores, in the pool
section.
• NaOH - also called lye - can be obtained from supermarkets in the "drain cleaner" section.
"Red Devil Lye" recommended.
• Ethyl Ether - aka Diethyl Ether - Et-0-Et - can be obtained from engine starting fluid, usually
from a large supermarket. Look for one that says "high ethyl ether content", such as
Prestone.
• Desoxyephedrine - can be obtained from "VICKS" nasal inhalers. These are found at any
drug store or grocery, etc. They contain 50mg of l-desoxyephedrin e per container. Also
known as methamphetamine. 6 containers will give 300mg of l-desoxyephedrine.
• Distilled water - it's really cheap, so you have no reason to use the nasty stuff from the tap.
Do things right.
List of equipment

• a glass eyedropper
• three small glass bottles with lids (approx. 3 oz., but not important)
o one should be marked at 1.5oz, use tape on the outside to mark it (you might want to
label it as ether)
o one should be clear (and it can't be the marked one)
• a Pyrex dish (the meatloaf one is suggested)
• a glass quart jar
• sharp scissors
• clean rubber gloves
• coffee filters
• a measuring cup
• measuring spoons

Preparing your reagents

Preparing Ethyl Ether

WARNINGS: Ethyl Ether is very flammable and is heavier than air. Do not use ethyl ether near
flame or non-sparkless motors. It is also an anaesthetic and can cause respiratory collapse if you
inhale too much.

Take the unmarked small bottle and spray starter fluid in it until it looks half-full. Then fill the rest
of the way with water, cap the bottle and shake for 5 minutes. Let it sit for a minute or two, and tap
the side to try and separate the clear upper layer. Then, draw off the top (ether) layer with the
eyedropper, and throw away the lower (water) and cloudy layer. Place the ether in the marked
container. Repeat this until you have about 1.5 oz. of ether. Put the cap on it, and put it in the
freezer if you can. Rinse the other bottle and let it stand.

Ethyl ether is very pungent. Even a small evaporated amount is quite noticeable.

Extracting l-desoxyephedrine

1. Break open the inhalers, a pair of real sharp scissors does this well. Place the cottons that
were inside in a bottle (the unmarked one) and close the lid. I use 6 cottons.
2. In the Pyrex dish, combine 2/3 oz. water and 1/3 oz. muriatic acid. Shred cottons in this
solution, and knead for 5 minutes with your gloves on. Squeeze all juice out of filters after
you knead, and discard them. This step bonds the HCl to the meth, forming the HCl salt
(what you want). The salt is soluble in water, and thus dissolves.
3. Filter the remaining liquid into the quart jar. It will be necessary to this several times to get
the awful smelling oils (check the packaging if you are interested in which ones). The
chemicals in the inhalers have been bonded to the HCl, and the oils have been filtered off.
Discard the filters and clean the Pyrex dish. Remember to wet the filters with distilled water
before you pour, otherwise you'll lose some product.
4. Pour enough of the solution into the clear bottle to fill it 1/3 full. Save any leftover juice for
the second batch.
5. Pour 1/8 teaspoon of the lye crystals into the bottle and agitate. Do this carefully, as the
mixture will become hot, and give off hydrogen gas and/or steam. H2 gas is explosive and
lighter than air; avoid any flames as usual. Repeat this step until the mixture remains
cloudy. This step neutralizes the HCl in the salt, leaving the insoluble free base (l-
 desoxyephedrin e) again. Why do we do this? So that we can get rid of any water-soluble
impurities. For 3 oz. bottles, this should take only 3 repetitions or so.
6. Fill the bottle from step 5 up the rest of the way with ethyl ether. Cap the bottle, and agitate
for about 8 minutes. It is very important to expose every molecule of the free-base to the
ether for as long as possible. This will cause the free base to dissolve into the ether (it -is-
soluble in ether).
7. Let the mixture settle. There will be a middle layer that is very thick. Tap the side of the
bottle to get this layer as thin as possible. This is why this bottle should be clear.
8. Remove the top (ether) layer with the eyedropper, being careful not to get any of the middle
layer in it. Place the removed ether layer into a third bottle.
9. Add to the third bottle enough water to fill it half-way. and about 5 drops of muriatic acid.
Cap it. Shake the bottle for 2 minutes. When it settles, remove the top layer and throw it
away. The free base has now been bonded to the HCl again, forming a water soluble salt.
This time, we're getting rid of ether-soluble impurities. Make sure to get rid of all the ether
before going to step 11!
10. If there is anything left from step 3, repeat the procedure with it.
11. Evaporate the solution in the Pyrex dish on low heat. You can do this on the stove or nuke it
in the microwave (be careful of splashing), but I have found that if you leave it on top of a
hot-water heater (like the one that supplies hot water to your house) for about 2-3 days, the
remaining crystals will be Methamphetamine HCl.

If you microwave it, I suggest no more than 5-10s at one time. If it starts "popping", that
means you have too little liquid left to microwave. You can put it under a bright (100W) lamp
instead. Microwaving can result in uneven heating, anyway.

First Batch: 120mg Meth HCl

Estimated: 300mg (100% of theoretical, disregarding HCl)

Estimated Cost of Material (in US dollars):

Ethyl Ether: $ 1.59

Inhalers: $19.73

Eyedroppers: $ 1.09

Pyrex dish: $ 3.92

Pyrex measuring cup: $ 2.55

Lye: $ 2.79

Catalytic Reduction
From: ez026264@dale.ucdavis.edu (Speed Raver)

A more credible sounding one mentions that "methamphetamine is prepared by the calalytic
reduction of pseudoephedrine in acetic acid" blahblahblah and then goes on to describe, not
catalytic reduction via acetic acid, but reduction with sodium borohydride. I'm sorry to say that no
method attempting to directly reduce (pseudo)ephedrine's hydroxyl group is going to work. You
can't expose it to a strong acid, or a weak acid, or sodium borohydride, or even lithium aluminum
hydride and expect it to reduce at all. As with the Vick's Inhalers "recipe," you get a lot of
SOMETHING, but it ain't d-meth. All you'll be left with is your (pseudo)ephedrine and a bunch of
acid, lithium, and/or sodium and lotsa hydrogen gas. This is because the hydroxyl group (the OH in
ephedrine) is on a very acidic carbon (the first carbon away from the ring) and a hydroxyl group is
very basic. If the hydroxyl were on the second carbon from the ring (the carbon with the amine
group, the NH2 or NHCH3), there might be some chance, but it's not and there's not. You're not
getting a basic group off an acidic carbon without a fight, and acids, borohydride, and LiAlhydride
aren't gonna fight that hard.

From: yshan@bcarh697.bnr.ca (Yogi Shan)

I'm sorry to say that no method attempting to directly reduce (pseudo)ephedrine's hydroxyl group
is going to work.

Your post was interesting, but this is not quite true. Direct hydrogenation over Pd or Pd on a carrier
is well known and facile. You add a little perchloric, phosphoric or sulphuric acid, which esterifies
the-OH group that you're complaining about.

Thus making the intermediate halide via SOCl2, like you mentioned, is unnecessary.

UTOPIAN PHARMACOLOGY
Mental Health in the Third Millennium
MDMA and Beyond
 1. MDMA/Ecstasy
2. A brief history of MDMA
3. The MDMA Experience
4. MDMA : neurotoxicity
5. MDMA : neuroprotection
6. Ecstasy for life?
7. The molecular machinery of magic
8. Post-Darwinian Medicine
9. Beyond MDMA : mental superhealth

MDMA/Ecstasy

Can safe, sustainable analogues of MDMA be developed? There is an urgent need for non-neurotoxic
empathogens and entactogens suitable for lifelong use. Alas no single "magic bullet" yet exists that
replicates the subjective effects of MDMA on a long-term basis. Hence most of us are doomed to
display the quasi-psychopathic indifference to each other characteristic of the MDMA-naïve state.

A brief history of MDMA

MDMA [3,4-methylenedioxy-methamphetamine: 'Ecstasy'] was first1 synthesized in 1912 by the

German pharmaceutical company Merck. MDMA was patented in Darmstadt, Germany on May 16th
1914, issue number 274,350; and promptly forgotten. Merck's researchers had no idea of the
significance of what they had done. Merck were searching for a good vasoconstrictor, a styptic to
reduce bleeding. In 1912 two of their chemists, G. Mannish and W. Jacobsohn, created MDMA as a
by-product while attempting to synthesise hydrastinin. MDMA is listed on Merck's patent-application
merely as a chemical intermediate "for products of potential pharmaceutical value".

MDMA surfaced again briefly as one of a number of agents used in clandestine US military
research during the 1950s. The CIA's Project MK-Ultra was investigating new techniques of
brainwashing, espionage and mind-control. MDMA, code-named EA-1475, was tested at the US
Army's Edgewood Arsenal in Maryland. However, unlike LSD or the ill-named "truth drug"
scopolamine, MDMA was used only on non-human animals: mice, rats, pigs, monkeys and dogs.
Thankfully, MDMA's military potential was not realised. For although MDMA is no infallible truth-
serum, its effects on the human user might indeed be abused for sinister purposes by skilled
interrogators. The heightened emotional responsiveness, lowering of defensive barriers, openness
and sense of closeness to others induced by MDMA can promote an honesty of self-disclosure that
might be manipulated for malign ends. Fortunately, this hasn't yet happened on an organised scale.

MDMA's parent and longer-acting metabolite, 3,4-methylenedioxyamphetamine [MDA] was

first synthesized in 1910 by the same two unsung Merck researchers who went on to create MDMA.
MDMA differs structurally from MDA only in its additional methyl group attached to the nitrogen
atom. MDA's own empathy-enhancing effect at low doses was explored by Chilean anthropologist-
psychiatrist Dr Claudio Naranjo in his private practice. Dr Naranjo discusses MDA-assisted therapy in
his classic The Healing Journey (1973). MDA was patented by drug company SmithKline French for
use as a tranquilliser (1960) and appetite-inhibitor (1961). SmithKline were interested in MDA's
potential as an antidepressant and a slimming-drug. In 1958 human trials were conducted;
unfortunately the compound was to prove too psychedelic for licensed clinical use. But MDA was
popular as "the love drug" in the counterculture of the 1960s.

The identity of the first human being to take MDMA/Ecstasy isn't known. The drug gained
prominence only in the late 1970s. Tipped off by Merrie Kleinman, a graduate student in the
medicinal chemistry group he advised at San Francisco State University, the legendary Californian
psychedelic chemist Alexander ("Sasha") Shulgin synthesized and taste-tested MDMA at
incrementally ascending doses. Ironically, Dr Shulgin had himself synthesized MDMA in 1965, but
hadn't tried it, an error of omission he later did much to repair. The effects of a 120mg dose of
MDMA are recorded in Dr Shulgin's lab-notes (Sept 1976):

"I feel absolutely clean inside, and there is nothing but pure euphoria. I have never felt so great or
believed this to be possible. The cleanliness, clarity, and marvelous feeling of solid inner strength
continued throughout the rest of the day and evening. I am overcome by the profundity of the
experience..."
In the first published scholarly paper [Shulgin,A.T. & Nichols,D.E.: Characterization of three new
psychotomimetics. In: Stillman,R.C. & Willette,R.E. (Eds.) The Pharmacology of hallucinogens. New
York: Pergamon, 1978] on MDMA use in humans, Dr Shulgin and Dr David Nichols describe the
effects of MDMA on the human psyche as "an easily controlled altered state of consciousness with
emotional and sensual overtones." The well-connected stepfather of MDMA soon introduced the drug
to the wider scientific community. Some of Dr Shulgin's friends, notably the "Johnny Appleseed of
MDMA", Leo Zeff, were professional therapists. They in turn introduced MDMA to colleagues as a
valuable adjunct to psychotherapy.

Later, in 1991, Dr Shulgin and his wife Ann published PiHKAL [Phenethylamines I Have Known
And Loved]: A Chemical Love Story. PiHKAL describes the synthesis and systematic testing on
human subjects of a range of novel or neglected phenethylamine research drugs. PiHKAL also offers
a uniquely sophisticated methodology for human psychopharmacology and the scientific study of
mind as an experimental discipline.

By the early 1980s, over a thousand private psychotherapists in the USA were using MDMA in
their clinical practice. MDMA was commonly known as "Adam", an allusion to "being returned to the
natural state of innocence before guilt, shame and unworthiness arose". MDMA was used discreetly;
no one wanted a re-run of the 60s. Dr Shulgin himself reportedly felt MDMA came closest to fulfilling
his ambition of finding the perfect psychotherapeutic drug.

Inevitably word leaked out. MDMA was profiled by the San Francisco Chronicle as "The Yuppie
Psychedelic" (10 June 1984). In Newsweek, J Adler ["High on 'Ecstasy", April 15 1985] likened his
MDMA experience to "a year of therapy in two hours". Harpers Bazaar described MDMA as "the
hottest thing in the continuing search for happiness through chemistry". Unsurprisingly, MDMA use
soon spread beyond the couch and clinic to the wider world. MDMA's now universal brand-name,
"Ecstasy", was coined in 1981 by a member of a Los Angeles distribution network. The unnamed
distributor, quoted in Bruce Eisner's Ecstasy:The MDMA Story (1989), apparently chose the name
"Ecstasy" because "it would sell better than calling it 'Empathy'. 'Empathy' would be more
appropriate, but how many people know what it means?" Condemned by purists as a cynical
marketing ploy, the brand-name "Ecstasy" isn't wholly misleading [ecstasy: "an overpowering
emotion or exaltation; a state of sudden intense feeling. Rapturous delight. The frenzy of poetic
inspiration. Mental transport or rapture from the contemplation of divine things"]. Many first-time
MDMA users do indeed become ecstatic. Some people report feeling truly well for the first time in
their lives.
 In the early 1980s, American production of MDMA beyond the research laboratory was
effectively controlled by chemists known as the "Boston Group". Somewhat incongruously, MDMA
was especially popular in Texas, where the Southwest distributor for the Boston Group launched his
own commercial operation. Mass-production of MDMA by the so-called "Texas Group" began in
1983; supply (and demand) soon mushroomed. Ecstasy was distributed openly in bars and
nightclubs in Dallas and Fort Worth. It could be purchased via toll-free 800-numbers by credit card.
The drug was even marketed via pyramid-style selling-schemes. Ecstasy could be bought in little
bottles at convenience stores under the label "Sassyfras", a tongue-in-cheek allusion to the
botanical origins of its precursor.

The DEA reacted by petitioning to have MDMA banned altogether. In 1985 the drug-warriors
succeeded in having MDMA made Schedule One. Schedule One is the most restricted of all drug
categories i.e. MDMA had allegedly "no legitimate medical use or manufacturer" in the USA; it
lacked safety for use even under medical supervision; and it carried a "high potential for abuse".
But by then MDMA's fame had spread across the Atlantic. MDMA had metamorphosed from "Adam",
the psychotherapeutic tool, to "Ecstasy", the party drug.

MDMA was first introduced to Europe via the sannyasins, disciples of the Bhagwan Shree
Rajneesh. "Sannyasa" is a Sanskrit word meaning complete or perfect renunciation. Cult members
slipped MDMA into the drinks of rich sympathisers to open up their hearts and their wallets.

Ecstasy became associated with the birth of Acid House music in the Spanish tourist resort of
Ibiza. By the summer of '86, Ibiza was popularly known as "XTC Island". Returning tourists and
disc-jockeys took the message back home. The UK's rave scene was born. Hundreds of thousands of
tablets were consumed each weekend in the famous "Summer of Love" (1988). The Conservative
Government and its allies in the British press were aghast. A moral panic set in at the threat to the
nation's youth. MDA, MDEA, MDMA and assorted psychedelic amphetamines had been outlawed in
the UK since 1977. Yet the Criminal Justice and Public Order Act 1994 sought to criminalize an
entire youth-culture by suppressing music played publicly with "sounds wholly or predominantly
characterised by the emission of a succession of repetitive beats".

Soon production and distribution of the world's leading empathogen-entactogen fell into the
hands of organised crime. By the turn of the millennium, perhaps 80-90% of the world's MDMA was
manufactured in Belgium and the Netherlands. Russian-Israeli syndicates and Eastern European
chemists are now increasingly active too. The expertise needed in MDMA production varies
according to the route of synthesis. Over twenty recipes have been described in the literature. Only
seven are common. Clandestine production is easiest starting with MDP2P. MDP2P (3,4-
methylenedioxyphenyl-2-propanone) is a commercial product used by the flavouring and fragrance
industry. Groups with access to MDP2P can make MDMA via a simple conversion process. Otherwise,
MDMA must be synthesized from piperonal, isosafrole, or safrole. These primary precursor
chemicals of MDMA are produced in India, China, Poland, Germany, and increasingly elsewhere.
Typically, safrole or isosafrole are first converted to MDP2P. The essential oil safrole occurs naturally
as the primary constituent of oil of sassafras. Oil of sassafras is found in the root-bark of US East
Coast tree Sassafras albidum and from the above-ground woody parts of the South American tree
Ocotea pretiosa. Safrole is also present in nutmeg (Myristica fragrans), dill, parsley seed, crocus,
saffron, vanilla beans, and calamus. If MDMA were on-patent, then today it might be marketed as
"natural" or "naturally-inspired"; but Nature has not been so kind.

Early in the twenty-first century, an estimated several million people worldwide were taking
Ecstasy and allied research chemicals each month on college campuses, in high schools and on
dance-floors. Purity varies; perhaps 10%-15% of tablets consumed contain MDMA as the sole active
ingredient. Illicit knowledge of the "penicillin of the soul" is spreading rapidly around the world, but
in corrupt and contaminated form.

The MDMA Experience

Pure MDMA salt is a white crystalline solid. It looks white and tastes bitter. The compound is
chemically stable. MDMA does not readily decompose in heat, air or light. The optimal adult dose of
racemic MDMA is probably around 120-130mg [around 2mg/kg of body weight i.e. about 125mg]
but optimal dose ranges from perhaps 75mg to as much as 250mg. Pills sold in clubs often contain
less. There are gender differences in response; proportionately to body-weight, women are normally
more sensitive than men to the sub-acute and longer-term effects of MDMA, so their optimal dosage
may be lower. The preferentially metabolised (+)-enantiomer ("mirror image") of MDMA is more
active, more stimulating, more dopaminergic, more subjectively rewarding, and more neurotoxic
than the (-)-enantiomer. MDMA is usually taken orally as a tablet, a capsule, or a powder. MDMA is
readily absorbed from the gastrointestinal tract into the bloodstream. More rarely, the drug is
snorted, smoked or injected.

Onset of action is normally within twenty to sixty minutes or so after administration. When
MDMA is administered by the oral route, "coming up" is naturally faster on an empty stomach.
Taking MDMA causes both an increased neuronal reuptake inhibition of the neurotransmitter
serotonin (5-hydroxytryptamine, 5-HT) and also, critically, its increased synaptic release. The MDMA
molecule is small enough to be taken up via the membrane-bound serotonin transporter into the
presynaptic serotonin axon terminals. Here MDMA acts to reverse the normal direction of the so-
called serotonin reuptake pump. Inside the nerve cell, MDMA alters the configuration of the
transporter protein so it binds to cytoplasmic serotonin, after which the transporter dumps serotonin
outside the cell, reversing the normal inward-bound direction of the transporter channel i.e. MDMA
increases the rate of transporter-mediated serotonin outflow. The consequent additional flood of
serotonin in the user's synapses is soon followed by an increased release of dopamine especially in
the reward centres of the striatum and nucleus accumbens. Release of oxytocin, the "cuddle
hormone", surges too via stimulation of the serotonin 5-HT(1A) receptors.

First-time MDMA users occasionally feel confused or anxious before the dose-dependent
dopamine-release kicks in. A transient hint of nausea is common when coming up. Most of the
body's serotonin is found outside the brain, notably in neurons of the enteric nervous system, our
"little brain" inside the smooth muscles of the gut. The user's peak experience or plateau phase
after the exhilarating dopaminergic "rush" doesn't last much more than ninety minutes to two
hours. MDMA's primary effects wear off after some 3-4 hours. MDMA is more fat-soluble than its
structural parent, so its speed of onset is slightly faster and its duration of action shorter. With oral
MDMA dosing, peak concentration in the plasma follows after around two hours. Therapists then
sometimes add(ed) a final 50mg booster-dose. Heavy recreational users are not always so
restrained either in dosage ["stacking"] or top-up schedule ["piggybacking"].

The clarity and unique psychological effects of MDMA can be impaired by ethyl alcohol. Thus
MDMA is best taken while completely sober, though a modest drink later to ease any comedown
may be useful.

MDMA has a complex nonlinear pharmacokinetics. Taking higher and/or more frequent doses
of the drug disproportionately increases levels of plasma MDMA. Higher levels substantially increase
oxidative stress and magnify the risk of toxicity. MDMA is metabolised via N-demethylation to the
active metabolite MDA; MDA can itself induce a state of sensual euphoria, though in humans the
conversion rate from MDMA in the body is low. At least four other metabolites have been identified.
MDMA is broken down mainly in the liver, primarily by the polymorphic cytochrome P450 enzyme
CYP2D6. However, other enzymes are involved in its degradation beside CYP2D6; some of them,
like CYP2D6 itself, are saturated at relatively low MDMA concentrations. MDMA metabolism seems to
run up against such a metabolic saturation-point somewhere between 120 and 150mg. When the
high-affinity enzymes are saturated, a disproportionately large increase in blood- and brain MDMA-
concentrations may occur if the user then takes more of the drug. A large but variable quantity of
the parent compound is excreted unchanged, especially when the drug is taken at higher doses; but
the opportunities for MDMA recycling by the cost-conscious are normally wasted.

MDMA is sometimes described as a cross between a psychostimulant and a mild hallucinogen.

Since it's a methoxylated amphetamine, MDMA is indeed structurally related to mescaline. MDMA's
methylenedioxy (O-CH2-O-) group is attached to positions 3 and 4 of the aromatic ring of the
amphetamine molecule. But hallucinations on MDMA taken at therapeutic dosages are extremely
rare; and psychostimulants, unlike MDMA, don't typically induce a profound sense of inner peace.
Thus MDMA exhibits a different profile both from the prototypical "serotonergic" 2,5-dimethoxy-4-
methylamphetime (DOM), with its psychedelic 5-HT2A-mediated mechanism of action, and also
from the prototypical "dopaminergic" stimulant (+)-amphetamine.

MDMA is perhaps best characterised as belonging to a functionally unique class of

"empathogen-entactogen". These words don't mean a great deal in the MDMA-naïve state. The term
"empathogen" to describe MDMA and other closely related phenethylamine "empathy drugs" [MDA,
MDEA, MBDB] was proposed by Ralph Metzner, Dean of the California Institute of Integral Studies,
at a 1983 conference at the University of California at Santa Barbara. The term "entactogen" was
coined in 1986 by Dr David Nichols, Professor of Medicinal Chemistry and Pharmacology at Purdue
University and co-founder of the Heffter Research Institute, to refer to substances that generate a
sense of "touching within" or "produce a feeling in one's innermost being". Both terms are quite apt,
though neither will win any marketing awards. MDMA can promote an extraordinary clarity of
introspective self-insight, together with a deep love of self and a no less emotionally intense
empathetic love of others. MDMA also acts as a euphoriant. The euphoria is usually gentle and
subtle; but sometimes profound.

Culture, set and setting inevitably shape the MDMA experience. Idiosyncratic responses to
MDMA aren't rare. MDMA has even been described as a drug that "could be all things to all people"
(Dr Shulgin). Even so, MDMA's primary effects on the user are surprisingly consistent, unlike the
wilder psychedelics such as LSD, psilocybin, or DMT. MDMA may feel mystical, magical or sublime;
but it doesn't feel weird. The drug's influence feels highly controllable. MDMA tends to enrich the
user's sense of self-identity, not diminish it. MDMA "provides a centering experience, rather than an
ego diffusing experience" (Dr. Philip Wolfson), though it may also cause a "softening of the ego-
boundaries". Sometimes a degree of derealisation on MDMA may occur, but rarely depersonalisation
in the ordinary sense of the term. On the contrary, users feel they can introspectively "touch inside"
to their ideal authentic self with total emotional self-honesty.

As well as acting as a "gateway to the soul", MDMA "opens up the heart". Taking MDMA
induces an amazing feeling of closeness and connectedness to one's fellow human beings. MDMA
triggers intense emotional release beyond the bounds of everyday experience. The drug also
enhances the felt intensity of the senses - most exquisitely perhaps the sense of touch. The body-
image looks and feels wonderful. Other people look and feel wonderful too. Minutes after dropping a
pill, a lifetime of Judaeo-Christian guilt, shame or disgust at the flesh melt away to oblivion.

When MDMA is taken outdoors, the natural world seems vibrant and awe-inspiring, perhaps
even enchanted. The experience of colour is gorgeously intensified. On MDMA, Dr Shulgin reported
how mountains he'd observed many times before appeared to be so beautiful that he could barely
stand looking at them. MDMA is not normally classed as an entheogen. "Entheogen" is a term
proposed in 1979 by the scholars R. Gordon Wasson, Carl A.P. Ruck, Jonathan Ott, Jeremy Bigwood
and Danny Staples for agents "generating the god or the divine within", shorn of any speculative
metaphysics. Yet MDMA is used by a variety of spiritual practitioners of widely diverse beliefs as a
gateway to the divine. Some MDMA users undergo life-changing spiritual experiences. Nicholas
Saunders, author of the book E for Ecstasy (1993), cites a Benedictine monk who finds MDMA
"opens up a direct channel to God". MDMA may not be "Christ in (al)chemical form", but if it had
been present in the Eucharist, then we would all still be devout Christians, possibly for ever. A
minority of first-time MDMA users undergo what the inventor of the Shulgin scale christened a Plus
Four...

"PLUS FOUR, n. (++++) A rare and precious transcendental state, which has been called a "peak
experience," a "religious experience," "divine transformation," a "state of Samadhi" and many other
names in other cultures. It is not connected to the +1, +2 and +3 of the measuring of a drug's
intensity. It is a state of bliss, a participation mystique, a connectedness with both the interior and
exterior universes, which has come about after the ingestion of a psychedelic drug, but which is not
necessarily repeatable with a subsequent ingestion of the same drug. If a drug (or technique or
process) were ever to be discovered which would consistently produce a plus four experience in all
human beings, it is conceivable that it would signal the ultimate evolution, and perhaps the end of,
the human experiment. (PiHKAL, pages 964-965)"
Plus Fours are rare, today. But on MDMA, even the most jaded and world-weary soul with a tin-ear
for poetry may "see a world in a grain of sand, And a heaven in a wild flower, Hold infinity in the
palm of your hand, And eternity in an hour."

MDMA is sensuous and sensual in its effects without being distinctively pro-sexual. Although
once dubbed "lover's speed", MDMA is proverbially more of a hugdrug than a lovedrug: "I kissed
someone I was in love with and almost felt as if I was going to pass out from the intensity", recalls
one American clubber. However, MDMA's capacity to dissolve a lifetime's social inhibitions, prudery
and sexual hang-ups means that lovemaking while under its spell is not uncommon. Superfluous
clothes tend to get shed. In men, orgasm is more intense than normal but delayed: MDMA retains a
residual sympathomimetic activity, triggering a detumescence of the male organ. To ease MDMA-
induced performance difficulties, flagging Romeos increasingly combine Ecstasy with Viagra
('Sexstasy'). Unless carefully premeditated, this is not a recipe for safe sex. MDMA may sometimes
cause "inappropriate bonding". Prudence should be exercised before taking it with ex-girlfriends,
boyfriends or culturally inappropriate love-objects. The effects of MDMA on bonobos ("pygmy
chimpanzees"), our sexually uninhibited primate cousins, are unknown.

On pure MDMA, subjects feel at peace with themselves and the world. They discover an
enhanced sense of self-worth, self-forgiveness and complete self-acceptance. Cynical thoughts and
negative feelings disappear. Aspects of life normally too sensitive to talk about can be explored
freely. Heightened feeling allows long-forgotten and repressed emotional memories from childhood
can be retrieved with unusual ease. In some settings, painful, highly-charged and even hitherto
unmentionable problems may be discussed with (rose-tinted) candour. On MDMA, a lifetime of
accumulated psychological barriers and defence-mechanisms go down, somehow magicked out of
existence with a pill. Anger, irritability and ingrained fear dissolve; the hostile amygdala is subdued,
if only for a few hours. Ecstasy users tell each other affectionately what beautiful people they are;
and they do so from the depths of their hearts.

Before the Orwellian-sounding Drug Enforcement Administration [DEA] placed MDMA on

Schedule 1 of controlled substances, professional therapists in the USA found MDMA a valuable tool
for counselling and marriage-guidance sessions. MDMA's capacity to induce empathetic bliss,
heightened introspection and an increased ability and desire to communicate feelings can create a
rapport with the therapist and accelerate a successful outcome. MDMA acts to boosts self-esteem
and self-confidence, while paradoxically diminishing egotism. The user's sense of social isolation
vanishes. "I love the world and the world loves me", affirmed one beneficiary of MDMA-assisted
therapy.

On a more sceptical note, it's hard scientifically to validate claims of long-lasting therapeutic
success. For MDMA's stunning short-term results make double-blind, placebo-controlled trials
effectively impossible. Such a problem doesn't always bedevil today's lame "antidepressants", the
results of whose trials often struggle to reach statistical significance. Investigational drugs are lab-
tested by Big Pharma to discover whether or not non-human animals will self-administer them.
Candidate compounds are normally discarded if the animals do so, arguably a perverse route to
uncovering antidepressants with good clinical efficacy and high patient compliance. By contrast,
MDMA is a warm, fast-acting, non-sedating mood-enricher that banishes social anxiety and physical
pain alike. Unlike opioids or the anxiolytic benzodiazepines, MDMA doesn't cloud consciousness even
at relatively high doses. This doesn't stop less cerebrally-inclined ravers from getting "cabbaged" by
swallowing pills all weekend.

Explored in a controlled setting, MDMA can be therapeutic for victims of Post-Traumatic Stress
Disorder (PTSD). A minority of subjects find they enjoy the experience too much to focus on the
emotional baggage of the past. Sessions are most likely to be productive with an experienced MDMA
therapist. In the Prohibitionist era, MDMA-assisted therapy-sessions are rare.

Dr David Nichols suspects that the related phenethylamine entactogen MBDB ("Eden": 2-
Methylamino-1-(3,4-Methylenedioxyphenyl)Butane), formed by extending the 3-carbon chain of
MDMA to a 4-carbon chain, might prove superior to MDMA as an adjunct to psychotherapy. This is
because Dr Nichols' creation lacks significant dopaminergic activity. It's thus less likely to induce a
distracting euphoria. On the other hand, if and when the substrates of blissful self-insight can be
sustained indefinitely, then who'll need therapy? Perhaps some inner demons are better left to die
of neglect, not awakened for exorcism. Either way, a case can be made that MBDB is indeed a
"purer" entactogen than MDMA. Yet as an empathogen, MDMA is unsurpassed and possibly
unmatched. MDMA's residual dopaminergic amphetamine-like action contributes a euphoric warmth
to the user's intensified feelings and also the desire and ability to express them freely. MBDB's
chemical cousin beta-keto-MBDB (bk-MBDB, "Butylone") is a more enjoyable and stimulating
empathogen than MBDB. As of 2010, its human use is still extremely limited.

Against formidable odds, the Multidisciplinary Association for Psychedelic Studies (MAPS) has
been seeking funding and FDA-approval for controlled trials of MDMA-assisted therapy for PTSD. If
these trials are successful, then MAPS hopes that MDMA could eventually become a prescription-
medicine. For on MDMA, many traumatized or seemingly emotionally frigid people who can never
otherwise speak about their innermost fears and feelings find they can spontaneously open up.
There is no compulsion to talk - just a dissipation of the social anxieties that make us normally
tight-lipped.

Functional analogues of MDMA may one day be employed in other kinds of insight-oriented
therapy as well. Safe, long-acting MDMA analogues may prove therapeutic in the treatment of social
phobia, eating disorders and obsessive-compulsive disorder (OCD).

In December 2004, the FDA granted permission for Dr John Halpern's proposed study of
MDMA-assisted psychotherapy for patients diagnosed with severe anxiety related to advanced
cancer. The likelihood of DEA approval of the protocol is unknown. If the magic of MDMA could be
replicated safely and sustainably, then the fear of death and dying could in principle be banished in
the population at large. This would be a substantial payoff, though the fear of personal mortality is
probably the prime mover of scientific progress in anti-aging research.

Dr Julie Holland, editor of the invaluable Ecstasy:The Complete Guide (2001), tentatively
endorses "the judicious, supervised and single oral doses of MDMA as a psychiatric medicine..." In
her introduction to the guide, Dr Holland notes that "Like any powerful tool, it should be used by
people who are properly trained, educated and supervised. And like any powerful tool, it should
come with an instruction manual. This book, I hope, will serve as that manual". It may be testimony
to the comparative safety of MDMA that millions of young people use MDMA in the absence of a
manual or any training, education and supervision at all. Alas Prohibitionism puts the young and
vulnerable at unnecessary risk; and squanders the therapeutic opportunities. In defiance of
scepticism from medical orthodoxy, Dr Holland also provides supporting evidence to back up
anecdotal reports that MDMA can induce temporary remission of symptoms in victims of otherwise
intractable schizophrenia. Less controversially, it's possible for victims of body dysmorphic disorder
(BDD), or simply anyone with a negative body self-image, to view themselves in the mirror while
euphorically loved-up on MDMA. The transformation can be magical, though it would be imprudent
to repeat the experiment two days later.

MDMA can also be used just to have fun. Most commonly today, teenagers and young adults
take Ecstasy to rave. Mozart sounds great on Ecstasy, but high-energy all-night dance parties
celebrated with techno-pop house music are more standard. Raves are held in clubs, warehouses or
more exotic outdoor settings and open fields. Often raves last a whole weekend. The music may be
techno, hardcore, jungle, trance or form an improvised, eclectic mix of styles harder to categorise.
The atmosphere is astonishingly friendly, the mood and ethos is well captured by the ravers' motto
P.L.U.R. ["Peace, Love, Understanding and Respect"]. In darkened clubs, the intoxicating
atmosphere of the rave is enhanced with artificial fog, lasers, strobe lights, glow sticks, whistles and
Vicks inhalers [on MDMA, aromas are fragrantly enriched]. In many cases, the product now passed
off as "Ecstasy" is adulterated with other agents. Individual pills bought by the end-user typically
cost between US$7 and US$25. The worldwide street price is falling. Tablets can be mass-
manufactured for as little as 50 cents. Professionally-made tablets of MDMA are stamped with
distinctive logos. This is because MDMA manufacturers and merchants seek to promote brand-
awareness and customer loyalty. Alas counterfeit goods are still rife.

Sometimes "Ecstasy" doesn't contain MDMA at all, but MDA; MDEA (3,4-
methylenedioxyethylamphetamine: "Eve"); 2-CB (4-Bromo-2,5 Dimethoxyphenethylamine:
''Nexus", "Venus", "Bromo"); 2C-I; PMA (paramethoxyamphetamine); amphetamine ("speed");
ephedrine; pseudoephedrine; caffeine; the dissociative anaesthetic ketamine ("Special K"); DXM
(dextromethorphan); GHB (gamma-hydroxybutyrate: "liquid ecstasy"); or some combination
thereof. This list is far from exhaustive. A minority of psychologically robust or reckless clubbers
purposely mix MDMA with LSD ("candyflipping") to impart a "warm, loving glow" to their acid trips.
Or they "hippieflip" with psilocybin mushrooms; or "kittyflip" with ketamine. Cannabis is widely
smoked as well. Ravers who want to dance all night may prefer Ecstasy laced with speed; a sub-
neurotoxic dose of MDMA can be made toxic by adding (+)-amphetamine. To outsiders, Ecstasy-
fuelled raving might seem mindless hedonism; its devotees have likened it to group-therapy or
meditation. But either way, chronic heavy use of the methoxylated amphetamines or any other
"club-drug" poses risks to the user's health.

MDMA: neurotoxicity

No compelling evidence exists that taking a single c.125mg dose of MDMA a few times or so a
year is likely to cause any long-term harm to the user's mental or physical health. Nevertheless,
even pharmaceutical-grade MDMA taken at moderate doses in optimal conditions is not a wholly
benign drug. The problem isn't (just) the toxic adulterants used by dance-floor pharmacologists or
the botched syntheses of bathtub chemists. Deceptively, and in contrast to most other
recreationally used drugs, ingesting pure MDMA can sometimes leave the user feeling better than
normal the next day, albeit tired and slightly spaced-out. Beyond warm memories, this afterglow
may in part be explained by MDMA's residual amphetamine metabolic by-products: MDMA itself has
a long, c.8-9 hour elimination half-life from the blood; and its main metabolite's longer-acting, less
stimulating (-)-MDA enantiomer has 5-HT2A activating effects resembling low-grade LSD. But two
days or so after taking MDMA, most users experience the serotonin dip. The dip ranges from the
almost imperceptible to the markedly unpleasant. The functional deficit the dip reflects may last ten
days or more - in some cases possibly weeks or months. A biphasic post-E serotonin profile in the
user has been reported: users' serotonin levels - though hard to measure and interpret - apparently
fall 3-6 hours after taking the drug, then recover to nearly normal levels after around 24 hours, and
then decline again.

Excessive MDMA intake triggers oxidative damage to the user's serotonergic nerve cell fine
axon terminal lipids and proteins via the production of toxic free radicals. However, the threshold
dose for any lasting MDMA-induced toxicity is unknown; and the identity and precise mechanism of
the chemical(s) causing the oxidative stress is unclear. The issue is also controversial. Currently the
three leading candidates for guilty agent are:

1] toxic metabolites of MDMA

2] toxic metabolites of dopamine

3] impaired cellular energetics

An excellent review of the published scientific evidence on neurotoxicity is offered by Matthew

Baggott and John Mendelson on the indispensable Erowid. A role has also been proposed for nitric
oxide; increased Ca2(+); and a toxic intraneuronal metabolite of serotonin. Elevation of body
temperature can seriously worsen possible MDMA-induced toxicity; and the thermogenic effect of
MDMA is magnified in a hot environment like an indoor rave. Certainly, hypothermia-inducing
agents are (partially) neuroprotective against Ecstasy damage; and the primary role of dopamine in
MDMA-induced toxicity may actually be to elevate body temperature via its increased action on the
dopamine D1 receptors rather than its uptake into the depleted serotonergic axon terminals. But
consensus on the molecular mechanisms behind MDMA megadose-induced damage remains elusive.

MDMA itself (probably) isn't the culprit. Experimental microinjection of MDMA, MDA or other
amphetamine analogues directly into the cerebrum doesn't produce the toxicity to the serotonergic
axons ascending from the dorsal raphé nucleus that follows high and/or frequent doses of the
peripherally administered drug. MDMA can be centrally injected to induce the release of just as
much serotonin as the toxic peripherally-administered dose; but there's still no sign of
neurotoxicity. Nor does experimental central MDMA perfusion trigger the toxicity-enhancing higher
body temperatures likely from the peripheral route. When MDMA is centrally administered in animal
experiments, not even artificially inducing hyperthermia in the victim is enough to produce
serotonergic damage. If systemic metabolism of MDMA is indeed necessary for neurotoxicity, the
nature of any such possible toxic metabolite(s) is unknown: thioether conjugates of alpha-methyl
dopamine have been mooted; and in 2009 neurotoxic thioether adducts of MDMA were detected in
humans. Since drug metabolites are normally more hydrophilic than their parent drug, specific
transporters are presumably needed to take up the neurotoxic metabolite into the brain; but their
identity or even existence isn't known either. If they do exist, then presumably they are
monoamines; otherwise selegiline wouldn't be protective against MDMA-induced neurotoxicity.
 Whatever the mechanism at work, most users eventually stop taking MDMA. They do so after
either they find the E-magic wears off, or the unwanted side-effects of heavy E-use begin to
outweigh its joys. Doctors report that one Englishman consumed an estimated 40,000 tablets of
MDMA over a nine year period. Such cases are exceptional. Even so, some heavy MDMA users claim
they don't experience any long-term adverse effects. Prolonged MDMA administration can even
cause a long-lasting increase in the dopamine content of the nucleus accumbens, possibly indicating
its disinhibition from normal serotonergic control. The persistent elevation of dopamine function
reported in the nucleus accumbens of some MDMA veterans might otherwise be expected to
enhance mood, not darken it. Likewise, MDMA users may be less anxious or panic-stricken in
response to the normally anxiogenic challenge of a 5-HT2C agonist such as m-
chlorophenylpiperazine (m-CPP). Depending on one's ideological agenda, this diminished response
to m-CPP can be described as evidence either of serotonergic "toxicity", or alternatively as a pointer
to the substrate of a long-lasting "therapeutic" effect. Again, MDMA use increases sensitisation to
the rewarding effects of euphoriant dopaminergics such as cocaine; and once more, this is not
inherently a sign of "brain damage". However, reports of real and serious health problems from
excess E-use are not all prohibitionist propaganda or part of a government-inspired conspiracy to
stop young people having a good time. Among heavy "recreational" MDMA users, self-medicating or
otherwise, the incidence of depression seems to be more common than healed minds or any
enduring therapeutic benefit. The prospect of serotonergic axon terminal degeneration doesn't
sound much fun, even if the axons re-sprout - one way or another. Worryingly, the MDMA-induced
pruning of the serotonergic axon tree seen at high-dosage regimens leads to altered patterns of
reinnervation by ascending axons projecting especially to forebrain sites. In the process of recovery
from a prolonged MDMA-binge, the hippocampus, a brain structure critical for episodic memory
formation, may actually be hyperinnervated, but reinnervation of the dorsal cortex is sparser. It has
been suggested that the heavy MDMA user who discerns no long-lasting ill effects, and who displays
minimal functional impairment, may still be subtly damaging his or her serotonergic "functional
reserve". The disturbing parallel drawn here is with neurodegenerative disorders: clinical signs of
Parkinson's disease, a progressive disorder caused by outright dopaminergic cell death and
frequently prefigured by depression, only become apparent after 70-80% of dopamine cells have
been lost. It is fiendishly hard to demonstrate MDMA-induced dopaminergic cell damage without
virtually killing the victim; in contrived circumstances it can be done. Yet the most notorious
attempt to show MDMA-induced dopaminergic neurotoxicity, Ricaurte's September 2002 paper
Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of
MDMA ("Ecstasy") in Science, actually demonstrated methamphetamine-induced dopaminergic
neurotoxicity instead. This unfortunate study, its publication timed to coincide with debate in US
Congress over the "Anti-Rave Act", was retracted in September 2003; but the spectre it raised of a
post-E generation of Parkinsonian zombies may prove harder to dispel.

Not even heroic doses of MDMA are likely to kill off serotonergic brain cells, though there have
been unconfirmed reports of MDMA-induced apoptosis in mega-dosed rats. Only the most alarmist
commentators anticipate a delayed epidemic of demented depressives as a result of serotonergic
carnage caused by MDMA abuse. But equally, no alien anthropologist in his right mind who merely
read the gruesome scientific literature on MDMA would want to self-experiment with such a deadly
neurotoxin. Taking weed-killer, glue sniffing or swallowing rat poison sounds marginally less
dangerous. Calling it dystopian pharmacology might seem more apposite. Even listening to glowing,
first-person accounts of the MDMA experience is curiously uninspiring when refracted through the
lens of our normal Darwinian consciousness. The prospect of love, peace and empathy seems less
exciting than a round of Quake 3. We are all prone to mood-congruent thoughts.

In any case, MDMA users themselves may find the magic of the initial drug-induced epiphany
tends to fade with frequent use. For many but not all users, a magical drug becomes just a feel-
good drug. Adverse side-effects tend to become more troublesome. Higher doses are needed to
gain the same effect. Users lament that "the E isn't as pure as it used to be"; and that the tablets
are weaker. Often indeed this is true; but a physiological explanation for so-called "cumulative
tolerance" must be sought as well. Enzyme-induction plays a role, though the phenomenon isn't
fully understood. Pharmacodynamic tolerance to a drug is normally reversible, yet some users of
MDMA report they never quite recapture the initial ecstatic glory even if they abstain for a year or
more. Researchers are still unsure if this fade-off is a symptom of long-term neuroadaptation or
serotonergic damage.

Perhaps we shouldn't be so surprised at the "loss of magic". The liver (and the brain) is
adapted to life on the African savannah. Our vital organs can't know the difference between the
elixir of life and a poison. MDMA has the attributes of both, and in the African bush, the latter is a
more realistic outcome. Yet we won't be trapped in brutish states of consciousness for ever. In the
near future, functional analogues of MDMA promise to enhance mental health, add perpetual magic
to our lives, and beautify our troubled minds. Empathetic bliss isn't inherently toxic; though its
reactive metabolites may be. In principle, the psychopathologies of everyday life can all be cured.
MDMA offers a foretaste of life in post-Darwinian paradise; but it delivers, at best, only a fleeting
hint of the magic to come.

MDMA: neuroprotection

No safe, indefinitely sustainable entactogens-empathogens yet exist. Drugs that consistently induce
the opposite syndrome are legion. Some such drugs are billion-dollar moneyspinners for Big
Pharma. They are clinically licensed and widely prescribed in the guise of psychiatric medicines.
Other psychoactive drugs are used mainly for "unrecognised" and non-medical purposes.
Psychostimulants like cocaine and amphetamine notoriously promote egotism and aggression.
Drinking ethyl alcohol tends to make the user relaxed, disinhibited and stupid.

So is MDMA itself best reserved as a sacrament for special occasions? Or can it be safely
taken "recreationally" and socially? What dosage, if any, is prudent? Is the MDMA experience so
tantalising that it's best avoided altogether lest the rest of one's life pall in contrast? Would one
want one's sixteen year-old daughter to take it; and with whom?

Currently the risk-benefit analysis of taking - or missing out on - MDMA is unclear. Probably
the gravest threat to the long-term emotional and physical health of the user is getting caught up in
the criminal justice system. Victims of the law-enforcement agencies frequently suffer long-term
neuropathological changes. Lowered serotonin levels, elevated cortisol, confusion, depression, sleep
problems, severe anxiety, and paranoia are common. In some cases, the neurological damage may
be permanent. Currently around 500,000 "drug-offenders" languish in American jails alone; and
millions more young people throughout the world are at risk. Yet repealing ill-conceived drug laws is
only part of the answer in protecting mental health.

Ever more alarming animal studies conducted over a decade by George Ricaurte, a
neurotoxicologist at John Hopkins University School of Medicine, suggest that taking high and/or
frequent doses of MDMA causes damage to the terminals of serotonin axons in the brain.
Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA), serotonin's major metabolite which serves
as a marker of central serotonin (5-hydroxytryptamine, 5-HT) neural function, may be lower in
human MDMA users than in putatively matched controls. The number of serotonin transporter sites,
structural protein elements on the presynaptic outer axonal membrane that recycle the released
neurotransmitter, may be reduced too. Long-term MDMA-induced changes in the availability of the
serotonin transporter may be reversible; but it is unclear whether recovery is complete. Currently
the balance of neurochemical and neuroanatomical evidence, and functional measures of serotonin
neurons, suggests that it is imprudent to take MDMA or other ring-substituted methamphetamine
derivatives without also taking neuroprotective precautions. Arguably, it is best to take MDMA
infrequently and reverently or not at all - Dr Shulgin once suggested a maximum of four times a
year.

MDMA's apologists aren't convinced that the neurotoxicity evidence is persuasive - except for
MDMA taken at unrealistically high doses. As Paracelsus (1493-1541) noted centuries ago, "All
substances are poisons: there is none which is not a poison. The right dose differentiates a poison
and a remedy." Most early studies of the possible long-term adverse effects of MDMA use in humans
have been methodologically flawed - inadequately controlled, retrospective rather than prospective,
and marred by a failure adequately to exclude confounding variables - e.g. the so-called stereotype
threat. Some published toxicity studies include a large percentage of self-reported "Ecstasy" users
who've never even taken MDMA. Other studies rely on a small minority of users whose drug-taking
methodology owes more to Hunter S. Thompson than Sasha Shulgin.

Yet the biggest problem in evaluating the published evidence isn't so much sloppy science or
value-judgements masquerading as statements of fact. It's rather that just as the strongest
predictive factor in the outcome of a published clinical trial of any psychiatric drug is the identity of
the funding body, likewise the investigation of MDMA isn't a disinterested search for scientific truth.
Published papers that examine possible confounding variables in MDMA "toxicity studies" omit to
mention the greatest biasing factor of all. Independent funding is critical to the integrity of
biomedical research; but MDMA is now a Schedule One drug. Studies of MDMA can be lawfully
conducted only under government license by ideologically-vetted researchers. Authors and licensed
researchers are implicitly paid to show how prohibited drugs are harmful, not that they can be
potentially therapeutic. Researchers certainly aren't paid to report that some illegal drugs are
potentially life-enhancing agents. Nor do their paymasters expect them to investigate the design of
safer, more sustainable analogues to improve the user experience.

Intuitively, at least, it might seem axiomatic that in a democratic free society every person
should have "the license to explore the nature of his own soul" (Dr Shulgin). Yet this license has
lately been revoked in the name of the War Against Drugs. Every law-abiding citizen is now locked
into traditional modes of consciousness on pain of criminal prosecution and imprisonment. The
chemical keys to the locks themselves have been outlawed. Most natural scientists are scornful of
social constructivists who think that power structures underwrite the way we see the world. But in a
daring extension of the Papacy's Index Librorum Prohibitorum, knowledge of entire state-spaces of
potential experience has been outlawed following passage of the USA's Controlled Substance
Analogue Enforcement Act of 1986. The UN's World Health Organization and foreign governments
have been leaned on, bribed or dragooned into the War On Drugs too. In the USA itself, the world's
most celebrated psychedelic chemist and leading authority on MDMA has been stymied from
conducting human research on Schedule One compounds after publishing his trailblazing
autobiography-cum-cookery book. Worried that his life's work might be quite literally destroyed by
the drug-warriors, Dr Shulgin acted to thwart the obscurantists before it was too late. "I can see
having maybe two or three people in the higher echelons of the government who may not like what
I do, and I did not want particularly to have all of this be seizable and burnable, So I published it.
Now you cannot get rid of it." Dr Shulgin had a DEA analytical license - a "Faustian bargain"
according to MAPS's Rick Doblin. But in 1994, Dr Shulgin fell victim to a DEA raid on his research
lab. Under the transparent pretext of "health-and-safety" infractions, Dr Shulgin's license to work
with scheduled drugs was withdrawn.

Suppression of "illicit" knowledge in academia and the overground research community isn't
normally so melodramatic or heavy-handed. But systemic bias and the habit of internalised self-
censorship extends throughout the apparatus of peer-reviewed journals, sponsored conferences,
and mainstream clinical medicine. On the one hand, negative results and non-results from toxicity
studies are difficult to publish or publicise. Conversely, "positive" toxicity results from studies run by
primate vivisectionists using chronic or near-fatal MDMA doses are newsworthy and fundable. Such
publication bias is insidious and endemic; it's underestimated because prospective authors are
broadly aware of what can - and can't - get published; and so they don't bother to submit what they
know can't be accepted. Even this biasing factor massively understates the problem. This is because
most potential psychedelic research projects can't get official permission or funding in the first
place. As noted by New Scientist in Ecstasy on the Brain (April 2002): "'It's an open secret that
some teams have failed to find deficits in ecstasy users and had trouble publishing the
findings...The journals are very conservative,' says [Andrew] Parrott. 'It's a source of bias.' Parrott
himself has had two papers of this sort turned down."

Of course bias cuts both ways. MDMA enthusiasts find it hard to write even-handedly too.
Among MDMA's "unlicensed" and independent researchers, there is a natural tendency to believe
any agent that triggers such sublime states must essentially be good for you. MDMA can indeed be
life-transforming; but unless it's used sparingly and at conservative doses, it is still a potentially
toxic drug. MDMA's defenders would say that the same is true of lithium, penicillin or paracetamol,
none of which are banned.

Some studies suggest that possible MDMA-induced neurotoxicity to the serotonin system can
be largely prevented by taking a double dose of fluoxetine (Prozac) or another SSRI shortly after
starting to "come down". Post-E Prozac in particular mitigates the oxidative stress and consequent
risk of serotonergic axon damage caused by reactive products of dopamine deamination. The long-
acting SSRI Prozac/fluoxetine, and its even longer-acting metabolite norfluoxetine, apparently
prevents the uptake of dopamine (and any toxic metabolite(s)?) into the serotonergic nerve
terminals by binding to the serotonin reuptake transporter with higher affinity than MDMA or
serotonin. Unfortunately, although liquid refreshment is now freely available at most MDMA-
propelled raves, most chill-out rooms don't offer Prozac. Two days and more after taking MDMA,
heavy recreational users are typically more irritable, subdued, unsociable and subtly less empathetic
than before their weekend binge: the "Terrible Tuesday's" syndrome of midweek blues. So with
cruel irony, two or three days after communing on Ecstasy and declaring their undying love, couples
are more likely to have rows and split up. Other heavy regular MDMA users, even those who aren't
self-medicating for a pre-existing malaise, may experience depression, anxiety, emotional burnout,
rejection-sensitivity, fatigue, insomnia, aching limbs, subtle cognitive deficits, immune system
dysfunction, body temperature dysregulation, and a sense of derealisation or depersonalisation for
several weeks or months afterwards. This litany of woe sounds a high price to pay even for the peak
experience of a lifetime.

Alas, adopting a prophylactic SSRI regimen isn't a realistic long-term option for frequent
MDMA users either, or at least not if they intend to continue using their hugdrug of choice. This is
because a sustained regimen of SSRIs largely blunts MDMA's empathogenic and entactogenic
effects. SSRIs inhibit the binding of MDMA to the serotonin transporter. Thus pre-treatment with
SSRIs prevents MDMA-triggered serotonin-release; and this in turn reduces dopamine-release in the
striatum. Some SSRI users who like to rave nonetheless continue to take MDMA. They consume
abnormally high quantities of pills to gain the desired E-like effect. At this dosage range, the
persistence of metabolite-induced MDA-like states of consciousness the next day is not unexpected.
In practice, the after-effects are often modulated by cannabis and alcohol.

Tolerance to MDMA itself develops quite rapidly with steady use. If MDMA is taken several
days in a row, amphetamine-like and eventually dysphoric effects start to predominate. Monoamine
neurotransmitters, most drastically serotonin, are depleted from the axon terminals; serotonin
synthesis is choked off following oxidative inactivation of tryptophan hydroxylase; and the nerve-cell
receptors re-regulate. Thus MDMA is not addictive in the conventional sense. Taken chronically, it
soon ceases to be rewarding. Even dedicated ravers typically don't binge more than once a week.
Wiser heads save the drug for "special occasions". Yet MDMA's non-addictive profile is no guarantee
that (as was once fondly hoped), "once you get the message you hang up the phone." The
mind/brain isn't built like that. If you really like a drug-delivered message, you want to hear it again
and again. But with MDMA, the message can subtly change with time; and its primal magic gets
sullied or forgotten.

There are other options for neuroprotection besides taking post-Ecstasy Prozac. On one
hypothesis of MDMA-induced serotonergic neurotoxicity, the extra dopamine released into the
synapses is transported into the depleted serotonin axonal terminals where it is deaminated by the
enzyme monoamine oxidase type-B present in the terminal. MAO has two isoforms, MAO-A and
MAO-B. These differ in their substrate affinities and inhibitor sensitivities: the MAO-A isoenzyme has
a greater affinity than the MAO-B isoenzyme for serotonin, but mainly MAO-B is present in the
serotonergic axonal terminals, where it breaks down "foreign" neurotransmitters. However, after a
subject has taken a high dose of MDMA, excess dopamine is taken up by the so-called serotonin
transporters into the depleted serotonin terminals. Here its oxidation produces a glut of toxic free
radicals - highly reactive chemicals with one or more unpaired electrons - such as hydrogen
peroxide (H2O2). These toxic free radicals are liable to exhaust or overwhelm the free radical
scavenging systems of the cell. In consequence, the serotonin fine axonal terminals are broken
down by lipid peroxidation. Why exactly the serotonin reuptake transporters lose their normal
selectivity for serotonin and take up dopamine isn't known for certain. Possibly it's because by this
time there's far less serotonin around for the reuptake pump to use. After the directionality of the
reuptake pump is reversed by MDMA, serotonin released into the synapse can't be recycled back
into the cell; and so it diffuses away. In any event, the monoamine oxidase inhibitor selegiline [l-
deprenyl/Eldepryl] appears to be neuroprotective at monoamine oxidase type-B-selective dosages
i.e. 2 x 5mg daily or less. Selegiline also protects against MDMA-induced inhibition of tryptophan
hydroxylase. Interestingly, Prozac too has MAO-B inhibiting properties; and these may contribute to
its neuroprotective effect. Selegiline itself has additional free radical scavenging properties that may
exert a neuroprotective action. It will be instructive to compare the neuroprotective efficacy of
selegiline with rasagiline (Azilect, Agilect) for E-users. Rasagiline is a selective MAO-B inhibitor
licensed from mid-2005 in the EC for the treatment of Parkinson's disease; rasagiline lacks
selegiline's trace amphetamine metabolic by-products. Whatever the older compound's
neuroprotective efficacy compared to rasagiline, selegiline is potentially valuable too because, unlike
taking a SSRI, adopting a long-term selegiline regimen doesn't impair MDMA's subjective effects.
Even so, no controlled clinical trials of their co-administration are currently planned.

One reason for such caution beyond a reflex Just-Say-No dogmatism is that it's potentially
dangerous to tamper with the MAO enzyme. Selegiline has lifespan-extending properties in "animal
models", and possibly in humans too; but if used recklessly, then it could abruptly shorten life
instead: selegiline is an irreversible MAO-B inhibitor. Prohibitionism and a consequent absence of
quality-control means that the "Ecstasy" sold in clubs often contains liberal quantities of
amphetamine. Amphetamine and MAO inhibitors should not be combined. Both enantiomers of
MDMA itself have MAO-inhibiting effects, preferentially for isoenzyme type-A. Taken at dosages of
above 2 x 5mg per day, selegiline loses its selectivity for MAO-B. Individual variation in MAO status
makes it imprudent for the MDMA user to take selegiline even at 10mg daily; and selegiline itself,
like MDMA, is a weak inhibitor of MAO-A. MAO-A deaminates serotonin; and the serotonin
syndrome, characterised inter alia by hyperthermia, autonomic instability and altered muscle tone,
is potentially lethal. Serotonin 5-HT2A antagonists like ketanserin (Sulfrexal) can inhibit the
syndrome; but they aren't widely available on the street or average dance-floor.
 Milder cases of the serotonin syndrome are not uncommon among the hard-rolling stackers
and piggybackers dancing all night at crowded ill-ventilated raves. Dehydration and overcrowding
tend to worsen drug-induced toxicity. Heat exhaustion and severe hyperthermia are probably the
gravest risk to the raver's health. MDMA tends to raise body temperature by a degree or so,
sometimes by quite a bit more if the user dances all night without rest ["Saturday night fever"].
MDMA also increases the body's secretion of antidiuretic hormone, arginine-vasopressin. Ravers
sometimes overcompensate for the risk of dehydration by gulping down too much pure water. This
can cause hyponatraemia (literally "low salt": "water intoxication"). Sipping a couple of sports-
drinks every hour or so instead is a prudent way to maintain electrolyte balance. Indeed it would be
safer if sports drinks were distributed with each E-tablet sold as a matter of course, perhaps
accompanied with a neuroprotectant mix and a health-tips sheet thrown in for good measure.

Unfortunately, tips found on the Net are no substitute for systematic, well-planned health-
education programs. Organisations like the Berkeley-based Dancesafe, funded by Microsoft
millionaire the late Bob Wallace and founded to promote safe raving, are rare; their activities are
also controversial. Until psychopharmacology becomes part of the educational core curriculum, any
responsibly designed drug cocktail, and any harm-reduction program, must be formulated with the
recklessness of a minority of sensation-seekers in mind, not just risk-averse research scientists.
Such a revolution in mental healthcare for young people is sorely needed. An examination system
akin to ritualised child-abuse wreaks terrible damage on the young minds incarcerated in our
educational institutions. Critics of exam-culture claim an "education" based around competitive
testing screws kids up far more than empathetic drugs. Unfortunately, what's tested in these rituals
of abuse isn't our children's emotional well-being, levels of reflective self-insight, capacity for loving
empathy or social intelligence. Nor do schools and colleges offer courses in effective technologies to
promote them.

A healthcare revolution of this magnitude isn't going to happen tomorrow. So more realistically
for now, clubbers seeking neuroprotection against MDMA-induced toxicity may do well to use
humble antioxidants such as ascorbic acid (Vitamin C), alpha-tocopheryl-acetate (Vitamin E), zinc,
alpha-lipoic acid, and L-cysteine. The optimal mix and dosage before, during, and after dropping an
E to maximise their respective neuroprotective action, and minimise any post-ecstatic hangover,
hasn't yet been established. Even at high dosage, the neuroprotection such antioxidants offer may
be inadequate for heavy MDMA users. More encouragingly, antioxidants also reduce tolerance
between exposures. Clearly a lot more research is needed, hopefully without the usual animal
holocaust that accompanies drug testing today.

The serotonin precursors L-tryptophan and 5-hydroxytryptophan (5-HTP) are also

neuroprotective against MDMA-induced toxicity, possibly in part because of their antioxidant effect
but mainly because of their precursor role. 5-HTP is the metabolite of L-tryptophan. It's the direct
metabolic precursor to serotonin (5-HT). In contrast to the catecholamine neurotransmitters
dopamine and noradrenaline, the synthesis of serotonin isn't subject to strong end-product
inhibition. Like L-tryptophan, 5-HTP is sometimes used as an antidepressant and antianxiety agent;
it seems to have a relatively narrow therapeutic window. Unlike SSRIs, L-tryptophan and 5-HTP can
be taken chronically without blunting MDMA's effects. Indeed some clubbers pre-load with L-
tryptophan or 5-HTP to intensify and enrich the MDMA experience and prevent serotonin depletion.
Serotonin depletion increases the vulnerability of the axon terminals to damage. Though such a
tactic is sensible enough in theory, excess preloading with 5-HTP may potentially precipitate or
exacerbate the serotonin syndrome. So care is in order.

With or without 5-HTP supplementation, an idealised stone-age diet can be especially valuable
for heavy MDMA users. Contrary to a once widely-propagated but now discredited myth, Merck
never planned to develop MDMA as an appetite-suppressant. Yet the company might well have done
so: MDMA's appetite-suppressing effect is quite strong. Drugs that directly or indirectly activate the
serotonin 5-HT1B and 5-HT2 receptors tend to be anorexiants. Lazy and reluctant eaters who
regularly take Ecstasy are at greater risk of vitamin and mineral deficiencies, and more vulnerable
to MDMA-induced serotonergic damage, than matched controls.

One novel and unlikely-sounding proposal to minimise MDMA-induced neurotoxicity is

pretreatment with aspirin. Aspirin inhibits the enzyme prostaglandin H synthase (PHS). PHS
catalyses the transformation of amphetamines into toxic free radical products. Therefore taking
aspirin before MDMA use may also indirectly block the conversion of amphetamines into reactive
oxygen species responsible for long-term neurotoxicity. As of 2010, no controlled trials of aspirin
have yet been conducted with MDMA-using humans. But if aspirin pretreatment does prove an
effective harm-reduction strategy, then this is potentially a godsend - not least because other
candidate neuroprotectants (SSRIs, selegiline, etc) carry hazards of their own in conjunction with E-
use. Aspirin itself cannot strictly be described as risk-free; but the risk/benefit ratio of its use is both
favourable and well-known.

However, the biggest long-term obstacles to preventing neurotoxicity and drug-related mental
health problems are ideological, not pharmacological. The discovery that MDMA is not always the
harmless fun-drug that a number of its recreational users (understandably) first supposed has
caused the medical establishment to demonise MDMA or dismiss its psychotherapeutic potential
completely. Critics of the drug-warrior mentality claim that MDMA's possible neurotoxicity served
only as a pretext for banning it. The case for making, say, tobacco a schedule-one drug isn't notably
less compelling, nor would any rush to judgement on the safety, medical use or addictive potential
of tobacco-products seem so premature. The size of the cumulative death toll in the tobacco
epidemic almost defies comprehension: yet we continue energetically to market a lethal drug to
hundreds of millions of youngsters in the Third World. The contrast between the treatment of
dealers in tobacco products and MDMA distributors couldn't be much starker. Instead of aiming to
prevent possible MDMA-induced neurotoxicity by tweaking or enhancing the agent in question, or
designing better functional analogues, or seeking ways to antagonise possible toxic metabolites, or
running health campaigns promoting the co-administration of free radical scavengers or other
neuroprotectants, the authorities opted simply to outlaw MDMA altogether. Users and independent
researchers alike were criminalised. Scientific investigation was crippled. MDMA was driven
underground, where it could mix with innumerable contaminants and organised crime.

Fortunately, scientific research on MDMA has lately revived, albeit under license and mainly on
non-humans. Rats and monkeys are in some ways uncannily similar - genetically, behaviourally and
biochemically - to human beings. Both the electrical-signalling properties and molecular machinery
of neurons are widely conserved across the animal kingdom. There are interspecies differences e.g.
MDMA is anxiogenic rather than anxiolytic in some mouse strains at low doses; MDMA administered
to rats in cold ambient temperatures induces hypothermia; and MDMA causes opposing
sensorimotor gating effects in rats and humans. Yet the fundamental similarity of "animal models"
to human beings is precisely why we use, vivisect and then "sacrifice" our fellow creatures in drug
discrimination studies and medical research. Using principles of interspecies scaling, it is possible to
estimate the crude physical effects of comparable MDMA doses on people after conducting animal
experiments, although species differences in MDMA's pharmacokinetics and active metabolites make
the details of such scaling controversial. If oxidative metabolites, not MDMA itself, are responsible
for neurotoxicity, then investigation of the particular ways MDMA is metabolised in humans will be
critical in determining safe dosages. But beyond the narrow physical effects of MDMA on the brain,
it's hard enough for articulate humans who take insight-and-empathy drugs to verbalise their
processes of introspection. What can we learn about entactogenesis by mega-dosing a rhesus
monkey? All sorts of intellectually fascinating physiological data can be gleaned from experimenting
on live animals - and even more data from experiments on live humans. Yet ethically, how can we
humanely experiment on members of other species when we can't "predict whether a particular
molecule will open the gates of heaven or stoke up the fires of hell" (Dr David Nichols). Clearly non-
humans can't describe the effects on their consciousness of psychoactives, even though they can be
taught to "discriminate" them - the so-called "animal model" of subjective drug effects. So members
of other species can't describe the illegal knowledge drug-naïve humans are missing out on - or the
horrors we inflict on their minds and bodies.

Even if animal research throws up a true wonderdrug ideal for human use - a safe, sustainable
miracle-pill with a well-defined therapeutic window, life-enriching subjective profile, and no
significant adverse side-effects - then under today's regulatory regime, the potential wonderdrug
couldn't get a product-license. In law, only medicines to treat well-defined clinical disorders can be
licensed, not investigational agents designed to enhance our quality of life or enrich "normal" human
mental (ill-)health. Short of labelling the agent as a "food supplement" - which might be stretching
it a bit for MDMA and its analogues - true pharmacological life-enrichers will be condemned to legal
limbo. Even if this perverse restriction on legal drug availability were lifted, then any prospective
blockbuster most likely still wouldn't get regulatory approval in practice. Human clinical trials cost
tens of millions of dollars to run. MDMA itself has long been off-patent. So profit-driven
pharmaceutical companies aren't interested in funding pilot studies. Empathy-And-Insight
Deficiency-Disorder isn't covered in DSM-IV, the psychiatrists' bible. A condition that isn't medically
acknowledged can't be treated by state-licensed pharmacotherapy.

The gloom-and-doom shouldn't be overdone. Eventually, safe long-lasting E-like super-

cocktails and enhanced functional analogues of MDMA may indeed be both patentable and judged
therapeutic for "officially" sanctioned medical conditions such as anti-social personality disorder,
refractory depression, PTSD, Asperger syndrome and autism. These super-cocktails and sustainable
MDMA analogues should prove life-enhancing for "normal" self-regarding people who would like to
improve themselves too. Such usage may or may not stay "off-label"; but it needn't be illegal.

In the meantime, bitter experience of the hedonic treadmill of Darwinian life instils a
reluctance to believe anything so magical as the MDMA experience could be sustained and enriched
indefinitely. ["You can't have the sweet without the sour"; "You need pain to appreciate pleasure",
etc.] But such superstition is pre-scientific; it may soon seem quaint. As intracranial self-stimulation
studies attest, pure pleasure induced by electrical stimulation of the ancient mesolimbic pleasure
centres of the brain shows no tolerance. Response- and remission-rates are 100%. In the present
era, depression, self-ignorance and sociopathy are demonstrably sustainable over a lifetime; but so,
in theory, are the biochemical substrates of happiness, lucid self-insight and even saintly empathetic
bliss. The hedonic treadmill can be dismantled, its inhibitory feedback mechanisms redesigned, and
its neurogenetics rewritten. In principle, and perhaps one day in practice, we can be nicer, happier
and smarter indefinitely. Unfortunately this utopian outcome won't result from a chronic regimen of
MDMA.

Ecstasy for life?

What are the presently available options for enhancing and extending the MDMA experience?
Two separate questions need to be distinguished. First, what if any drug or drug-cocktail can safely
replicate the acute subjective effects of MDMA? Second, what if any drug or drug-cocktail or gene-
therapy can best induce E-like consciousness over the long-term?

The holy grail of safe, sustainable entactogen-empathogens almost certainly won't be found in
the guise of structurally-tweaked chemical homologues of MDMA. A long-term regimen doesn't seem
feasible even if the exact structural requirements needed to reproduce MDMA's acute stimulus
effects were understood. To make the magic last for ever, or at least to induce it at will over several
decades, only a long-lasting homeostatic re-regulation of the central nervous system will work. Thus
the substrates of a lifelong capacity for E-like consciousness can't be engineered via, say, a
mechanism akin to the MDMA-induced reversal of the serotonin reuptake pump. Depleting the
brain's serotonin or, even worse, inhibiting the molecular machinery needed for its renewed
synthesis, is a recipe for clinical depression, not Heaven-on-Earth. Nor can the substrates of
perpetual empathetic bliss be delivered by tonic stimulation of the same pre- and post-synaptic
receptors activated by an acute flood of extra serotonin/dopamine in the synapses - or at least not
in the same way. Prolonged receptor activation typically leads to receptor desensitisation and/or
down-regulation. The inhibitory feedback mechanisms that keep our Darwinian brains so mean-
spirited need to be sabotaged, not kicked into gear.

Such a profound homeostatic shift in normal waking consciousness might conceivably be

delivered by functional analogues of MDMA. The idea here would be to reproduce E-like euphoric
and empathogenic-entactogenic effects, not acutely, but via delayed receptor subtype-specific re-
regulation. MDMA itself rapidly depletes serotonin from the axon terminals and inactivates the
enzyme tryptophan hydroxylase needed for its renewed biosynthesis. By contrast, altering the
density and signal-transduction efficiencies of the mission-critical receptor subtypes [5-HT1B(?), 5-
HT2A(?), dopamine D2(?)], could, ideally, deliver sustained ecstasy without emotional burnout.
Such receptor re-regulation might involve a time-lag of one-to-three weeks, as is normal with
conventional "antidepressants". Delayed-onset magic, if achievable, would offer an immense social
and therapeutic advantage. This is not just because the magic should be sustainable without limit,
but because postponing the onset of drug-induced reward minimises a medicine's "abuse-potential"
without compromising its efficacy. The practice of tobacco-smoking, for instance, is so addictive not
because of the surpassing joys of inhaling a cigarette, but because a tobacco abuser need wait only
seven seconds or so between taking a puff and the miniscule hit. The reward from oral MDMA takes
somewhat longer; but the delight of E-like consciousness needs to be divorced from its intimate
association with pill-popping.

Alas the brain's post-synaptic signal-transduction mechanisms aren't yet sufficiently

understood to bring about a magical E-like re-regulation of waking consciousness indefinitely.
Inducing lifelong egoistic bliss is less of a technical challenge. Wireheading is uniquely effective,
though most of us might prefer the services of a molecular psychiatrist to a neurosurgeon.
Fortunately, our options may soon extend beyond the crudely hedonistic. Indeed within a few
decades, taking a controlled-release maintenance dose of functional analogues of MDMA may seem
as natural as swallowing a multivitamin pill; and just what the doctor ordered.

Alternatively, the neurochemical substrates of MDMA-like magic may be preserved, or

continually re-created as desired, via a cocktail of agents rather than monotherapy. On this
approach, each individually designed ligand would be targeted selectively at the potentially magic-
signalling receptor subtypes [or at second-messenger pathways coupled to the G-protein-linked
signal-transduction system, or in theory direct mechanisms of gene regulation and expression]. This
may be feasible; but its orchestration will be much harder than it sounds. As the catalogue of
serotonin receptor subtypes has grown, so has our library of serotonergic molecular probes; yet so
too has a realisation that agents previously reckoned to be selective for a particular class of
serotonin receptor are less selective than originally claimed. Hence there is a need for novel
agonists, antagonists and inverse agonists with far greater selectivity for each receptor
subpopulation. This multiple targeting strategy is technically challenging, but it's probably more
promising than relying on a single "dirty" non-specific indirect serotonin agonist like MDMA.
Although there are indeed other, non-neurotoxic amphetamine derivatives that acutely induce
transporter-mediated serotonin release, achieving the all-important goal of sustainability may entail
the use of drug cocktails. Thus one might explore combining e.g. 1] new synthetic allosteric
modulators of the serotonin 5-HT1B autoreceptors that regulate the evoked release and synthesis of
serotonin; 2] agents acting selectively on the 5-HT1B-autoreceptors and heteroreceptors; 3] the
right 5-HT2C receptor antagonist or inverse agonist to make the E-like state more ecstatic; 4] the
right dopaminergic(s) or, ideally, agents targeting the medium spiny GABAergic projection neurons
in the rostromedial shell of the nucleus accumbens directly. This is all still very speculative and
unfunded.

Alternatively, and perhaps more plausibly, locking in the neural substrates of empathetic bliss
as a default-state of consciousness may be achievable only via gene therapy, or perhaps a hybrid
gene-and-drug combination treatment. One option here would be inserting "good" variants of the
tryptophan hydroxylase gene, which codes for the rate-limiting enzyme of serotonin biosynthesis,
and then once again co-administering receptor subtype-selective ligands and/or serotonin releasers.
Our immediate options are limited. Pharmaceutical interventions aimed at extending, for example,
profound emotional depth over many decades rather than a few hours may entail, not flooding the
synapses with extra serotonin followed by extra dopamine release as in acute dosing with MDMA,
but instead using e.g. serotonin reuptake accelerators analogous to the memory-enhancing
antidepressant tianeptine (Stablon); or perhaps enhancing the love-and-nurturance-promoting
oxytocin system; or perhaps using better designed analogues of the emotion-deepening agent
Gamma-HydroxyButyrate (GHB).

A brief comparison of GHB and MDMA may be instructive because one therapeutic challenge
ahead will be to design agents that reverse SSRI-like flattening of affect without inducing mawkish
sentimentalism (cf. ethyl alcohol). In contrast to mainstream psychiatric drug therapies, both GHB
and MDMA deliver a rare emotional intensity of experience, albeit an intensity different both in
texture and molecular mechanism. GHB is known by clubbers if not structural chemists as "liquid
ecstasy". GHB and MDMA are indeed sometimes mixed at raves; but the two drugs are chemically
unrelated. GHB is an endogenous neuromodulator derived from GABA, the main inhibitory
neurotransmitter of the brain. A naturally-occurring fatty acid derivative, GHB is a metabolite of
normal human metabolism. GHB has its own G protein-coupled presynaptic receptor in the brain.
Sold as a medicine, GHB is licensed as an oral solution under the brand name Xyrem for the
treatment of cataplexy associated with narcolepsy. Unlike MDMA, GHB stimulates tissue serotonin
turnover. GHB increases both the transport of tryptophan to the brain and its uptake by
serotonergic cells. Taking GHB stimulates growth hormone secretion; hence its popularity with
bodybuilders. GHB offers cellular protection against cerebral hypoxia, and deep sleep without
inducing a hangover. GHB also stimulates tyrosine hydroxylase. Tyrosine hydroxylase converts L-
tyrosine to L-dopa, subsequently metabolised to dopamine. Unlike MDMA, the acute effects of GHB
involve first inhibiting the dopamine system, followed the next day by a refreshing dopamine
rebound. GHB induces mild euphoria in many users. In general, the neurotransmitter GABA acts to
reduce the firing of the dopaminergic neurons in the tegmentum and substantia nigra. The
sedative/hypnotic effect of GHB is mediated by its stimulation of GABA(B) receptors, though GHB
also modulates the GABA(A) receptor complex too. The main effect of GABA(B) agonism is normally
muscle relaxation, though interestingly, pretreatment with the GABA(B) agonist baclofen also
prevents an MDMA-induced rise in core body temperature. Whatever the exact GABA(A), GABA(B),
and GHB-specific mechanisms by which GHB works, when taken at optimal dosage GHB typically
acts as a "sociabiliser". This is a term popularised by the late Claude Rifat (Claude de Contrecoeur),
author of GHB: The First Authentic Antidepressant (1999). Rifat was GHB's most celebrated
advocate and an outspoken critic of Anglo-American psychiatry. Similar therapeutic claims have
been made for GHB as for MDMA, despite their pharmacological differences. GHB swiftly banishes
depression and replaces low mood with an exhilarating feeling of joy; GHB has anxiolytic properties;
it's useful against panic attacks; it suppresses suicidal ideation; it inhibits hostility, paranoia and
aggression; it enhances the recall of long-forgotten memories and dreams; and it promotes
enhanced feelings of love. Like MDMA, and on slightly firmer grounds, GHB has been touted as an
aphrodisiac: GHB heightens and prolongs the experience of orgasm. GHB disinhibits the user, and
deeply relaxes his or her body. Inevitably, GHB has been demonised as a date-rape drug ["I was at
this party, and this guy gave me a drink. Next thing I know, it's morning and I'm in someone's bed.
I've no idea what happened in between..."]. GHB has a steep dose-response curve. Higher doses
will cause anterograde amnesia i.e. users forget what they did under the influence of the drug. It's
dangerous to combine GHB with other depressants. So despite GHB's therapeutic and pro-social
potential, GHB is probably unsafe to commend to clubbers. This is because a significant percentage
of the population will combine any drug whatsoever with alcohol regardless of the consequences to
health. If used wisely, sparingly, and in a different cultural milieu, then GHB could be a valuable
addition to the bathroom pharmacopoeia. But even then, it's still flawed. GHB may intensify emotion
and affection, but not introspective depth or intellectual acuity. Unlike taking too much MDMA,
overdoing GHB makes the user fall profoundly asleep. If our consciousness is to be durably
enhanced, then sedative-hypnotics have only a limited role to play in the transition ahead.

So what are the prospects for richer, intenser, sustainable insight-and-empathy drugs from
MDMA's phenethylamine sisters and cousins?

Post-Shulgin, the quantified structure-activity relationships of MDMA and related compounds

(MDEA, MDA, MBDB, MMDA,, etc) have been investigated, even though systematic overground
exploration of their effects on the human psyche has been strangled at birth. Research chemists
have designed a host of ring-substituted amphetamine derivatives with one or more substituents
attached at different positions to the phenyl ring of the amphetamine or methamphetamine
structure. Other such derivatives have been devised by entrepreneurs whose synthesis of designer
drugs aims more at circumventing legal restrictions than pushing back the frontiers of knowledge.
In general, different monoamine-releasing amphetamine analogues become less subjectively
rewarding as their serotonin-releasing potency is increased relative to dopamine-releasing potency.

Whatever their parentage, the phenethylamines as a whole exert a spectrum of action from
the purely stimulant activity shown by "noradrenergic/dopaminergic" amphetamine to the almost
entirely psychedelic activity of the "serotonergic" DOM - distributed at ultra-high doses in Haight-
Ashbury San Francisco 1967 under the name of 'STP': Serenity, Tranquillity, and Peace. In drug
discrimination studies, MDMA's subjective effects only partially cross-generalise to DOM and
amphetamine. Indeed MDMA only partially cross-generalises to the other two hypothetical family
prototypes currently identified, PMMA [N-methyl-1-(4-methoxyphenyl)-2-aminopropane] and TDIQ
[5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline] from the "fourth dimension". MDMA itself is
truly "one of kind" (Dr Shulgin), both structurally (i.e. the effects of the N-methylation of its primary
amine, exclusive 3-4 di-substitution on the aromatic ring, its anomalously potent (+)-enantiomer)
and subjectively. There's no obvious new tweak of its molecular structure, or to structurally related
agents, that promises to deliver SuperEcstasy Mark 2, or even if there were, to suppose the
supermagic would be truly sustainable. Thus MDMA's immediate homologue and closest relative,
MDEA (3,4-methylenedioxyethylamphetamine: "Eve"), formed by swapping the 1 carbon methyl
group for a 2 carbon ethyl group, is an interesting agent in its own right, but it's not going to deliver
lifelong empathetic bliss. Indeed MDEA is actually less warm and empathetic, and more introverted
in its typical subjective effects, than its sister molecule. Instead of taking MDEA as the racemate,
one option is administering only (+)-MDEA, the optical isomer responsible for racemic MDEA's
entactogenic quality. Yet pure preparations of individual enantiomers are not always readily to hand,
nor a route to lifelong wisdom if they were.

Curiously, the beta-ketone analogue of MDMA, methylone (3,4-methylenedioxymethcathinone,

MDMCAT), is poorly researched. Only a handful of papers appear in the published scientific
literature. Methylone is another creation of Dr Shulgin. The drug is sold (expensively) as a "research
chemical" over the Net. Branded rather unsubtly as "Explosion", methylone is also available in
several Dutch smartshops. Recently it has become very popular in the scientific counterculture.
Methylone is not specifically scheduled (as of 2010); it may nonetheless fall within the scope of
analogue drug laws. It is not as potent as MDMA; and it has a higher dosage range. Methylone
causes less inhibition of serotonin reuptake and triggers less serotonin release than MDMA; but its
potency in promoting the synaptic accumulation of the catecholamine neurotranmitters
noradrenaline and dopamine is similar. Thus methylone has activating and empathetic effects while
inducing less emotional outpouring. Many subjects experience an E-like "magic", though the two
drugs can readily be distinguished by experienced users. It should be stressed that the comparative
safety of methylone has not yet been well established, even at relatively low dosage levels of 120-
150mg. This is still a new drug. Methylone is mood-elevating; higher doses induce a clear-minded
and serene euphoria. Reputedly there is less serotonergic toxicity than MDMA; but there can still be
a very noticeable comedown. If methylone is taken chronically, its stimulant effects become more
pronounced. Its empathogenic qualities diminish. Tolerance soon sets in: a sad and familiar story.
Likewise, the empathetic euphoriant mephedrone (4-Methylmethcathinone; 2-Methylamino-1-p-
tolylpropan-1-one) can be acutely rewarding; but it is a short-acting stimulant whose
pharmacokinetics and toxicology are unknown. Alas our knowledge (2010) of its properties comes
wholly from user reports rather than peer-reviewed scientific journals.

From a theoretical perspective, PMMA [N-methyl-1-(4-methoxyphenyl)-2-aminopropane] a

structural hybrid of paramethoxyamphetamine and methamphetamine, is interesting. PMMA
arguably better represents a pure entactogenic [inward-looking, self-accepting, peaceful] family
prototype than MDMA. However, the warm self-acceptance and empathetic love of others
experienced on MDMA feels so clean and pure precisely because its mechanism is so messy. PMMA,
on the other hand, lacks MDMA's residual psychedelic or speedy effects: PMMA is thus clearly
distinct from the other hypothetical family prototypes, DOM or amphetamine, and also from TDIQ,
about whose psychotropic effects rats currently know more than Homo sapiens. Unfortunately
PMMA, like most methoxylated amphetamines, is potentially neurotoxic. In any case, it's completely
unsustainable in regular use, though its ortho-isomer, methoxyphenamine, was once UK-licensed in
tablet form as the bronchodilator Othoxine. PMMA itself is a potent drug with a very low therapeutic
index: the combination of serotonin-release and MAO-A inhibition integral to its entactogenic profile
makes it hazardous in overdose. In general, taking MAO-inhibiting agents with anything
serotonergic is normally contraindicated because of the risk of the serotonin syndrome.

PMMA's reduced dopamine-releasing action makes it less "abusable" than other family
members with overlapping psychostimulant effects. Yet rather than scorning the pleasure principle
by seeking to minimise drug-induced reward, it might instead be more rational to design safer,
benignly addictive lead compounds that maximise the user's well-being in lastingly empathetic,
entactogenic and socially responsible ways. Well-designed (or serendipitously rediscovered)
empathetic euphoriants can trigger socially responsible happiness. This is the distinctively E-like
happiness that inspires love, nurturance and understanding rather than egotism and dominance
behaviour. It's hard to imagine that any such futuristic love-drugs won't be "abusable" too. But if a
drug isn't remotely rewarding or habit-forming, then it probably isn't any good. In the immortal
words of Jeremy Bentham...

"Nature has placed mankind under the government of two sovereign masters, pain and
pleasure...they govern us in all we do, in all we say, in all we think: every effort we can make to
throw off our subjection, will serve but to demonstrate and confirm it."

Alas application of means-ends rationality is rarely the norm in drug-policy debate or in psychiatric
medicine. Nor is the pursuit of happiness undertaken much more rationally elsewhere. Thus we
continue with Rube-Goldbergish efforts to improve our well-being via environmental scene-shifting -
with mixed success.
 Of course the biological route to nirvana has its share of pitfalls too; and MDMA is merely one
of its most alluring seductions. Seekers of sustainable ecstasy would be rash to fetishise any
particular drug or family of pharmacological tools - however magnificent their acute action on the
user. For what matters, presumably, is the otherwise inaccessible modes of experience such agents
can unlock in the mind/brain - and ways to sustain them - not the chemical structure of the agent
that happens first to disclose their existence. "All science is either physics or stamp-collecting",
Rutherford provocatively once proclaimed; and if some organic compounds didn't have the potential
to unlock the doors to the kingdom of heaven, then Rutherford might have been right. As it is,
school chemistry-lessons and standard textbooks rarely set young imaginations ablaze. They might
conceivably do so if the PiHKAL-inspired compounds they ought to contain evoked the magical
experiences their structures should ignite. Yet even the most astonishing centrally active
compounds are only research tools or therapies, not sacraments. At least until we can genetically
enrich the human mind/brain, no drug or research chemical, nor indeed any irritation of the body's
surface sensory transducers by the environment, can do more than select from a pre-existing menu
of brain-states composing the subject's mind/virtual world. In this sense, we're trapped.

Fortunately there is an escape-route; the false prison can be transcended. Within a few
decades, the insertion of entirely new genes and variant alleles into our genome promises to
revolutionise our stunted Darwinian minds. Novel neurally-expressed polypeptide sequences should
disclose modes of experience hitherto unknown. The creation of genetically enriched neurons should
allow the exploration of multidimensional search-spaces of consciousness which we presently lack
the molecular wetware to imagine or even name. No psychoactive drug currently gives access to
these hypothetical state-spaces. Such modes of consciousness have been barred to us by natural
selection. They either diminished their user's Darwinian fitness or would have entailed crossing gaps
in the evolutionary fitness landscape to get there. Whereas merely E-like states are normally
inaccessible because their owners would get eaten or outbred, these unDarwinian modes of
consciousness are quite possibly orthogonal to anything accessible today within our existing mental
architecture. Each new state-space may be as different from the others as is sound from vision, or
volition from cognition or emotion. The differences in gene-expression profile between neurons
mediating the experience of, say, colour, or disgust, or humour (or being loved-up) may strike us as
subtle. Yet the subjective differences in texture ("what it feels like") that their respective post-
synaptic intracellular cascades generate are clearly spectacular. Who knows what else is accessible
from Nature's psychoactive library by means of even "trivial" molecular genetic tweaks to our nerve
cells? Disparate new categories of experience, and hopefully revolutionary conceptual schemes to
navigate them, are presumably waiting to be unlocked just by inserting new sets of neurological
instructions. Unfortunately we lack any God's-eye taxonomy of consciousness that might let us act
like physicists and "carve Nature at the joints". The lack of an overall map, or even the ghost of a
theory of consciousness to guide us, makes it impossible to place MDMA, or the spectrum of altered
experience disclosed by psychedelic amphetamines, within any adequate scheme of classification.
"Empathogen", "entactogen", "entheogen", and "psychedelic" are provisional and theoretically ill-
motivated terms. A mature psychoactive taxonomy will need to be formulated relative to the
architecture of particular phenotypes of mind, not the structure and pharmacology of the molecular
probe alone. Alas the results of animal "drug discrimination studies" are no substitute for
explanatory depth. In practice, today's psychonauts are reduced to describing the subjective effects
of psychoactive drugs by contrasting them with their "normal" states of being. Inevitably this is all a
bit lame. In retrospect, today's entire dreaming and waking consciousness may prove to be only
minor variants on a theme whose motif can't be grasped from within.

Needless to say, the genetic choices, varieties of drug habit and modes of consciousness of
our post-human descendants are a matter for conjecture. We've barely begun to ring the changes
within the state-space of consciousness we've got. In order to replicate and sustain the family of
MDMA-like magical states safely and reliably, it's necessary first to find the specific neurochemical
signature of the family of enchanted states we're targeting. Thus by using, for example, transgenic
receptor-knockout "animal models", SPECT (Single-Photon Computed Tomography), PET (Positron
Emission Tomography) and MRI (Magnetic Resonance Imaging) scans, quantitative EEG with dense-
mapping electrode arrays, antisense regulation of protein expression, and pre-treatment with other
pharmacological ligands that activate or antagonise or act as inverse agonists at particular subtypes
of receptor in the brain, it should be possible for ideologically committed bioscientists to discover
what is crucial - and what's unwanted or inessential - to MDMA's psychological and physiological
effects. Once the E-like signature is established, neuroscientists can then work how to mimic, refine
and extend its magic, even if sustainable ecstasy is only a staging-post on the route to a richer
biochemistry ahead.

First, however, MDMA's acute adverse side-effects i.e. teeth-grinding ["bruxism"], jaw-tension
["trismus"], loss of coordination ["ataxia"], eye-wiggling ["nystagmus"], profuse sweating
["diaphoresis"], nausea, appetite-suppression, tachycardia, dry mouth, hyperthermia or
idiosyncratic reactions to MDMA need to be eliminated and not just minimised. The really nasty stuff
- hepatotoxicity, cardiac arrhythmias, hyponatremia-induced cerebral and pulmonary edema
(caused by drinking too much water), rhabdomyolysis (the breakdown of skeletal muscle), and
disseminated intravascular coagulation (inappropriate blood-coagulation leading to severe bleeding)
are statistically very rare. MDMA-induced incidence of these syndromes was apparently unknown in
clinical practice prior to the drug's legal proscription. However, not all the problems of MDMA use
can be blamed on Prohibition and the lethal mix of ignorance and criminality it spawns. Even pure,
low-dose MDMA does not suit everybody. In the era of pre-genomic medicine, atypical reactions to
any drug at all should be expected. Conversely, with adequate medical research the mildest bad
experience on MDMA should be preventable.

Much more speculatively, the use of personalized somatic gene-therapy may enable future
scientists of the mind, or unabashed hedonists, to sustain an otherwise neurotoxic drug regimen in
safety. For instance, transgenic mice carrying the sequence of the human CuZn superoxide
dismutase enzyme are resistant to MDMA-induced serotonergic damage. Ideology aside, humans
can benefit from genetically enhanced neuroprotection no less than intoxicated rodents. If ever we
wish to adopt a potentially life-enhancing but otherwise hazardous drug-regimen indefinitely, then
one option may be to protect ourselves by inserting new genes or new alleles into our legacy
genome. Or we may simply induce the overexpression of endogenous antioxidant enzymes already
coded for. We're already on the brink of tailoring our drugs to our genes, but in principle we can
tailor our genes to our drugs. Or we may choose to design, insert, and switch on and off as desired
a suite of structural and regulatory genes for whatever life-enriching chemical exotica (or old
favourites) we seek to enjoy. The modes of experience they generate may thereby become
available, as it were, on tap. Nature uses lateral gene transfer; and rationally, so can we. Or by
contrast, it's possible some or all genetically enriched post-humans may shun adulterants of their
beautiful forms of consciousness altogether. If one's soul has been purified, why defile it?

To suppose that we might opt deliberately to micromanage even a subset of the thousands of
neurally active genes of one's genome, and intervene to regulate their complex post-transcriptional
editing, sounds far-fetched, even as the biotech revolution gathers pace. The prospect that we
might personally choose to enrich our genetic repertoire from an ever-expanding library of newly-
created DNA sequences, and an ever vaster neuroactive proteome, sounds still more remote. Could
we really cope with such an enlarged freedom of choice? In practical terms, and perhaps
surprisingly, yes. Sustainable E-like consciousness is just one option among myriad flavours of
sentient existence. Radical enhancements of, say, the sorts of user-friendly visual interface we rely
upon to interact with our PCs today can potentially be exploited to manage the neuroactive
expression and regulation of one's individual genotype. End-user ignorance of the low-level
molecular machinery is fully compatible with everyday expertise acquired in managing the kinds of
consciousness one's genes code for - and mastering the types of mind/virtual-world these genes
express. Thus the non-specialist user of genetic management software could, in principle, be
shielded from the complex chemical minutiae of what is happening many virtual layers of complexity
below, just as most PC users today wouldn't recognise machine code if it bit them on the nose.

Pessimists might argue that the opportunity for such life-transforming manipulations will be
solely the privilege of a rich elite. This anxiety is (probably) misplaced. For the time-lag between the
introduction of a new technology and its diffusion to the population at large has been progressively
shrinking. It took perhaps 50 years to democratise the radio; some 20 years for the TV; around 10
years in the case of the PC; and even less for the mobile phone. With information-based products,
the time-lag effectively collapses. Thus the gap between an expensive software release in Redmond
and its availability to the population of Thailand is perhaps a few hours. Irritating bottlenecks
notwithstanding, information is cheap. Technically, the "counterfeit" generic version is in no way
inferior to the brand-name product. In a mature information-based society, "scarcity" is a far more
elusive concept than in the era of material commodities. On this analysis, the resources of, for
instance, tomorrow's domestic quantum computers may be harnessed anywhere and everywhere to
more humanly empowering pursuits than the factoring of thousand-digit numbers that so excites
contemporary cryptographic theorists. A good place to start will be simultaneously screening an
unimaginable multitude of alternate histories of gene- and drug-combos in search of promising
leads for one's personal development program. The friendliest, voice-activated, most visually
compelling user-interfaces that creative designers can build may make seizing control of one's
destiny from a legacy genome a less daunting challenge than it seems today. This doesn't mean we
won't need all the help we can get in mastering the awesome software tools soon available to
personalise our own genome and drug-regimen of choice. But choosing who and what we want to be
should feel exhilarating rather than intimidating.

In this optimistic scenario, a product-pipeline of better, faster, cheaper and safer designer-
drugs and drug-and-gene-combos should in principle be accessible to everyone within 15-20 years.
Sustainable E-like empathogen-entactogens may become as familiar as aspirin; much safer in
overdose; and far more ubiquitous. The design of E-like hugdrugs, lovedrugs and euphoriants, and
perhaps later the genetic programming of E-like waking consciousness, could be just the beginning
of a whole new genetic and chemical cornucopia for mature post-Darwinian life. For now, certainly,
the prospect of a loved-up world reads like overheated science-fantasy. In practice, such predictions
may prove too tame to be realistic.

The molecular machinery of magic

Lifelong ecstatic wonderpills and genetic self-mastery are at best some way off. So which
ingredients of MDMA's primal magic are most worth mimicking pharmacologically in the near-term
future? Preventing tolerance, promoting safety, and indefinitely extending duration are vital. Yet
how desirable is inducing more or less euphoria, more or less calmness or behavioural activation,
purer empathogenic or entactogenic action, and a greater or lesser hint of trippiness?

Pre-treatment studies with receptor antagonists indicate that dopamine D2 antagonists such
as haloperidol (Haldol) attenuate MDMA's positive hedonic effects; 5-HT2A antagonists like
ketanserin suppress MDMA's residual psychedelic activity; and SSRIs like citalopram (Celexa /
Cipramil, the most selective of the SSRIs) diminish if not abolish the full spectrum of MDMA's
psychoactivity. Drug discrimination studies performed on captive rodents may overlook certain
subtleties of the MDMA experience. Intriguingly, in mice at least, the behavioural and physiological
effects of MDMA are selectively antagonised by the plant alkaloid nantenine (9,10-methylenedioxy-
1,2 dimethoxyaporphine). Nantenine is "antiserotonergic" and an alpha1-adrenoceptor antagonist;
the effects of nantenine on ecstatic human subjects are unknown. But on present evidence, it's
primarily a combination of enhanced oxytocin release and the interplay between the serotonergic
and dopaminergic systems that underlies MDMA's discriminative stimulus effects/sublime magic.

The full story is complex and still poorly understood. As the user "comes up", serotonin
released into the synaptic cleft activates multiple serotonin receptor subtypes (5-HT1, 5-HT2, 5-
HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7), and subpopulations (most notably, 5-HT1B, 5-HT2A and 5-
HT2C). The hierarchy of their relative contributions to the subjective and behavioural effects of
MDMA use may shift with increasing dosage and the course of the trip. Several of these serotonin
receptor subtypes have functionally opposing roles, notably the effects of 5-HT1A and 5-HT2C
receptor agonism on anxiety. As well as inducing a synaptic flood of serotonin, taking MDMA
indirectly induces the release of extra dopamine in the mesolimbic reward centres. Activation of the
serotonin 5-HT1B and 5-HT2A receptors leads to an increase in the vesicular release of dopamine.
Dopamine levels are also increased by reuptake inhibition. In addition, dopamine synthesis is
increased and turnover reduced. Increased synaptic availability of dopamine in turn inhibits
glutamate-evoked firing in the nucleus accumbens. Dopamine released in the shell of the nucleus
accumbens inhibits the firing of GABAergic medium spiny projection neurons. Inhibited excitability
of the spiny projection neurons in the rostral shell of the nucleus accumbens - whether it's mediated
by dopamine, glutamate antagonists or mu opioid agonists - is the neurological signature of
euphoric bliss, whatever its guise.

On MDMA, there's much more going on as well. MDMA induces the release of noradrenaline
(norepinephrine), and inhibits its reuptake. MDMA also triggers the enhanced release of
acetylcholine in the striatum and prefrontal cortex via serotonin 5-HT4 and dopamine D(1) receptor
mechanisms. Taking MDMA activates the poorly understood sigma(1) receptors, contributing to its
locomotor stimulant action. The role of MDMA in activation the cannabinoid CB1 receptors to
modulate its rewarding action is poorly understood. MDMA exerts (weak) binding to the alpha-2
adrenergic and histamine H1 receptors; this binding contributes in unknown degree to behavioural
stimulation. Activation of the noradrenaline system causes an acute elevation of blood pressure.
Additionally, taking MDMA increases plasma cortisol, prolactin, and dehydroepiandrosterone (DHEA)
and aldosterone secretion. MDMA use alters the expression of several proteins involved in GABA
transmission. To thicken the plot further, MDMA triggers the release of hypothalamic arginine-
vasopressin and oxytocin (the "cuddle hormone"). These hormonal changes may influence some of
MDMA's psychological effects. But the current consensus is that enhanced serotonin and dopamine
release are crucial to the magic, even though they don't explain it.

The serotonin system is uniquely complex. A whistlestop tour can't do it justice. The existence
of the serotonin molecule in Nature long predates the brain; serotonin is found in both the plant and
animal kingdoms. However, the effects exerted by a neurotransmitter on the post-synaptic
membrane aren't determined by the chemical itself, but rather by the structure of the post-synaptic
receptor subtypes to which it binds. Our serotonin-producing neurons belong to a phylogenetically
ancient neurotransmitter system. In the vertebrate CNS, serotonin-producing neurons regulate
aggression, impulse-control, mood, anxiety, cognition, temperature, appetite, circadian rhythms,
sexual activity, sleep, sensorimotor integration, sensitivity to pain, emotional resilience and
romantic love. Serotonin entering the axonal vesicles is released over time in response to action
potentials by exocytosis into the synaptic cleft, the narrow gap 10-20 nm across between pre- and
post-synaptic neurons. Seven distinct families of serotonin neuronal receptors have been isolated;
14 sub-populations of G-protein-coupled receptors and one family of ligand-gated ion channels (the
5-HT3 receptor) have been cloned. Distribution, density and regulation of the serotonin receptors
vary in different areas of the brain. So does both the affinity of serotonin for its different receptor
subtypes and the effects of serotonin agonists on second-messenger systems. Only a few hundred
thousand of the 100 billion or so neurons in the brain manufacture serotonin. The serotonergic cell
bodies are confined to the raphé area in the brainstem, but their projections extend to almost all
areas of the brain and spinal cord. Most notably for E-users, serotonergic projections innervate the
dopaminergic nigrostriatal and mesocorticolimbic circuits. The serotonin system has co-evolved with
dopaminergic projections in the course of primate evolution. Amongst many other roles, the
serotonin system helps to regulate a lifetime spent in complex social hierarchies where more ancient
fight-or-flight reactions have been offset by the need for an increasingly complex cognitive,
emotional and behavioural response. This unique signalling complexity of the serotonin pathways
and their multiple receptors ensures we can now be (un)happy in more ways than ever before.

The serotonin/5-hydroxytryptamine molecule itself is an indole amine synthesized from the

essential amino acid L-tryptophan through the intermediate 5-hydroxytryptophan. Although some
serotonin is present in the cytoplasm of serotonergic cell bodies and nerve terminals, most
serotonin in the axonal terminals is sequestered in small membrane-bound sacs, i.e. the synaptic
vesicles. This prevents the neurotransmitter from being metabolised by the enzyme MAO. Serotonin
is metabolised, mainly by MAO-type A, into the inactive metabolite 5-hydroxyindoleacetic acid (5-
HIAA). Numerous studies have shown self-destructive violence, aggression, poor impulse-control,
reduced social status, suicide, and some types of depression are associated with low concentrations
of cerebrospinal fluid 5-HIAA. Consequently, these conditions are often conceived as disorders of
"low serotonin function". Firing of the serotonin neurons causes exocytosis, a rapid calcium-
dependent process of neurotransmitter release. Depolarisation of the axon induces opening of
voltage-sensitive calcium channels; the resultant calcium influx causes synaptic vesicles to fuse with
the plasma membrane, where they empty their load of serotonin into the synaptic cleft. In the
synapse, serotonin exerts an action on both pre- and post-synaptic receptor sites. Extracellular
serotonin is then normally taken back up into the serotonergic neuron via the highly efficient
presynaptic transport pump. The structure of the transporter protein determines how it couples ion
gradients to substrate transport in ways that still need to be clarified.

Whatever the precise details, taking MDMA causes a remarkable role-reversal of normal
transporter function. The MDMA molecule binds with high affinity to the serotonin transporter and
enters the presynaptic axon terminal. Current theory suggests that MDMA causes serotonin release
via a diffusion exchange mechanism involving the serotonin transporter, not by calcium-dependent
exocytosis of the serotonin-containing secretory vesicles. MDMA taken up into the presynaptic
terminal unbinds from the uptake transporter, triggering a reconfiguration of the transporter so it
binds to serotonin inside the cytoplasm of the nerve terminal. The reconfigured transporter then
reverse-pumps the newly-bound intracellular serotonin out of the cell, changes configuration again,
dumps the serotonin into the extracellular space, and then takes up MDMA once more, repeating the
process of depletion rather than recycling the neurotransmitter.

The ensuing flood of serotonin in the user's synapses sets the MDMA magic rolling. The
neurotransmitter binds to multiple serotonin receptor subtypes. The subtypes play different
excitatory and inhibitory roles. So which receptor subtypes are of most long-term therapeutic and
social-recreational interest to a notional paradise-engineer? Like the proverbial drunkard who
searches for his lost keys only under a lamp-post "because that's where the light is", investigators
focus first on wherever they can probe most easily. The receptor-based account below will soon be
superseded by something deeper. But it probably at least offers clues to the full story.

Serotonin 5-HT1 agonists, sometimes termed serenics, show pronounced anti-aggressive

properties. Aggressive behaviour is modulated in by the 5-HT1B receptors in particular. The
presynaptic 5-HT1B terminal autoreceptors form a vital part of a feedback mechanism regulating
serotonin synthesis and release. Receptor knock-out mice lacking the 5-HT1B receptor are
superficially normal in appearance, feeding patterns and breeding behaviour; but they are ferocious,
and highly reactive. Such knockout mice are also unusually partial to alcohol and supersensitive to
the effects of cocaine, though these traits may reflect a compensatory enhancement of the
dopamine system rather than offer a direct pharmacological model of 5-HT1B receptor function. By
contrast, 5-HT1B receptor agonists such as the drug anpirtoline exert "serenic" effects. In "animal
models", 5-HT1B receptor agonists diminish alcohol-heightened aggression. Surprisingly, perhaps,
there is substantial evidence to indicate that some endogenous serotonergic pathways normally
activate rather than suppress motor output. Acute activation of 5-HT1B receptors is known to play a
role in MDMA-induced locomotor activity: 5-HT1B agonists and MDMA show cross-tolerance,
suggestive of a common mechanism of action. 5-HT1B antagonists restrain the hyperlocomotion
that rodents and clubbers typically undergo on serotonin-releasers like MDMA. Perhaps with this
crude behavioural measure in mind, some "unlicensed" psychonauts try combining a supposedly 5-
HT1B-selective agonist such as the piperazine derivative TFMPP [1(3-
trifluoromethylphenyl)piperazine monohydrochloride] with psychostimulants like 1-benzylpiperazine
(BZP, "A2", "Frenzy", "Nemesis", "Flying Angel", "Altitude", etc) to try and replicate the acute
effects of taking MDMA. The effect can indeed be E-like; but results are mixed. It is now known that
TFMPP binds at multiple serotonin receptors with only limited selectivity. Taken in the absence of a
dopaminergic psychostimulant, TFMPP does not feel akin to MDMA. Even combined with a
dopaminergic, TFMPP's activation of the 5-HT2C receptors makes some users feel anxious. The
MDMA effect is hard to emulate: MDMA is "a multifaceted jewel", not a cheap-and-cheerful
euphoriant.

Some 1-benzylpiperazine users report that low-dose BZP is itself mildly E-like. So-called Party
Pills, Social Tonics, Legal Party Drugs, Legal Herbal Highs and the like are marketed under
numerous brand names, commonly mixed with various amino acids, vitamins, herbs and other
agents designed to modulate the core BZP experience and minimise side-effects. Over 20 million
such tablets and capsules have reportedly been sold in New Zealand, currently the world leader in
BZP consumption and export. BZP use is now spreading world-wide. Consumption is mostly by
clubbers seeking a safer legal alternative to MDMA or amphetamines. BZP is relatively safe if used in
moderation. No fatality has yet been recorded from BZP use alone. Many BZP-based preparations
contain black pepper, a tribute not to BZP's wholesome natural origins (it's synthetic), but to
discourage thrill-seekers who might otherwise snort rather than swallow it. The Social Tonics
Association of New Zealand (STANZ) has developed a Code of Practice to encourage responsible
use. Inevitably, the FDA has now banned BZP on grounds of abuse potential. In 2002 the drug was
made Schedule 1 and its US users criminalised. Sale in the UK was banned in 2007. BZP was
originally (1944) synthesised, developed and manufactured by Wellcome as a potential anti-
parasitic. Many piperazine drugs tend to paralyse intestinal parasites, allowing unwanted fauna to
be flushed from the body. In the 1970s, BZP was investigated as an antidepressant. Used
experimentally, BZP proved effective in reversing melancholic/retarded/hypersomnolent depression.
The BZP analogue N-ben-zyl-piperazine-picolinyl fumarate was even briefly marketed in Hungary
under the brand name Trelibet as an antidepressant, though no clinical trials have been conducted
into its long-term efficacy. Development was halted after BZP was discovered to have
amphetamine-like properties. Amphetamine, methamphetamine and BZP alike do indeed release
dopamine from non-vesicular pools; and the subjective effects of high-dose BZP cross-generalise to
amphetamines in drug discrimination studies. However, the subjective effects of BZP are more
subtle than crude speed; BZP promotes the release and (to a lesser degree) inhibits the reuptake of
the monoamine neurotransmitters dopamine, noradrenaline and serotonin with different relative
potencies. BZP also acts as a relatively non-selective serotonin agonist. The affinity of BZP for the
serotonin 5-HT2A receptor is quite low, so psychedelic effects are comparatively minor at sensible
doses. Taking BZP doesn't give rise to the inner serenity, emotional release or extraordinarily
empathetic compassion of MDMA; but nor is BZP a classic dopaminergic power-drug like
amphetamine. Moderate behavioural activation, sensory enhancement and a low-key euphoria are
typical. Dry mouth, appetite suppression and insomnia are common adverse side-effects. Unlike,
say, cocaine, BZP use tends to be self-limiting, a critical advantage for a recreational drug. Yet
subjects who hope to replicate the full richness of the MDMA experience will be disappointed.
 There are further subtleties in the way of replicating MDMA's acute effects; and even more
obstacles to sustaining the magic indefinitely. The serotonergic system has both 5-HT1B
autoreceptors and post-synaptic 5-HT1B heteroreceptors; they play different functional roles. 5-
HT1B receptors acting as autoreceptors regulate serotonin release via inhibitory feedback at the
presynaptic terminals of serotonergic neurons; turnover and release of serotonin are typically
increased under conditions of acute stress. 5-HT1B heteroreceptors are located on the terminals of
nonserotonergic neurons. Thus 5-HT1B heteroreceptors regulate the release of other
neurotransmitters. A single serotonin neuron can modulate different brain functions and multiple
cellular targets in virtue of the thousands of non-synaptic varicosities on its axonal branches that
project to multiple areas and neurotransmitter systems. 5-HT1B receptors within the ventral
tegmental areas (VTA), for instance, function as heteroreceptors to inhibit GABA release. Since the
GABA terminals in the VTA and substantia nigra exert a tonic inhibitory influence on dopamine
function, inhibition of GABA by inhibitory 5-HT1B heteroreceptors leads to the disinhibition of
dopamine activity. Thus agents acting directly or indirectly as 5-HT1B agonists can cause the
release of dopamine in the striatum and nucleus accumbens. Indirectly again, dopamine release is
also regulated by 5-HT1B heteroreceptors within the glutamatergic hippocampo-accumbens
pathways. Regulation of 5-HT1B receptor function itself is under the control of 5-HT-moduline, an
endogenous tetrapeptide that controls 5-HT1B receptor efficacy. 5-HT-moduline is a so-called
allosteric modulator. Allosteric modulators bind to a different binding site from the natural agonist
and can, potentially, circumvent the development of tolerance. 5-HT-moduline is released from
adrenal medulla in response to acute stress. 5-HT-moduline plays a pivotal role in synchronising the
serotonergic signalling activity of the different terminals of individual neurons, coordinating their
effects on a variety of different cerebral functions. Rationally designed synthetic drugs that
recognize the 5-HT-moduline binding-site on the 5-HT1B receptors, and act on the 5-HT1B
receptors as allosteric modulators themselves, may potentially exert long-term serenic, anxiolytic
and mood-brightening effects by increasing serotonin release.

In general, however, care must be taken in describing serotonin 5-HT1 agonists as "serenics",
even if such agents induce a syndrome outwardly suggestive of inner tranquillity. The demeanour
that an animal exhibits after "serenic" administration may indeed be submissive, passive and timid -
in contrast to the fierce, assertive and aggressive behaviour of 5-HT1B knockouts. Yet "serenity"
tends to connote an inner E-like peace that may be lacking - and not just in the unfortunate
laboratory rodent. In fact some so-called "serenics" may enhance fear/anxiety reactions: it's only
their use in combination with dopamine-releasing euphoriants that makes such agents especially
interesting to the psychonaut. Indeed supersensitive 5-HT1B autoreceptors are implicated in
depression and obsessive compulsive disorder. By introducing extra copies of the gene for 5-HT1B
receptors into serotonin neurons, researchers can breed passive and depressive rats that show signs
of abject misery [i.e. "learned helplessness" and "behavioural despair"]. The syndrome of learned
helplessness is associated with excess production of 5-HT1B receptors that are churned out in
greater profusion by the depressive brain. This isn't to deny that 5-HT1B agonists may have
therapeutic potential, whether in bipolar disorder, autism, alcoholism or disorders of impulse-control
and aggression. Thus the triptans, serotonin 5-HT1B/1D receptor agonists, are clinically effective for
treating migraines; they can also curb aggression. But 5-HT1B antagonists and inverse agonists
such as SB-236057-A are under investigation for possible clinical use as long-term and relatively
fast-acting antidepressants. Acute 5-HT1B autoreceptor blockade can increase serotonin release.
Cognitive function is affected by their use too. Whereas 5-HT1B agonists may adversely affect
memory via inhibition of acetylcholine release in the hippocampus, antagonists and inverse agonists
of the 5-HT1B receptor can improve the consolidation of learning. This simplified outline of the
neurobehavioural role of a single family of serotonin receptor subtype illustrates how inducing
lifelong E-like states - as distinct from "mere" raw bliss - is going to pose a formidable technical
challenge. In this case, the possible existence of multiple subpopulations of 5-HT1B autoreceptors
and heteroreceptors makes inadequate selectivity of ligands even more of a problem, especially for
seekers of precision-tools rather than chemical coshes.
 Whereas serotonin 5-HT1B receptor knockout animals are aggressive by nature, 5-HT1A
knockouts are timid, anxiety-ridden creatures. Whereas serotonin 5-HT1B receptors are found
mainly on terminal processes, 5-HT1A receptors are located solely on serotonergic nerve cell bodies
within the dorsal raphé nucleus. Intriguingly, 5-HT1A receptor density is reported to be inversely
correlated with susceptibility to spiritual experience, opening up the possibility of genetically
amplifying our capacity for spirituality beyond anything humanly accessible today: it may be
premature to assume that our descendants will be secular rationalists. Density of the 5-HT1A
autoreceptors is also inversely correlated with the reactivity of the amygdala to threatening stimuli.
However, the role of the 5-HT1A receptors in MDMA's acute subjective effects still isn't clear.
Pretreatment with a serotonin (5-HT1A) receptor antagonist apparently reduces MDMA's pro-social
effect, in rats at least. Taken over a prolonged period, selective 5-HT1A receptor agonists typically
exert a delayed-onset anxiolytic as well as (sometimes) a mood-brightening activity. Their (modest)
therapeutic efficacy relies on an adaptive neuronal response. Acute activation of the presynaptic 5-
HT1A receptor on the raphé nuclei tends to reduce both the rate of firing of serotonin neurons and
the corresponding release of serotonin from the nerve terminals; chronic activation causes the
receptors to desensitise, leading serotonergic neuronal activity to rebound. Clinically, buspirone
(Buspar), a 5-HT1A partial agonist, is licensed for generalised anxiety disorder. Similar agents like
gepirone (Ariza), flesinoxan, tandospirone and ipsapirone are under investigation. Alas taking them
doesn't remotely engender the extraordinary sense of inner peace induced by MDMA. In rats at
least, 5-HT1A agonists facilitate male sexual behaviour, hypotension, increased food intake and
produce hypothermia, none of which are prominent sequelae of MDMA use. In general, 5-HT1A
agonists are well tolerated. But they may also on occasion induce dizziness, nausea, and headaches,
probably linked to their postsynaptic receptor action rather than presynaptic anxiolytic effect.
Buspirone itself is also a dopamine D2 antagonist, albeit a weak one. This may explain why it's
never been wildly popular with patients. It's also very slow to work. Gepirone, on the other hand,
allegedly lacks significant activity at the dopamine D2 receptors. Gepirone acts as an agonist at the
presynaptic 5-HT1A receptors and a partial agonist at the post-synaptic 5-HT1A receptors.
Hopefully, gepirone will prove a clinically useful anxiolytic and antidepressant. However, though 5-
HT1A antagonists reduce discrimination of MDMA in animal models, the role of 5-HT1A receptor
activation in MDMA's effects needs elucidation via more first-person experimental studies.

Recent research from Sydney University neuropharmacologist Iain McGregor suggests that
post-synaptic serotonin 5-HT1A receptors contribute to MDMA's acute pro-social action via the
enhanced release of oxytocin. Oxytocin in turn reduces activity and weakens connections in the
fear-processing circuitry of the amygdala. MDMA activates post-synaptic 5-HT1A receptors of the
paraventricular nucleus and supraoptic nucleus of the hypothalamus. The paraventricular nucleus
and supraoptic nucleus contain oxytocin neurons. Oxytocin is a nine amino-acid peptide hormone
and neurotransmitter that promotes pair-bonding, trust and social recognition. Commercially,
oxytocin is marketed by Verolabs as a spray: so-called trust-in-a-bottle: "Liquid Trust Spray - the
first Oxytocin product, formulated to enhance people's trust in you!"[sic]. In future, MDMA
analogues may conceivably be marketed with similar restraint. MDMA typically causes its users to
trust each other to an exceptional degree, confiding intimate personal feelings and secrets they
would never otherwise share. Such drug-induced intimacy may partly be mediated by an increased
release of oxytocin via MDMA-activated 5-HT1A receptors. Co-administration of MDMA and an
oxytocin antagonist would test this hypothesis in humans. There are methodological problems with
the use of rats as test subjects in this context; but the evidence is suggestive.

The MDMA molecule, especially the dextrorotatory "+" isomer, has only a low affinity for the
serotonin 5-HT2 receptor. This is why taking the drug within the normal dose-range typically
induces only minor perceptual changes. If prompted, many Ecstasy users report altered time
perception, but any visual distortions are usually mild: the N-methyl group of the MDMA molecule
prevents it from fitting as comfortably into the 5-HT2A receptor as does the trippier (-)-MDA
enantiomer of its structural parent. Experiments with human as well as non-human animals show a
correlation between a drug's psychedelic potency and 5-HT2A receptor binding affinity. Activation of
the 5-HT2A receptors is a prerequisite of the "classic" hallucinogenic effects exerted by tryptamine
psychedelics such as LSD and phenethylamine psychedelics like DOM. Conversely, 5-HT2A receptor
inverse agonists act as antipsychotics. Despite the low affinity of MDMA for the 5-HT2 receptor,
pharmacological blockade or genetic knock-out of the 5-HT2B receptor abolishes MDMA-induced
hyperlocomotion and serotonin release in the nucleus accumbens and ventral tegmental area of the
brain.

None of this neurobabble should disguise the fact that psychedelia is still scientifically
uncharted. It's often too weirdly exotic for words. Materialistic neuroscience has failed to close the
ontological gulf between neural porridge and consciousness - whether "ordinary" or "altered" states.
Some psychonauts, understandably enough, feel the neurobabblers have lost the plot. Most of
today's storytelling about altered states and the chemistry of mind will doubtless seem no less
archaic to our descendants than the Greek humoral psychology of classical antiquity strikes the
contemporary molecular biologist. Yet fortunately for the engineering purposes of inducing
sustainable E-like bliss, we need manufacture only the sufficient neural conditions for beautiful
states of consciousness. We don't need a deep understanding of how and why consciousness is
generated (or alternatively, some philosophers allege, its fundamental immanence in the world). We
can guess even less about the possible altered states of consciousness of our redesigned
successors. We don't know whether the "explanatory gap" between the physical facts and
phenomenal mind can ever be closed. But either way, our emotionally invincible descendants should
be able to explore entheogens, and map out even the most outlandish reaches of psychedelia, in
safety. Unlike us, our genetically enriched descendants may revel in the assurance that bad trips
are inconceivable, and psychological damage is impossible. This is because their obnoxious
molecular substrates will have been edited out.

Alas our own less robust minds are psychologically vulnerable to even "physically" harmless
psychedelics that aren't also euphoriants. Dual-action dopamine- and serotonin-releasers like MDMA
are the latter, though they aren't always harmless. With MDMA, as with so many psychoactive
drugs, very often "less is more". This piety is easy to intone but hard to practise, especially when
taking fast-onset euphoriants. The lucidity of the entactogenic effect of MDMA may be especially
pronounced at low-to-moderate dosages. "Optimal" dosage of psychotropic agents taken for "non-
approved" purposes is most often empirically determined by the user investigating what level
induces maximal enjoyment. Yet the effects of lower, "sub-optimal" dosages that more subtly
modulate consciousness may be of greater value for facilitating personal growth. Low-to-moderate
dosage E-experience may be easier to integrate into the rest of one's E-less life. Nonetheless at
higher, quite possibly neurotoxic doses of 200mg or so, MDMA can itself sometimes deliver
psychedelic euphoria, entheogenic rapture, and some very interesting exotica indeed. Alas the
unique effects of such doses [and likewise higher doses of other stellar phenethylamines] cannot
safely be investigated in depth until the neurotoxicity of MDMA's metabolites and/or toxic free
radicals can be prevented.

In the meantime, if the user desires a completely clear sensorium, then perceptual alterations
might seem eliminable altogether, in principle, by taking only the (+)-MDMA enantiomer rather than
the standard racemate. Sadly, pure (+)-MDMA is scarce; it's also hard to prepare at home. Thus
one unintended consequence of scheduling MDMA has been to widen youthful exposure to
psychedelia, albeit psychedelia in its warmest and most gentle introductory guise. (-)-MDMA at
normal doses is only minimally active at the "psychedelic" 5-HT2A receptor owing to its
(comparatively) bulky methyl group. By contrast, MDA (which lacks it) is an all-in-one cocktail that
can be hallucinogenic as well as empathetic and slightly speedy.
 Alternatively, if uncomplicated perceptual clarity is sought then a 5-HT2 antagonist such as
ketanserin or the 5-HT2A selective MDL-11939 might help preserve total lucidity. 5-HT2A
antagonists have the additional advantage of preventing MDMA-induced hyperthermia that
exacerbates toxicity. Neurotoxic hydroxyl radical formation is temperature-mediated; conversely,
hypothermia-inducing agents enhance neuroprotection.

However, there are complications. Stimulation of the serotonin 5-HT2A receptors contributes
to the rewarding effects of MDMA, or at least plays a permissive role in dopamine release. So trying
to eliminate perceptual alterations completely while retaining the full-blooded E-magic may be
difficult. MDMA is often reckoned a "serotonergic" drug. Compared to amphetamine this is true:
MDMA's affinity for the serotonin transporter is greater, and its ratio of serotonin to dopamine
release is higher, than amphetamine. Even MDMA's extra release of dopamine partly depends on its
activation of the 5-HT2A receptors. But serotonin-releasing agents [e.g. the halogenated
amphetamine appetite-suppressant fenfluramine (Pondimin)], taken on their own, aren't notably
rewarding or entactogenic/empathetic, at least at ordinary dosages. The enhanced release and
reuptake inhibition of dopamine is essential to MDMA's tendency to promote blissful well-being and
to colour its entactogenic-empathetic effect.

Convergent strands of evidence indicate that dopamine release is critical to the MDMA magic.
Dopaminergic activity in the brain and motor behaviour may be crudely interpreted as under the
inhibitory control of the serotonin system. Yet the multiple serotonin pathways play functionally
different roles. According to one hypothesis, the extra serotonin released by MDMA stimulates 5-
HT2A receptors located on inhibitory gamma-aminobutyric acid (GABA) striatonigral neurons. VTA
dopaminergic neurons in the brain's reward centres are under continuous inhibition by GABA.
Stimulation of the 5-HT2A receptors inhibits these GABA neurons, thereby allowing the disinhibition
of dopamine biosynthesis. Post-E levels of dopamine in the mesolimbic reward circuitry are far
higher than would be explained by MDMA's relatively weak additional release of dopamine via the
uptake carrier.

Animal drug discrimination studies, and the human behavioural evidence, tend to support this
dopaminergic account. Although some MDMA users prefer reflective tranquillity and intimate group
hug-ins, many loved-up clubbers opt to dance for hours at raves - a form of hyperlocomotion one
would expect from Peruvian marching-powder rather than a serotonergic agent.

However, this account is still simplistic. The release of serotonin following an MDMA-induced
reversal of the reuptake pump results in a stimulation of the 5-HT1B receptors and, at higher doses,
increasingly of the 5-HT2A receptors as well. Such receptor stimulation can trigger marked
hyperactivity, especially in young MDMA users who rave. At lower doses, MDMA-induced locomotor
activity is caused mainly by the released serotonin's preferential activation of the 5-HT1B receptor.
This is because serotonin has a somewhat higher affinity for the 5-HT1 receptors than the 5-HT2
receptors. The greater flood of serotonin in the synapses triggered by higher doses of MDMA
promotes locomotor activity via 5-HT2A receptor-mediated dopamine stimulation as well. To
complicate matters, MDMA may itself bind, albeit weakly, to the 5-HT2A receptor. A further
complicating factor is that MDMA-induced release of serotonin stimulates the 5-HT2C receptors.
Activation of the 5-HT2C receptors serves to mask expression of MDMA-induced hyperactivity,
sometimes evidently more effectively than others. The various subpopulations of 5-HT2C receptor
located on GABAergic neurons in the ventral tegmental area and the substantia nigra tend to exert a
tonic inhibitory influence over the mesolimbic dopamine system. Thus 5-HT2C receptors tonically
inhibit dopamine release in the nucleus accumbens, mostly it seems in virtue of their constitutive
activity i.e. entering the activated receptor state in the absence of an agonist. Other things being
equal, activation of 5-HT2C receptors is anxiogenic, demotivating and generally unpleasant.
Certainly the stimulant effects of MDMA are greatly enhanced following treatment with a 5-HT2C
antagonist. Sustained antagonism of the 5-HT2C receptors might well we harnessed to intensify the
hedonic properties of long-lasting E-like consciousness. Less speculatively, 5-HT2C antagonists such
as agomelatine (Valdoxan) are under investigation as potential clinical antidepressants.

As usual, there are complications: all 5-HT2C receptors are not the same. Numerous 5-HT2C
receptor isoforms are produced as a result of RNA editing, and their individual roles in modulating
the MDMA effect aren't properly understood. In general, the receptor story illustrates at the
molecular level that being blissful isn't the same as being blissed out. To sustain empathetic love,
simply banishing all capacity for social anxiety isn't going to work. Specific and selective 5-HT2C
receptor antagonism may well prove a worthwhile goal; but it's too early to say what the MDMA
experience may gain or lose in consequence, whether socially or subjectively. Empathy entails
caring about others, not lacking a care in the world. Thus the MDMA-induced disinhibition from
social anxiety, and the lowering of psychological defensive barriers, is radically distinct from the sort
of anxiolysis induced by SSRIs or the benzodiazepines - or indeed by alcohol or opiates. With none
of these drugs or drug categories is a reduction in the user's social anxiety matched by an E-like
upwelling of empathy or sensitivity to the feelings of others - in fact quite the reverse. There are
subtleties of the MDMA experience that haven't yet been explored.

If acute serotonin-mediated enhanced dopamine-release is indeed essential to the magic of

MDMA, then a wide range of safe long-acting dopaminergics are already on offer to augment any
hypothetical subtype-selective "serotonergic" therapies. Compared to our descendants, we're
probably all anhedonic. So some form of dopaminergic augmentation is a therapeutic step in the
right direction. "Dual-deficit" models of everyday E-less malaise are plausible; and they naturally
invite dual-action remedies. Clearly, inhibition of glutamate-evoked firing in the nucleus accumbens
is an ingredient of the E-magic: it is known that firing-inhibition depends on both dopamine and
serotonin release; and this process is mediated by both dopamine and serotonin receptors. But
beyond these superficial generalities, working out how to replicate sustainably at the molecular level
the precise neurochemical signature of peak experiences will be hard. Until the dawning of the era
of wholesale genomic rewrites and true designer babies, using a cocktail of subtype selective
serotonin agonists and gentle dopaminergic psychostimulants still looks like the easiest way to
mimic and enhance the entactogenic-empathogenic effect induced by MDMA-like compounds.
However, there are many pitfalls in choosing the right dopaminergic for the job.

In contrast with intracranial electrical stimulation, a direct chemical assault on the hedonic
treadmill rarely works. This failure is witnessed by the unsatisfying and usually counterproductive
effects of using catecholamine-depleting psychostimulants. Darwinian-era mood and motivation is
regulated via a multitude of indirect mechanisms of feedback-inhibition. So it's worth reviewing how
and why the substrates of human well-being are held in check; and what can be done about it. First,
an unavoidably fast-and-furious tour of the dopamine system is in order. The CNS has three main
dopaminergic pathways. They regulate movement, hormonal secretion, and emotion. Each projects
from dopaminergic cell groups in the midbrain. 1) The nigrostriatal pathways extend from the
substantia nigra pars compacta to the striatum. This pathway is critical to the control of involuntary
motor movement; its dysfunction is implicated in the tremor, rigidity and akinesia of the "dopamine
deficiency disorder" Parkinson's disease, and several other neuropsychiatric disorders such as
Tourette's Syndrome. 2) The tuberoinfundibular system extends from the hypothalamus to the
pituitary gland. It's involved in prolactin- and growth hormone-secretion, and the regulation of
lactation and fertility. 3) The mesocorticolimbic pathway extends from the ventral tegmental area to
the nucleus accumbens and the medial prefrontal cortex. The mesocorticolimbic system is central to
emotion, motivation, willed action and, more subtly, the modulation of thought-processes. In crude
terms again, dopamine is critical to sensorimotor integration; appetitive behaviour of all kinds; the
capacity to switch from one course of behaviour to another; and the orchestration and activation of
the motor output system. Dopamine has also traditionally been described as the brain's "pleasure
chemical", cueing potentially (Darwinian) fitness-enhancing stimuli so they can acquire control over
an organism's behaviour. Certainly, consistent with the dopamine theory of reward, electrically or
pharmacologically stimulating microcircuits in the rostromedial shell of the nucleus accumbens
produces intense pleasure in the absence of any goal-seeking behaviour. But this formulation can be
misleading. The mesolimbic dopamine system mediates "wanting" more than "liking"; and its drug-
induced or electrical stimulation may increase incentive-salience rather than the raw intensity of
pleasure itself. Dopaminergic neurotransmission is critical to incentive-motivation and all forms of
purposeful behaviour. Dopamine levels tend to rise if one is anticipating a rewarding event; and
levels then tend to fall if the anticipated reward fails to materialise. Couched in the language of
psychology rather than neuroscience, enhanced dopamine release in the pleasure centres imparts a
sense of urgency, significance and a feeling of things-to-be-done. The molecular substrates of pure
pleasure are still elusive.

At the cellular level, the dopamine system doesn't quite rival the molecular, pharmacological
and functional diversity of the serotonin system; but the two "classic" types of dopamine receptor
(D1-like and D2-like receptors) have several subtypes and alternate splice-forms. Further, the
number of different messenger RNA and dopamine binding sites substantially exceeds the five
dopamine receptor genes of the human genome, a diversity that reflects the genetic polymorphism
and alternative splicing events in normal dopamine gene-expression. However, each type of
dopamine receptor belongs to the superfamily of G-protein-coupled receptors that activates or
inhibits different forms of adenylyl cyclase inside the cell. Intriguingly, the presence or absence of
variant alleles of dopamine receptor subtypes and their signal-transduction mechanisms is
correlated with variants of human behaviour and personality. For example, individuals with
genotypes containing the seven-repeat allele of the dopamine D4 16-amino acid repeat
polymorphism tend to exhibit the personality trait of "novelty-seeking". This trait is characterised by
a tendency to impulsiveness, risk-taking, exploration, excitability, and an optimistic mood, though
alas not a loving, E-like temperament. For better or worse, within a few decades prospective
parents will be able to select such alleles and their rationally redesigned enhancements when
choosing the parameters of their future offspring. Such naturally loved-up kids may prove more
easily adorable than today's Darwinian default-models.

Like the other catecholamine neurotransmitters, dopamine itself is synthesised from the non-
essential amino acid L-tyrosine. L-tyrosine is transported across the blood-brain barrier into the
dopaminergic nerve cell. L-tyrosine is converted to L-dopa by the enzyme tyrosine hydroxylase. L-
dopa is then rapidly converted to dopamine by L-amino acid decarboxylase. Next dopamine is
sequestered in synaptic vesicles by a dopamine transporter. At the synapse, the dopamine nerve
terminal displays high-affinity uptake sites. They rapidly terminate the action of the
neurotransmitter on the receptors if it isn't metabolised by the MAO or COMT enzymes. Depending
on concentration gradient, the dopamine carrier can transport dopamine back into the nerve cell,
recycling it as normal, or alternatively, after a user has taken a classic amphetamine, the carrier
can transport dopamine from the cell terminals into the synaptic cleft. In common with
amphetamine, MDMA inhibits the neuronal reuptake of dopamine, albeit more weakly than MDA.
Further, increased post-E administration activity of the serotonin 5-HT1B and 5-HT2A receptors
causes the dopaminergic neurons themselves to fire more rapidly. This higher impulse-frequency
causes increased dopamine-release via exocytosis of the dopamine-containing vesicles in the normal
manner.

So what leaves so many "normal" Darwinian people - who are neither clinically depressed nor
loved-up on MDMA - comparatively anhedonic and hypodopaminergic? The dopamine
neurotransmitter is under powerful homeostatic control. So is the density and signal-transduction
efficiency of the receptors to which it binds. Feedback-inhibition of dopamine synthesis, dopamine
release and spontaneous action-potential generation in dopamine-producing cells is modulated by a
variety of functionally distinct dopamine autoreceptors that regulate membrane excitability. The
dopamine neurotransmitter itself functions as an end-product inhibitor of tyrosine hydroxylase, the
rate-limiting step in dopamine production. Dopamine plays this role by competing with a
tetrahydrobiopterin co-factor for a binding site on the enzyme. Dopamine synthesis is also
modulated by the rate of impulse-flow from the nigrostriatal pathway. In addition, presynaptic
dopamine receptors modulate the rate of tyrosine hydroxylation; and most mesolimbic dopamine
neurons possess cholecystokinin-autoreceptors and neurotensin-autoreceptors that regulate
dopamine function as well. Indeed activity of the mesocorticolimbic dopamine system is regulated
by multiple neuronal pathways containing different neurotransmitters, notably serotonin, opioids,
GABA and glutamate. Precisely what dopamine actually does in the all-important dopamine-
sensitive shell of the nucleus accumbens is unclear. The main effect of its release seems to be the
inhibition of the GABAergic medium spiny projection neurons (MSNs). These neurons come in two
types. One subtype expresses dopamine D2 receptors and enkephalin. This sort of GABAergic
medium spiny cell projects from the nucleus accumbens to the ventral pallidum. It is activated by
"reward stimulation" of the ventral tegmental area. The other subtype of GABAergic medium spiny
projection neuron co-expresses substance P, dynorphin and dopamine D1 receptors. This subtype
projects directly back to the ventral tegmental area. It regulates motivation and pleasure, or our
deficit thereof.

So how can this cruel and complex web of inhibitory feedback mechanisms best be modified?
If our aim were pure-and-simple cloud nine euphoria, then better drugs to decrease glutamate and
GABA currents in the critical medium spiny neurons of the nucleus accumbens might be adequate -
at least until new genes and gene networks can be more readily inserted in the genome, and the
regulation of old ones improved. But well-controlled, high-functioning euphoria is more elusive than
mind-blowing rapture. Crude "natural" interventions to enrich dopamine function aren't effective.
For instance, some psychonauts, clubbers and alternative therapists alike have explored taking free-
form amino acid supplements of L-tyrosine and L-phenylalanine in a bid to boost native dopamine
levels or reanimate a drug-frazzled brain. But tyrosine hydroxylase is normally saturated. So unlike
tryptophan-loading and/or 5-HTP-loading to increase neural levels of serotonin production, this
"dopaminergic" precursor strategy typically doesn't work. On the other hand, taking L-dopa does
increase synaptic dopamine levels. This is especially so when L-dopa is combined (as in Sinemet for
Parkinsonians) with a peripheral decarboxylase inhibitor such as carbidopa to prevent its
metabolism outside the brain, At least for a minority of "normal" subjects, taking L-dopa can be an
effective motivator, libido-enhancer and mood-brightener. In a more controlled setting, rodents
engineered so they can't synthesize dopamine initially develop quite normally, only to die miserably
a few weeks after birth following a failure to eat, drink or do very much in this world at all. Yet when
such dopamine knock-out mice are abundantly maintained on L-dopa, they can flourish. Indeed L-
dopa-maintained dopamine knock-out mice become hyperactive and sexually vigorous. This
manipulation has not yet been attempted in dopamine knock-out humans. Augmentation should in
any case be tried only cautiously and in controlled-release preparations (e.g. Sinemet SR) since
high levels of L-dopa may increase oxidative stress. Whatever the mechanism, simply increasing
raw dopamine levels per se is not enough. For instance, an agent such as alpha-methylparatyrosine
that inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, might be
expected to produce a state of melancholic depression; but in non-depressives it doesn't reliably do
so. This complicates any simplistic catecholamine-depletion theory of retarded depression.
Nevertheless, dopamine-releasing agents demonstrably tend to induce euphoria. By contrast,
dopamine receptor antagonists like haloperidol are dulling and dysphoric. All the classical dopamine
D2-blocking neuroleptics blunt will-power and flatten emotion. Administering dopamine D2-blockers
tends to induce apathy and anhedonia, and ruins the MDMA magic. Nasty but instructive, such
magic-prevention experiments are an important pointer to what's needed to sustain the MDMA
spectrum of consciousness. It's known that stimulation of the dopamine D2-like receptor causes an
increase in phosphatidylinositol hydrolysis by activating enzyme phospholipase C. Enhanced
phosphatidylinositol hydrolysis is implicated in euphoric mania. Conversely, the lithium used to treat
"uncontrolled" euphoria inhibits the phosphatidylinositol second messenger system and darkens
mood in nondepressed "euthymic" people. Understanding the principles behind the pharmacological
induction of controllable non-stop euphoria will be a first step on the route to designing lifelong
variations of the subtler forms of magic.

In the meantime, dopamine antagonists like amisulpride (Solian) can be used at low doses
preferentially to antagonise the synthesis-, release- and impulse-modulating presynaptic dopamine
D2/D3 autoreceptors. Thus a regimen of low-dose amisulpride may potentially enhance dopamine
release and boost mood and motivation, whereas many dopamine reuptake inhibitors [e.g.
vanoxerine, bupropion, nomifensine] "adaptively" diminish the neuronal release of dopamine over
time, even though their action on reuptake inhibition increases the neurotransmitter's synaptic
availability. Unfortunately, pre-treatment with high doses of dopamine reuptake inhibitors blunts
MDMA-induced release of dopamine, though not to the same degree as SSRIs blunt MDMA-induced
release of serotonin. Other crude strategies to augment dopamine function involve taking
dopaminergic agents such as the dopamine agonists pergolide (Permax) and bromocriptine
(Parlodel); the potent, pro-sexual, long-acting D2 agonist cabergoline (Dostinex); selective D2/D3
agonists such as pramipexole (Mirapex) or ropinirole (Requip); catechol-o-methyltransferase
(COMT) inhibitors such as tolcapone (Tasmar); selective MAO-B inhibitors such as selegiline
(Eldepryl) or rasagiline (Azilect); adenosine 2A receptor antagonists; and centrally active nicotinic
receptor agonists. Oral, centrally-active dopaminergic "pro-drugs" with higher bioavailability and
fewer adverse side-effects are also under investigation. But there are obvious problems. For
instance, dopamine-release promoting agents, if fast-acting and taken in the absence of anything
subtype selectively "serotonergic", may not induce serenely motivated well-being as distinct from
compulsive pleasure-seeking, thought disturbances or manic excitement. Any tendency to cause
uncontrolled dose-escalation is likely to cause toxicity, florid psychoses and abuse. Regrettably,
these worries about the "abuse-potential" of psychostimulants frequently generalise in mainstream
wisdom to an unwarranted fear of all "dopaminergic" antidepressants/mood-brighteners.

This taboo against "excessive" well-being can have serious medical consequences. Even
victims of melancholic or retarded depression are widely denied access to clinically effective
catecholaminergic antidepressants. This is one reason why so many remain depressed or "partial
responders"; another is opiophobia. MDMA itself rapidly banishes all kinds of depression, albeit not
for long. In spite of its relatively powerful indirect dopaminergic activity, MDMA is sometimes
likened in the media to the much more commonly prescribed selective serotonin reuptake inhibitors;
fluoxetine (Prozac) was the first and most famous SSRI. In reality there are profound differences
between MDMA, the SSRIs and other "serotonergic" antidepressants. Like an SSRI, MDMA occupies
the serotonin transporter and prevents serotonin from binding, increasing its availability in the
synapse. However, MDMA is small enough to be taken up by the serotonin reuptake transporter into
the serotonergic cell. The serotonin transporter pulls the MDMA molecule up into the axon, where its
release from the transporter allows the transporter to bind to intracellular cytoplasmic serotonin,
which it releases into the synapse before taking back more MDMA into the terminal. Quite aside
from their different molecular mechanisms of action, however, there are striking differences in
subjective effect between MDMA and "serotonergic" centrally active psychiatric medicines. Clinically-
licensed SSRIs [fluoxetine/Prozac; sertraline/Zoloft; fluvoxamine/Luvox; paroxetine/Paxil; and
citalopram/Celexa] may make a small minority of people feel durably "better than well". More
typically, SSRIs are mood-blunters and even, for some people, psychic anaesthetisers. SSRIs
commonly make those who take them more resilient and less anxious. But they don't promote
depth of feeling, intellectual dynamism or clarity of thought. SSRIs can also diminish the intensity of
love. MDMA, by contrast, is a veritable love-potion, what Claudio Naranjo aptly christened a "feeling
intensifier". On MDMA, emotions are heightened as well as enriched. Compared to loved-up
ecstatics on MDMA, the rest of us have the emotional intensity of zombies; and zombies have no
real insight into what they're lacking, even if some of us can talk as though we do. Ironically, at a
time when the loss of personal liberty entailed by prohibitionist drug laws is justified by the societal
costs of illicit drug-taking, "psychiatric" drugs are clinically prescribed by physicians regardless of
the likely effect of a medication on the personal relationships of the patient. SSRIs, by enhancing
the user's emotional self-sufficiency, can either save marital relationships or wreck them. By
reducing "neediness", SSRIs also diminish what today passes for love. SSRIs are prone to impair
romantic ardour as well as libido. One technical (and ideological) challenge of the pharmacogenomic
revolution in prospect at the interface between genetics and drug-design will be to investigate how
the emotional honesty and extraordinary depth of feeling induced by MDMA can be sustained over a
period of months, years and decades rather than for two-hour bursts.

There are further complications to overcome if any bid to replicate and sustain full-spectrum
E-like consciousness is to succeed. MDMA triggers the release of the neurotransmitter acetylcholine
via a histaminergic H1 mechanism. MDMA is also a weak agonist of the acetylcholine muscarinic M1
receptors. MDMA's modest cholinergic activity may contribute to the exquisite lucidity of
consciousness characteristic of pure MDMA taken in a therapeutic setting. For the cholinergic system
is vital to memory, higher thought-processes and verbal fluency. Cholinergics such as piracetam
(Nootropil) are used as nootropics or "smart drugs"; and acetylcholinesterase inhibitors like
galantamine (Reminyl), rivastigmine (Exelon), tacrine (Cognex) and donepezil (Aricept) are used as
palliative treatments of Alzheimer's disease. Acetylcholine-release and muscarinic receptor
activation probably play no direct role in the rewarding hedonic effects of MDMA. Yet their subtle
contribution to the texture of the magic can't be discounted. "Dumb-drug" antimuscarinic agents
commonly induce mild euphoria via their indirect enhancement of dopamine function. Their mood-
brightening effect stands in contrast to many cholinergic (e.g. muscarinic M4 receptor) agonists and
cholinesterase inhibitors which have a tendency to subdue mood. A wide range of cholinergics is
now under development for the palliative treatment of Alzheimer's disease, a progressive
neurodegenerative disorder characterised by profound cholinergic deficits. Some depressives,
however, may actually benefit from the antimuscarinic anticholinergic effects that more intellectually
fastidious clinicians would call an adverse side-effect of the older tricyclics. While a great many
depressed people report intellectual sluggishness and poverty of thought, other melancholic and
introspective depressives endure "hypercholinergic frenzy", possibly owing to dysregulation of the
cholinergic-adrenergic axis. Sadly, innumerable depressives among life's walking wounded today
find the examined life scarcely worth living: they cope with life only by "just getting on with it". By
contrast, MDMA allows introspection to become insightful and enjoyable even to the naturally angst-
ridden. On MDMA, both philosophising and emotional self-honesty can be illuminating and fun. It's a
shame that such self-insight can't more readily be prolonged.

Another enigma is the role of DHEA. MDMA causes a rise in the adrenal corticosteroid
dehydroepiandrosterone (DHEA). DHEA is the precursor to testosterone, progesterone, estradiol and
other steroids. The rise and peak physiological values of DHEA between around 1 to 2½ hours post-
MDMA administration is correlated with user-reported euphoria, though DHEA's precise contribution
to the mood-elevation is unclear. In general, levels of DHEA decline with age after early adulthood.
Long-term supplementation with DHEA seems to have beneficial effect on libido, immune function
and some forms of cognition. However, in spite of a wealth of research, no firm conclusions have
yet been reached on the advisability of taking DHEA supplements, or an optimal dosage if taken.
Nor is it known what role enhanced DHEA might play in sustaining enriched quality of life over the
longer term. Taken on its own, DHEA may brighten mood; but it's scarcely an E-like effect.

One unwanted effect of MDMA, especially when taken at higher doses, is its tendency inhibit to
tryptophan hydroxylase by triggering a rapid oxidation of the enzyme's sulphydryl sites. Tryptophan
hydroxylase is the rate-limiting enzyme in serotonin synthesis. Even though the acute functional
loss of tryptophan hydroxylase in the cell terminal is reversible, the axon's vulnerability to oxidative
stress is increased. In order sustainably to enhance our capacity for empathetic bliss, and certainly
to prevent any functional serotonergic deficit, tryptophan hydroxylase function must be enhanced,
not inhibited. However, to date no stimulator (or inhibitor) of the biosynthesis of serotonin has been
commercially marketed. Interestingly, the use of interventions to increase the biosynthesis of
serotonin prior to MDMA use tends to trigger an increased synaptic release of dopamine, thereby
enhancing the user's euphoria. Unfortunately, increased serotonin synthesis also aggravates post-E
neurotoxicity. The two mechanisms are separable in principle. In the meantime, restraint is prudent.

Ultimately, we may be able to generate sublime MDMA-like states - at will, to order, and
indefinitely - only when the intracellular signal-transduction mechanisms, and regulation of genetic
switching beyond the post-synaptic cascade, are better understood. The orchestrated
"overexpression" of some genes and the receptor proteins they code, the redesigned "under-
expression" of others, and perhaps the selective silencing of gene expression via RNA-mediated
interference of anything really nasty, can amplify desirable facets of our consciousness and suppress
its darker and more poisonous variants. Thus at one terrible extreme, suicide victims, for instance,
tend to show heightened levels of serotonin 5-HT2A receptors. Before death, they show a greater
activity in the genetic machinery churning out the 5-HT2A receptor itself. So as well as developing
gene-therapy to prevent suicidality - and forestall the whole spectrum of deeply unpleasant para-
suicidal and self-destructive states - it should be possible, conversely, to engineer an unimaginably
richer love of life, of ourselves and each other by genetically enhancing our own minds. Freedom to
optimise (or at least improve) one's genome should prove at least as personally liberating as the
freedom to optimise one's drug-regimen. Doubtless a regulatory minefield lies ahead.

One momentous development is perhaps only a decade or so away. In the imminent era of
genomic healthcare, we may each enjoy access to a read-out of our own individual genotype i.e. the
set of particular forms of genes - alleles - peculiar to each individual who isn't a monozygotic twin
[triplet etc]. Harnessed to pharmacogenetics, the study of how an individual's distinctive genetic
inheritance affects the body's response to drugs, such intimate genetic self-knowledge should allow
the design and prescription of a drug-regimen tailored to each unique person, whether for medical,
social, research or "recreational" purposes. At first, only the crudest stratification of patient
populations by genotype may be the medical norm. This is because commercial drug companies
prefer large markets. Yet eventually we should all have optional access to the gene-expression
profile of each neurotransmitter-specific neuronal subtype in the mind-brain. Such access offers
scope for fine-grained manipulations of the chemistry of our souls inconceivable in the Dark Ages of
pre-genomic medicine.

Genetically personalised medicine offers another bonus. It should eliminate the possibility of
idiosyncratic drug reactions caused by genetic abnormalities - for example rare polymorphisms of
the cytochrome P450-2D6 system critical to drug metabolism. Owing to genetic polymorphisms in
drug-metabolising enzymes, receptors and transporters, a range of drugs beneficial to c.99% of the
population can't get regulatory approval. In some cases, valuable licensed medicines are pulled
after post-marketing surveillance. This therapeutic opportunity is wasted because, say, 1%, 0.1%,
or even 0.01% of people who take such agents suffer severe adverse reactions. The advent of
genetically personalised medicine should mean that these atypical cases can be excluded; and given
other medication instead. Useful older drugs can be dusted off the shelves and re-licensed. New
agents can be developed and given faster regulatory approval.

Psychoactive drug users in particular should benefit from the prospect of genetic self-
knowledge. Cytochrome P450 forms a superfamily of hepatic enzymes with hundreds of different
isoforms that catalyse the oxidative metabolism of a huge diversity of substrates, including MDMA.
The duration of action and/or intensity of the effect of numerous drugs are determined by their rate
of metabolism by cytochrome P450. Whereas some "housekeeping" enzymes are expressed
constitutively i.e. they are perennially active, other enzymes are expressed essentially only when
triggered by the presence of the exogenous chemical. Inducible enzyme isoforms increase both in
amount and activity in response to drugs.

The precise role of CYP2D6 in MDMA pharmacology is still unclear. MDMA is not merely a
substrate for CYP2D6; it also binds to the enzyme, forming an inhibitory complex. The CYP2D6
enzyme is soon saturated even in efficient metabolisers. Other human cytochromes P450 such as
CYP-1A2, CYP-3A4 and CYP-2bB are critically involved in the oxidative metabolism of MDMA. It is
possible these other metabolic pathways play an important role in everything from idiosyncratic
responses to MDMA to the notorious "loss of magic". If enzyme induction accounts wholly or in part
for the loss, then the roots of disenchantment can be investigated and prevented, whether for
MDMA or perhaps its still imperfect successors. If, however, central processes of neuroadaptation
are at work, either instead or as well, then longitudinal neuroimaging studies comparing the brain-
scans of, say, drug-virgins ninety minutes or so after dropping their first magical E (or perhaps its
safer successor(s)) with brain-scans taken during their hundredth-odd trip should allow the
neurochemical basis of any loss of magic to be pinpointed and reversed. Indeed the magic itself can
presumably be amplified, probably more delightfully than an unenchanted Darwinian mind can
grasp.

More broadly, genomic medicine will deliver the freedom to choose who or what we want be,
both as individuals and collectively as a species. In the long run, a spectrum of mental superhealth
that is orders of magnitude richer than anything accessible today can be genetically pre-
programmed. "Phenotypic plasticity" (the nearest analogue to free will a molecular geneticist will
recognise) can be both vastly extended to enhance personal autonomy and, no less importantly,
constrained where it's cruel and unwanted. Thus better designed gene-and-drug combinations can
perpetuate truly sublime modes of consciousness whereas, conversely, a predisposition to such
ancient Darwinian horrors as sociopathy or suicidality can be genetically cured. A rewritten genome
can potentially liberate us from all trace of psychopathy and depression - the enemy from without
and, all too often, the enemy within. When taken today, MDMA rapidly banishes the horrors of both.
Alas they soon return; the acute effects of MDMA are mostly all too reversible. Prediction is always a
hazardous business, but to our descendants, breeding kids with anything like our own corrupt code
may seem like wanton child abuse.

Post-Darwinian Medicine

Decoding the human genome offers the promise of lifelong emotional health via somatic or germline
therapy. Such well-being may be modulated at will via entactogens-empathogens akin to MDMA; by
entheogens, psychedelics, nootropics; or agents from categories currently too exotic to imagine. Or
alternatively, our descendants may opt to abandon psychotropic drugs as pollutants of their
genetically-enriched minds.

The biotechnology revolution throws up darker scenarios too. The spectre of biowarfare,
bioterrorism, and perhaps totalitarian state control over our reproductive decisions tends to loom
larger in the contemporary imagination than utopian visions of boundless love and joy. Clearly
genetic engineering and designer-drugs, like the printing press, can be put to unethical use.
Nightmarish dystopias make spine-chilling science-fiction and, maybe more plausibly, better
futurology than wide-eyed technophilia. The near future may indeed be bleak. Those of us who
aren't morbidly interested in pain and suffering probably underestimate how dreadful primordial
Darwinian life can be at its worst. Some mental and physical torment is so bad its victims would
snuff out the whole world to end it. Disturbingly, the sense in which its victims could be deluded in
evaluating its dreadfulness is unclear.
 Yet human nature as encoded in our DNA isn't immutable. Mankind's barbaric track-record to
date is an unreliable guide to our post-human future. If Homo sapiens' nastier alleles and their more
sinister combinations can be silenced or edited out of the genome, and new improved code-
sequences inserted instead, then the pessimists will be confounded. A major discontinuity in the
development of intelligent life lies ahead. Providentially, we've learned that the DNA-driven world
isn't written in God-given proprietary code it would be hubris to tamper with, but in bug-ridden open
source amenable to improvement.

Given our current design-limitations, any planning for a post-human population endowed with
invincible mental health sounds ambitious in scope if not messianic in spirit. Even granted that
paradise-engineering is technically feasible, the abolitionist project still amounts, by today's lights,
to a breathtakingly bold strategic move for our species. It may never happen. Most philosophers
assume that suffering will endure as long as life itself. Only the horrific, purposeless cruelty of a
living world evolved by natural selection makes an abolitionist agenda of "unnatural" selection so
morally urgent. That said, any mental health plan aimed at underwriting lifelong emotional well-
being for the world's population no more entails developing a millenarian blueprint for a post-human
Utopia, or prophesying the imminent End Of History à la Francis Fukuyama, than the still radically
incomplete conquest of "physical" pain dictates specifying the particular kinds of pain-free lives we
should all lead. The lifestyle options following success in either case are effectively limitless. Thus
any fleshed-out examples of possible post-Darwinian forms of life are purely illustrative. If mental
superhealth does become the societal norm, then gradients of genetically predestined bodily and
emotional well-being can constitute the presupposed backdrop to the diversity of everyday life, not
its focus. Gradients of lifelong happiness can enrich our autobiographical narratives, not supplant
them. Ecstasy needn't be orgasmic; though it can be.

As contemplated today, scenarios of a post-Darwinian era of lifelong bliss demand a greater

effort of imagination than the possibility of lives spent "merely" without "physical" suffering. The
futuristic scenarios feel "unreal". The prospect of lifelong happiness strikes us as far more utopian in
conception than the prospect of lifelong bodily health. Yet in both cases, gradients of well-being can
play a role informationally analogous to their nastier Darwinian counterparts while shorn of their
unpleasant (and sometimes harrowing) subjective textures. Assuming here without argument a
functionalist model of computational mind, what's indispensable to intelligence in the broadest
sense of the term are the triple processes of information, computation and feedback. The "raw
feels" of unpleasantness are neither necessary nor sufficient for intellectual progress. Thus our
silicon robots don't suffer anguish, even when we recode their "affect programs"; and it seems
they're getting smarter a lot faster than we are.

The existence of lives animated by gradients of well-being should be distinguished from lives
spent in a state of uniform well-being. Chronic heavenly bliss, like chronic pain and despair, is a
condition that's technically possible to implement in the vertebrate CNS. For good or ill, such
uniformity would be a recipe for stasis. The intra-cranially self-stimulating rat or monkey - or human
wirehead - isn't going anywhere. By contrast, if a predisposition to gradients of ecstatic well-being is
ever genetically encoded as our default mood-spectrum, then critical discernment can be
functionally retained, and self-motivation enhanced, without sacrificing the humane ethic of a
cruelty-free world. This conjecture isn't idle. Some bioethicists would argue a world without
suffering is the precondition for any civilised society. Plausible or not, the lack of any inevitable
tradeoff between happiness and critical insight undercuts one ideological obstacle to global mood-
enrichment.

Predicting the dial-settings on the emotional thermostats of our descendants is unavoidably

speculative. But if (very controversially) post-Darwinian humans will innately feel superwell, albeit
in varying degree, precisely what modes might their genetically enhanced and perhaps
pharmacologically modulated well-being most plausibly take? Will such well-being be the egoistic
happiness of amoral, emotionally self-reliant ubermenschen? Or could being loved-up on Ecstasy, or
perhaps long-acting brands of entactogen-empathogen cleaner and safer than MDMA, offer a better
model of social life in centuries to come?

This sort of crystal-ball gazing clearly demands scepticism as well as a lively imagination. As
Dr Shulgin reminds us elsewhere, any prediction is hopelessly entangled with the wishes of the
predictor. Such bias might seem to defeat the enterprise from the start. Fortunately (or otherwise),
however, some scientific prophecies can become self-fulfilling if ever their makers acquire the power
to implement them. In this instance, technically at least, Homo sapiens will soon have the collective
scientific expertise to redesign our own nature. So if we ever aspire to enjoy, say, lifelong ecstasy
for our minds and bodies, then we can have it. If we're so minded, then apes can become angels.
The ultimate stumbling-block, if there is one, will be traditional Darwinian-era ideologies, not
scientific ignorance of how to redesign the molecular machinery of emotion. For sure, the vision of a
whole civilisation, and not just an all-weekend rave, founded on the neural substrates of an E-like
"Peace, Love, Understanding and Respect" sounds sociologically naïve and (socio-)biologically
impossible. Stated so bluntly, the loved-up edition of scientific utopianism is perhaps the most
implausible (and unreadable) premise for a sci-fi novel one can imagine. The non-specific prediction
of genetically preprogrammed well-being for our descendants is contentious enough as it stands.
Any more detailed explorations of the possibility that such enriched well-being might be, say, E-like
rather than egoistic are therefore hugely more speculative; and quite probably mistaken. But for the
following reasons, a civilization based on relationships of, say, mutual loving empathy and
intensified E-like consciousness is not impossible, just far-fetched. At a minimum, it's worth
sketching out an extended family of E-like scenarios as a corrective to a routine but unargued
assumption that underlies rival predictions. This assumption is that societies based on the
behavioural genetics of primate-style dominance-and-submission hierarchies will endure indefinitely.
Thankfully, both the reproductive biology and mode of selection pressure at work in the new era of
genomic medicine will be different from the evolutionary past. Our genetic programming will no
longer be "blind", even if its early (re-)programmers will be only partially sighted. Varieties of
(post-)human genotype won't just be quasi-randomly generated via sex, genetic crossing-over and
mutation. Instead, genotypes will be purposely (re)designed - even if the early designers barely
know the ramifications of what they'll be doing.

For we're presently on the brink of the era of "unnatural" selection. Throughout the living
world, a regime of blind natural selection acting on effectively random mutations has governed the
evolution of information-bearing self-replicators since the origin of life itself. The Darwinian Era has
lasted for over four billion years. Most recently, in the aftermath of the post-Cambrian explosion of
multicellular animal life and the evolution of central nervous systems, selection pressure has created
suffering beyond belief. Mercifully, a regime change is imminent. Within a few centuries at most,
intelligent life will be able to rewrite the vertebrate genome and redesign the planetary ecosystem.
Sooner still, if we want our genetically enriched (grand-)children to be happy, then in the impending
reproductive era of preplanned designer babies we will also have to choose - either actively or by
default - whether the kinds of heritable well-being our offspring enjoy will tend to be solipsistic or
social, orgasmic or intellectual, hypomanic or serene, loving or self-centred, or perhaps ultimately
take forms that can't be grasped by the contemporary Darwinian mind. Whatever criteria are used,
an increasing range of genotypes will soon be chosen in deliberate anticipation of their phenotypical
effects. Needless to say, no such calculated sets of genetic decisions can be taken by prospective
breeding couples at present. "Genetic choice" in the early 21st century usually means nothing more
ambitious than choosing the gender of one's child, often in less than ideal circumstances. Yet as the
human genome is deciphered, and eventually the "transcriptome" and proteome beyond, a
staggering extension of freedom of choice will be thrust upon us. As wiring up the neural reward
centres with microelectrodes shows, the practicalities of inducing - and then sustaining - the neural
substrates of bliss are technically quite easy. Viewed as an engineering problem, no one needs to
suffer; suffering is an unnecessary evil. This is true even with today's embarrassingly clumsy
interventions. Modulating bliss in controllable ways is trickier - whether by drugs, microelectrodes or
gene-therapy. Short-term technical snags aside, our state-space of life-enriching options is poised
rapidly to expand. Of course even with utopian biotechnology and mature nanotechnology,
constraints won't be absent. The menu of practical choices on offer to our enriched descendants
isn't entirely limitless. For instance, decades spent in unceasing, paroxysmal super-orgasms, or
perhaps immersion in fantasy wish-fulfilment in virtual reality software, may well be viable lifestyle
options one day for individuals. They are technically feasible to implement. Yet it's hard to imagine
parents wanting such modes of existence for their kids, or to devise evolutionary game-theoretic
models where the prevalence of genotypes that permit such lifestyles could be globally stable. In
any post-Darwinian reproductive era ahead, "unnatural" selection pressure will still be at work, at
least until the abolition of senescence brings the throwaway era of traditional DNA mortals to a
close. Thus any currently foreseeable civilisation will be social in character, not quasi-solipsistic. If
so, then one urgent challenge will be to make our social interactions less emotionally costly. Today,
for a few hours, MDMA offers perhaps the richest chemical tool for social intimacy in existence. If
nothing else, the MDMA experience demolishes the conventional wisdom that "artificially"-induced
happiness must be amoral and selfish - hedonistic, one-dimensional and shallow. More generally,
the sense of heightened authenticity, love and self-insight induced by entactogen-empathogens will
no longer seem an escapist holiday from Real Life when entactogenic-empathogenic states can be
sustained indefinitely - whether by gene-therapies or soul-medicines or varieties of both. In theory,
at least, mental superhealth can become the new benchmark of consensus-reality against which any
departures are defined, not drug-induced psychotic episodes.

It's safe to say MDMA itself isn't going to change the world. Yet as a taster of what's feasible in
post-prohibitionist culture and a possible genetically-enriched future beyond, the MDMA experience
shows social life at its best. MDMA promotes a more altruistic mode of consciousness than has
maybe ever existed on the planet, certainly among testosterone-driven young males. On MDMA,
one can love thy neighbour as thyself; and the lion can lie down with the lamb. Feelings of hostility,
bigotry and intolerance evaporate. Competitiveness is replaced by love, tolerance and respect. Such
social harmony seems "unnatural" if not miraculous when viewed from the poisonous miasma of
mainstream society. For outside the embraces of loved-up ecstatics, we tend to pay a terrible price
for the benefits of group living. The costs of social existence are attested by the grisly chronicles of
human history, Gibbon's "register of the crimes, follies, and misfortunes of mankind". It's not as
though we have much choice about living together. Even in the absence of MDMA, human beings
are still compulsively sociable. This compulsion to socialise is generally seen as healthy rather than
dangerously addictive, despite the traumas it brings. In abnormal conditions of social isolation, the
personality starts to deteriorate: solitary isolation, whether real or figurative, is rightly viewed as a
cruel and unusual punishment. Our genes, via the reward pathways and the neural projections they
code, make us chronically hooked on the company of others. Our very identities are bound up with
our social roles. We are physiologically dependent on the opioidergic, oxytocinergic, dopaminergic
and serotonergic mechanisms that friends, family and colleagues may trigger within us.

At its best, this chronic dependence on human company gives short-term highs and even
warm afterglows. But dependency, craving, and withdrawal-reactions are common when significant
others are taken away from us or adulterated. Purity varies; supply is erratic; and adverse reactions
are common. Cue-elicited craving readily triggers relapse. Our sociability can spin out of control into
a financially ruinous habit. We spend lots of time and effort thinking about how to get more of
whoever stimulates our mesolimbic reward circuitry most vigorously, possibly romanticised under
more poetic descriptions. Without friends, lovers or family, most people tend to become lonely,
sometimes agonisingly so. In extreme cases, loneliness and lovesickness can induce suicidal
despair. Bereavement and abandonment can be as traumatic as heroin-withdrawal; and they share
similar neural substrates.
 Alas given a Darwinian genome the compulsion to socialise is all too often a dangerous, self-
destructive addiction. Living without Ecstasy, we are predisposed by our genes to conflict with each
other: mothers and children, men and women, brothers and sisters, friends and relatives - all have
different and often conflicting genetic interests. Only monozygotic ("identical") twins may hope to
be spared this insidious rivalry. Camouflaged genetic conflict underlies our disposition to squabble
and fight amongst ourselves, even though we compulsively need each other's company too. Thus
testosterone-driven males find themselves enacting decades-long competitive rituals to attract and
retain genetically superior mates. Competitive status-seeking in its subtle - and not-so-subtle -
guises is a cross-cultural universal, deeply rooted in our biology. Conflict to the point of warfare is
genetically predisposed in our make-up. It's endemic to human society. Right from conception and
the implantation of the conceptus in the womb, genetically-driven conflict plays itself out, often
leading to trauma (e.g. preeclampsia etc.) for mother and unborn child alike. Later on, even the
noblest of human sentiments are fragile. Love all too easily turns into hatred, admiration into
contempt. By way of illustration, consider, say, proverbial "lover's quarrels". There are innumerable
"proximate" explanations of why star-crossed lovers often argue so painfully and vehemently. But
the "ultimate" evolutionary explanation seems to be, at least in part, that tempestuous rowing and
its consequences serve as a brutal but effective way for prospective breeding couples to test each
other out. Evolutionary psychology suggests that, from a gene's eye view, it's better to discover if a
prospective partner will let you down sooner, when (s)he's goaded under conditions of stress, rather
than later after you've sunk a substantial investment of time and resources in the partnership.
Arguing can be traumatic; but the capacity to do so is [genetically] adaptive.

Human relationships can bring psychological rewards too. Anyone having fun right now would
find this drumbeat of misery, heartache and emotional squalor all a bit overblown. Yet if anything
the nastiness alluded to here is understated; the worst pains in life are inexpressible. Under the
genetic status quo, most of us are condemned at different stages of a lifetime to re-enact the messy
- and sometimes desperately sad - personal dramas of our ancestral past. TV soap-operas and
teledramas serve to sanitise just how emotionally unpleasant Darwinian life can be. For as human
generation succeeds human generation, we replay the age-old sagas of sexual betrayal, jealousy,
loneliness, and rejection. We are forced to endure the savage competition of lookism - an
inadequate, frivolous term for a cruel and omnipresent phenomenon in human society. Less
colourfully, a multitude of pettier but still wounding frustrations, humiliations and
misunderstandings can mar daily social life and sour personal relationships.

The genetic rot goes deeper. Evolutionary psychiatry suggests that the cross-culturally
ubiquitous phenomenon of depression, and the wider spectrum of depressive and dysthymic
disorders, is not a genetically dysfunctional anomaly. Counter-intuitively, a conditionally activated
tendency to depression may represent a fitness-enhancing adaptation to group living. The
(involuntary) capacity for depression is one of a number of ancient, genetically adaptive
mechanisms and strategies for dealing with "social defeat" in a tribal environment. Group living
conferred advantages on otherwise vulnerable individual primates on the African savannah.
Embracing tribal life forms a valuable defence for a puny "naked ape" against big predators. But
thanks to the pressure of sexual selection, human tribal society imposes a cruel pecking-order of
subordination relationships among members of the tribe. For sure, depression has many proximate
causes; there are many subtypes of depression; and not all depressive moods and behaviours are
genetically adaptive. Yet viewed in evolutionary perspective, a syndrome of sustained melancholy,
behavioural suppression, and a preoccupation with personal failure and inadequacy is the
internalised correlate of the yielding or "losing" behavioural sub-routine. On this "rank theory"
hypothesis, the involuntary activation of submissive and depressive states is an unpleasant but
effective defence-mechanism for weaker individuals where any tendency to initiate or escalate
conflict with a powerful dominant rival might easily be disastrous. Thus states of depression or low
mood ensure the weak "keep their heads down" and don't overreach themselves. By contrast, the
(hypo-)manic spectrum of mood and behaviour is a manifestation of the "winning subroutine".
Clearly, not all submissive people are unhappy, and not all dominant and/or aggressive people are
(hypo-)manic. So there are complications to the hypothesis and a legion of exceptions. A capacity to
switch mode can sometimes be adaptive too; hence the probable evolutionary origins of bipolarity.
Yet down at the bottom of the social heap, there are proportionately far more crushed and wounded
spirits than there are at the top. Socially dominant Alpha males tend to be temperamentally
expansive and optimistic. Conversely, even life's "winners", if deposed and defeated, may become
depressed themselves, and slink away to die, metaphorically or otherwise. Depression in human
societies is far more prevalent than (hypo-)mania, albeit far less visible. This greater prevalence
probably reflects conditions in the evolutionary environment of adaptation where the spectrum of
depression, mania and bipolarity first arose. But whatever the ultimate evolutionary roots of mood
variation and affective disorders as interpreted by rank theorists, contemporary humans in all
known societies are obsessively status-conscious. Status-competition corrupts personal relationships
in societies stratified by caste, class and money alike. Even apparent counter-examples don't
challenge the generalisation. Thus societies based around the potlatch, the Pacific Coast Native
American custom of conspicuous gift-giving rather than wealth-accumulation, reflect a disguised
expression of competitive power relationships. Indeed the tradition of rival displays of gift-giving
finds echoes today in the competition between billionaire American plutocrats to endow the biggest
charitable trust foundations.

The poison of competitive status-seeking might seem incurable. ["If everybody is somebody,
then nobody is anybody"; "It's not enough to succeed. Others must fail"] Yet short-term
symptomatic relief for this syndrome already exists; and its long-acting analogues may one day
offer complete remission. Taken communally, MDMA induces an almost miraculous transformation in
the structure and relationships of any social group. At MDMA-animated raves, no one who's loved-
up is trying to "diss" anyone else. MDMA abolishes the desire to put anyone down. On MDMA,
primate dominance hierarchies dissolve in an egalitarian love-in. A lifetime's inferiority-feelings,
snobberies, and status-anxieties dissipate in a flood of augmented serotonin and dopamine release.
Intriguingly, the euphoria experienced by MDMA users doesn't take the form of uncontrolled manic
excitement, even where the drug induces "behavioural activation". MDMA's indirect, serotonin-
mediated enhanced dopamine-release produces psychostimulant, emotional and perceptual effects
that feel very different from crude dopamine-releasing amphetamine. Even the most animated
ravers taking pure MDMA tend to experience a profound sense of inner calm, a "peace that passeth
all understanding". Identifying the neurochemical signature of states combining inward serenity and
outer dynamism presents a wonderful therapeutic opportunity. The contrast between raves packed
with loved-up clubbers on hugdrugs and parties fuelled by alcohol or cocaine is striking.

Back in the harsh, E-less world, inferior social status is associated with low serotonin function
and low mood. Thus dominant males tend to have far higher serotonin function, as measured by
CSF 5-HIAA levels, than subordinate males. The neurological basis of social rank order can be
investigated by various manipulations. Experimentally boosting or depleting the serotonin levels of
social animals enhances or sabotages an individual's place in the pecking-order. Revealingly, there
are also gender differences in serotonin activity. The mean rate of serotonin synthesis in men is
over 50% higher than the mean rate of serotonin synthesis in women. Women are more sensitive
than men to both the MDMA magic and MDMA's adverse side-effects. Women are also more likely to
suffer from the post-E serotonin dip; more prone to depression; and more likely to benefit from
Prozac. Yet such comparisons are invidious. Men and women alike of any social status at all can
flourish far better in E-like states - while they last. Unfortunately, communal E-like consciousness
simply isn't sustainable via chronic MDMA use. In wider E-less society, "winners" probably don't do
[serotonin-depleting] drugs, though idealistic E-users might suggest that zero-sum status-games
are best not played at all. For better or worse, a heavy, serotonin-depleting E-regimen can disrupt
the user's social status in the competitive urban jungle - and probably elsewhere. Admittedly, there
are too many confounding variables to test this hypothesis in methodologically rigorous studies on
humans. Even so, a proposed "E-users are losers" research proposal is more likely to gain official
funding than a well-controlled trial of, say, the health benefits of MDMA-assisted psychotherapy.

Of course the aspiration for a civilisation founded on relationships of shared love and respect
sounds impossibly idealistic. A society based on "winners" and "losers" intuitively strikes us as
natural. With today's genes and the kinds of culture they promote, adversarial social relationships
are probably inevitable. Like depression, the evolutionary roots of everyday sociopathy run deep.
For speculatively, applying here Richard Dawkins' "extended phenotype" theory, not merely has it
been genetically adaptive for weaker social primates to have an inbuilt conditionally-activated
capacity for depression, it can also be genetically adaptive for Alpha males (and aspiring Alpha
males) to subdue potential rivals by making them depressed too. Perennially chastened, socially
anxious and chronically depressive potential competitors are less likely to be sexually active and
promiscuous. Crushed, anhedonic and submissive, they are less of a challenge to the inclusive
fitness of one's genes. Happy, dominant, extroverted males, by contrast, are potential sexual rivals
who directly or indirectly threaten one's reproductive success. Thus we witness their downfall with
equanimity. Even within the bounds of holy wedlock, too much happiness for one's nearest and
dearest doesn't always suit one's genetic interests. A cowed and depressive wife, whose only solace
in life is looking after the kids, can be less threatening to one's genetic prospects than an
exuberant, sociable and possibly sexually adventurous bundle of joy. If we are looking for an
evolutionary perspective on why we often behave so vilely to each other - sometimes seemingly
gratuitously so - then this kind of sexual selection pressure offers one possible explanatory
framework. If it is adaptive to have others exhibit a spectrum of behaviour characteristic of low
mood or high social anxiety, then other things being equal, alleles and allelic combinations may
flourish if they conditionally promote the capacity to induce such anxiety and depression whether in
strangers or tribe members who aren't allies or close kin - and if occasion demands, even in those
who are both. Depending on a lot of other factors too, the (behavioural effects of the) happiness of
others, male or female alike, can indirectly detract from our own Darwinian fitness. Consequently
their perceived happiness doesn't tend to give us as much joy as moralists might wish. Sad to say,
reports of good fortune befalling our fellows do not always inspire a warm glow of vicarious
satisfaction. On the contrary, news of another person's lottery-win, for instance, or its traditional
counterpart on the African savannah, is liable to trigger involuntary feelings of jealousy and
resentment, or at best an envious ambivalence. Of course, it's worth stressing that natural/sexual
selection doesn't care about the subjective textures of misery or happiness per se. Selection
pressure works on the spectrum of behaviour such mood traits engender. What was selected for [as
distinct from adventitiously selected] in the ancestral environment of adaptation wasn't the capacity
to make others feel miserable as distinct from behave miserably. To selfish DNA, our suffering itself
is incidental. The distinction, however, is of limited comfort to its victims.

Fortunately we're not systematically spiteful, even though we're not naturally loved-up. If
human malice were really genetically hardwired, then any nostrums for social reform, life-enriching
lovedrugs or improving the vertebrate genome would be futile. Thankfully, a malignant streak of
human nastiness is matched by a common if ineffectual desire to improve ourselves and help
others. This good-will just needs genetic and pharmacological amplification.

So granting human beings no more than a minimal and diffuse benevolence, what can be done
to make us temperamentally nicer to each other as well as happier and smarter? Would we
individually and collectively be better off if perpetually loved-up on more advanced and sustainable
analogues of E? Or are loved-up ecstatics just too vulnerable to genetic invasion by "defectors" and
wolves in sheep's clothing for such genes or allelic combinations to flourish? Vulnerability to
predatory and Machiavellian genetic rivals is presumably the reason why sweetheart suckers living
in blissfully E-like states are thin on the ground in the drug-free Darwinian world. What reasons are
there, if any, for predicting that the nature of adaptive traits in the era of genetic engineering will
change in ways that make beautiful minds more widespread?

If genetic engineering or rational drug design are to deliver us from the Darwinian rat-race
into everyday states of ecstatic grace, or anything at all like it, then there are short-term and wider
evolutionary constraints to be overcome. Truly far-sighted genetic re-programming is a formidable
challenge. Some genetic manipulations may involve computing the interactions between dozens or
ultimately hundreds of alleles. Often their contributions to mental and behavioural traits won't be
additive but dependent on a plethora of environmental contingencies. This Problem of Conditional
Activation threatens a combinatorial explosion of possibilities to calculate. It presents a daunting
task of prediction and control. Other interventions, however, might seem (comparatively) more
straightforward. For instance, the action of testosterone, and its hormonally active
dihydrotestosterone metabolite, is in large part responsible for war, social violence and competitive
dominance behaviour, territoriality, sexual aggression, reduced male life-expectancy, and going
bald. The genetic and/or pharmacological manipulation of testosterone may play a vital role in
undercutting the darker horror scenarios for the future so popular in the science-fictional literature.

Yet first there are many problems to be resolved here too. Testosterone can't, realistically,
just be edited out of the genome, as distinct from edited and re-regulated. The eradication of
testosterone would indeed spell a world without war. But androgenic hormones can't be deleted
altogether, even if the option of rearing functionally emasculated or chemically castrated offspring
were an idea palatable to prospective parents, an unlikely prospect right now. Testosterone is the
stereotypical "male hormone". Yet testosterone is present in women too, albeit in smaller amounts:
it's important to female sexual response, just as it's responsible for spontaneous nocturnal erections
in males. Testosterone plays a role in female bone-strength, muscle-mass and a general sense of
well-being. Moreover, expository convenience aside, androgenic hormones are no more intrinsically
evil than the MDMA molecule is intrinsically good. Thus testosterone promotes what might be
described as "strong-mindedness". Today the trait of strong-mindedness fosters what's often little
more than callousness in pursuit of unworthy ends. But not always. Even in a mature post-
Darwinian civilisation, most of us may well prefer to cultivate "strong personalities". The popularity
of performance-enhancing anabolic steroids with athletes and bodybuilders stems only in part from
the way such drugs enhance strength, power, speed, endurance and muscle-mass. For anabolic
steroids are popular because they can also act as mood-elevating, mind-toughening personality-
pills. Taking anabolic steroids induces a sense of well-being sometimes amounting to euphoria, an
increased tolerance of stress, and a sense of competitive "edge". The price of using such drugs can
be hypermasculine aggressiveness ["roid rage"], increased dominance behaviour and even a
propensity to sexual violence. Normal endogenous male production of their native anabolic
counterparts is risky enough already. If our species is to survive its newfound capacity to build
weapons of mass-destruction, and tackle the genetic origins of male violence and all-round
nastiness, then we must somehow curb the biological roots of masculine aggression. This particular
intervention strikes us as a disconcerting prospect. Darwinian sexual and gender identities are
central to social existence today, and usually integral to who we think we are. However, the long-
term role of the Y chromosome in the evolution of intelligent life is uncertain; and the ethical value
of testosterone-driven masculinity is unproven at best. The phenomenon of sexual reproduction
itself has only persisted and evolved as a defence against parasitism; an additional mechanism that
promotes genetic variability is a powerful weapon in the evolutionary arms race against pathogens.
In the new reproductive era ahead, however, genetic diversity can be intelligently pre-planned. So
at the very least, enlightened biomedicine should be able to edit out a predisposition to the more
sociopathic forms of masculinity from the genome. More far-reaching strategies can be
contemplated too. On the other hand, recalling H.G. Wells' The Time Machine (1898), we don't want
to turn into enfeebled and weak-minded Eloi, even if we live in a world without Moorlocks. It's good
to wake up each morning feeling ready to take on the world and win, even if we eventually discover
that the rest of the world is on our side; and some day it may be conspiring to help us.
 Today the world generally isn't on our side. Low testosterone function is associated with social
defeat, passivity and subordination. Low testosterone levels are also implicated in depressed mood.
The syndrome of depression has both proximate and evolutionary roots. Depression is popularly
viewed as a sign of weakness; and folk-wisdom is right. Such a perception leads to its systematic
underreporting, especially among males, thereby painting a falsely rosy picture of (male) mental
health. Depressive illness is reported to be twice as common among women as men. Conversely, it's
sexy for men to be cool, confident and 'sussed' - the sort of personality often faked if you aren't,
though for evolutionary reasons depressives find it harder to bluff. Therapists and sensitive
physicians may take determined steps to reassure their clients that depression isn't a sign of
weakness. Alas this assurance typically isn't true. Depressives characteristically tire quickly, act
ineffectually and give up too easily. Potential new antidepressants are correspondingly tested for
their capacity to reverse the learned helplessness and behavioural despair induced by chronically
"stressing" [torturing] non-humans in "animal models". Whereas exuberant hypomania is a signal of
strength and resolve, albeit a risky signal, depressives can't pursue their projects with fanaticism,
nor can they work indomitably to pursue what they believe to be morally right. For their capacity to
anticipate reward is blunted. Life for depressed people too easily seems meaningless, absurd and
pointless - the nihilistic polar opposite to a hyperdopaminergic sense of urgency and significance.
For the mesocorticolimbic dopamine system mediates not just the salience and intensity of
anticipated reward; it also determines strength of will. By contrast, the spirit of depressives is easily
broken; and there's no natural remedy for weakness of will.

This grim diagnosis isn't a counsel of despair. On the contrary: well-designed genetic and
pharmacological interventions should in principle allow weaker spirits to be invigorated and frailer
personalities empowered. With better drugs and better genes, one's idealised persona can be made
flesh. We'll soon have the option of making ourselves stronger, better-motivated and more steely-
minded in character than even the bravest palaeo-Darwinian primitive or Nietzschean ubermensch.
It's an open question whether such strength of character will be egoistic or empathetic, cocaine-like
or E-like, or something different altogether. Yet with the right gene-and-drug combos, we can be
superheroes, even if the need for heroism may shortly pass. In the meantime, innovative
pharmacotherapy and/or genetic medicine will be vital if the weak-mindedness and weak willpower
blighting so many lives today is to be overcome.

Weak-mindedness takes many forms. One effect of administering MDMA is the way it
eliminates jealousy. Even anti-abolitionists, normally so eager to hymn the character-building
virtues of suffering stoically borne, rarely find many positive words to say about the ennobling
attributes of the green-eyed monster. Jealousy is a persistently nasty, vicious, and pervasive
feature of Darwinian human social relationships. It's also about as voluntary as sneezing; and far
harder to cure. Like MDMA, SSRIs tend to diminish jealousy. SSRIs also act more sustainably than
short-acting clubdrugs. But SSRIs also tend to diminish the intensity of being in love. On MDMA, by
contrast, people of either sex can and frequently do spontaneously embrace and caress each other -
complete strangers as well as intimate friends. On MDMA, everyone naturally tends to love each
other, almost as if we were clones rather than genetic rivals.

Such behavioural effects present a bizarre and perhaps disturbing spectacle to the E-less
Darwinian outsider. Yet the lessons to be drawn from the use of today's crude hugdrugs and
lovedrugs extend far wider than the recipe for a good weekend out clubbing. One way to put the
world to rights invokes the tired nostrums of socio-economic and political reform. Such social
engineering hasn't proven effective at curbing the frightfulness of life to date. Pursued in a biological
vacuum, so to speak, any kind of environmental approach to building a world without cruelty, fear
and pain is bound to fail. The other, biologically based strategy for saving the world will involve
treating our, say, congenital androgenic, serotonergic, opioidergic, dopaminergic, PEA and
endocannabinoid dysfunction via gene-therapy and rationally designed pharmaceuticals. Critically, it
entails choosing kinder genotypes for our offspring. This option doesn't amount to a very soul-
stirring prospect. Like our notions of psychoactive drugs, the concept of "eugenics" is horribly
tainted. The word itself, originally a coinage of Sir Francis Galton (1822-1911), is indelibly tarred
with the pseudoscientific quackery of the Third Reich - though it's worth recalling that Nazi "race-
hygienists" didn't use happiness as their touchstone of genetic excellence. Yet the lethal dangers
posed by the genetic status quo coupled with advanced military technology are far greater than the
risks of a genetic reform program predicated on the goal of world-wide personal happiness.
Warnings from history aside, unless the Darwinian masculine identities of our evolutionary past are
superseded, then jealousy, conflict and warfare will go on for ever (or kill us off); and the prophets
of doom will be right.

Alas Ecstasy itself is something of a false prophet. MDMA-induced love is no more everlasting
than its older and fitness-enhancing counterpart. Two days after taking the magic lovepill(s), the
drug-catalysed outpouring of affection has subsided. "Natural" love sometimes lasts longer; but
Darwinian love is still ephemeral, eventually killed off by receptor desensitisation and down-
regulation no less effectively than E-induced love is ended by serotonin depletion. For the fickleness
of Darwinian affection has hitherto been genetically adaptive. It's an adaptation that remains a
shabby substitute for genetically-underwritten true love. Only by subverting some exceedingly cruel
feedback-inhibition mechanisms can the depth and range of our affection for each other be enriched
and sustained. As it is, most Darwinian social life is soulless and loveless. But our genes do allow
their vehicles to fall in and out of love with a small percentage of prospective mates in ways that
tend to serve our reproductive success. In a largely anonymous mass-society, love and affection are
in even shorter supply than among tribal hominids in African prehistory. Where love does
sporadically flicker or flare up among us, its expression is tightly regulated. E-less love is rarely all-
embracing: such Darwinian love tends to be jealous, possessive and exclusive. The law and social
sanction impose penalties for loving too much or too little, loving the wrong person at the wrong
age or the wrong gender. "He who is rational about love is incapable of it"; but this isn't true in the
eyes of the law or of our peers.

At MDMA-driven raves, by contrast, women can feel safe in public, gay people feel truly at
ease, and sexually straight or bisexual clubbers can express love and affection for each other free
from overt or internalised homophobia. Taboos on touching and the whole gamut of tactile
experience are relaxed. The body no longer feels like a prison for the soul but an extension of it.
The classic dopaminergic psychostimulants like cocaine promote a hard-edged, don't-touch-me
egoism. MDMA promotes intimacy, warmth, and an empathetic sense of other humans beings as
fellow subjects rather than objects.

Of course, after a weekend of being "loved-up", mood-congruent post-E "reality" soon sets in.
Did one really let slip those gushing effusions to strangers one barely knew? Did one really hug that
hateful brute of a rival for the affections of one's heart's desire? Viewed from [state-dependent]
"reality" again a few days later, being nice to everyone, truly loving oneself, and feeling (and being)
wonderful all seem faintly embarrassing, perhaps even a chemically-fuelled madness. "It was the
just the E talking". One may recall from English literature the effect of taking soma, the "ideal
pleasure drug" featured in Aldous Huxley's uncannily prescient Brave New World (1932). After John
the Savage threatens to disrupt their soma supply, the angry low-caste Deltas riot. They are
promptly pacified by the riot police with soma-gas, and the rioters end up hugging each other:

"Two minutes later the Voice and the soma vapour had produced their effect. In tears, the Deltas
were kissing and hugging one another - half a dozen twins at a time in a comprehensive embrace.
Even Helmholtz and the Savage were almost crying. A fresh supply of pill-boxes was brought in
from the Bursary; a new distribution was hastily made and, to the sound of the Voice's richly
affectionate, baritone valedictions, the twins dispersed, blubbering as though their hearts would
break. "Good-bye, my dearest, dearest friends, Ford keep you! Good-bye, my dearest, dearest
friends, Ford keep you. Good-bye my dearest, dearest..."
Too far-fetched? In 1998, a former South African government scientist told a hearing of the Truth
Commission that the minority Apartheid government had planned to use MDMA on rioters.
Desperate to retain their faltering grip on power, the embattled regime apparently ordered its
chemists to make one tonne of Ecstasy for riot-control. Thus the Calgary Herald (10 June 1998)
reports:
"Dr. John Koekemoer, former head of chemical and biological weapons research, at the secret Delta
G facility, said he disapproved, "I did not believe Ecstasy was a good incapacitant and I told my
superiors that", he told the commission, which is investigating human rights abuses during the
apartheid era. "Ecstasy enhances interpersonal relationships. I told them I did not want to kiss my
enemy."
The scary notion of kissing one's enemies, perhaps half-recalled cameos from Huxley's satirical
fiction - and the reality of strangers of either sex at raves hugging each other on E and telling each
other how wonderful they are - contribute to the perception that E-like states of blissful empathy
are inauthentic, shallow or false. How can the MDMA experience have true emotional depth if the
cosmic hug-bunny of the dance-floor reverts back at the office next week to his old Darwinian
mindset - and the (anti-)social vices it spawns? A corrosive cynicism easily sets in. For that's the
nature of social reality, an emotionally frazzled post-Ecstatic may reflect, not the magical interlude
of Peace, Love and Understanding and Respect.

Sadly, in today's world, this may be so. The depressive realism of the serotonin-depleted and
jaded cynicism of the chronically world-weary are often justified. Yet our descendants may
recognize that we are the sociopathic emotional primitives in the grip of an affective psychosis.
Jealousy, envy, resentment, ridicule, hate, anger, disgust, spite, contempt, schadenfreude and a
whole gamut of nameless but mean-spirited states we undergo each day are a toxic legacy of our
Darwinian past. More commonly, perhaps, our genetic make-up ensures we simply feel indifference
to the plight of all but a handful of significant others in our lives. Right now, for instance, one knows
dimly at some level that there is frightful and preventable suffering in the world. Yet most of us feel
no overpowering moral urgency to do anything about it. Idealists might vaguely entertain the
second-order desire to care more deeply and give, say, a larger proportion of one's money to Third
World charities dedicated to those who need the resources more urgently than we do. Yet the
biological roots to sustain "saintly" self-sacrifice just aren't there in most of us. In contrast, taking
MDMA can give rise to a prodigious sense of compassion in even the otherwise morally inert.
Regrettably, such compassion is usually ineffectual; it's too short-lived to do much good. If and
when we understand the neurochemical basis of empathy, however, then sustaining the molecular
substrates of empathetic love can turn boundless compassion into an automatic reaction to distress,
not a sign of drug-induced psychiatric disorder. Intervention can go further. If we decode and opt to
amplify the molecular machinery of volition too, then such heightened compassion can be translated
into effective action.

Fortunately, compassion if not empathy for others may ultimately be redundant. In the long
run, if biotechnology can be used to eradicate suffering from the living world, then a shared
celebration of life, not sympathy for the misfortunes of others, may come to seem as natural as
breathing. Yet right now too many people walk the Earth who have no cause to celebrate anything.
Therapeutic agents designed to deepen empathy and sustainably awaken our compassion are a
priority. The functional prototype of what's needed exists today in the form of a fast-acting
hugdrug; but MDMA itself is not the recipe for perpetual sainthood.

The design of richer functional analogues of MDMA entails more than finding medicines to
make us sweeter-natured. Improving human nature is perhaps ethically all-important, but MDMA is
also an entactogen - a more elusive concept than that of an empathogen. MDMA offers "insight
without fear" (Dr Shulgin). The nature of entactogenesis is far harder to fathom, let alone
communicate, than the nature of empathy. The word for such states comes close to being a
primitive term, its sense semantically inaccessible to the MDMA-naïve. The clarity of MDMA-
mediated self-insight is perhaps a form of what Dr Charles Tart calls "state-specific knowledge". E-
less cynics may be sceptical. Just what's the propositional content of this so-called "insight"?
Couldn't it be delusive? ["It's not hard to hear voices. It's knowing whether they tell you the truth."]
But on pure MDMA, the subject can inwardly access the kind of person s/he wants to be; "the ideal
me". Whether this idealised self-identity is created or discovered may be philosophically debatable.
But the deeply-felt sense of authenticity and emotional self-honesty of the MDMA experience is an
unexpected delight. One just won't ever get to read about its nature in the peer-reviewed Journal of
Introspective Studies.

In Western culture, a capacity for reflective self-insight is not highly prized. Introspective
genius and a talent for meditation aren't respected in either academia or business. Nothing in our
education system is geared toward making young people feel that introspective self-analysis,
enhanced self-awareness or personal growth matters in the slightest. How can they be tested,
graded and quantified? What's their market value? Anyone in Western society with a tendency to
quiet contemplation is likely to be stigmatised as lazy, feckless and unenterprising - unlike the
sound and fury of the lionised Man Of Action, and his larger-than-life ego on whose life-energies
lesser mortals may feed. In similar manner, our (limited) vision of future civilisations tends to focus
on their technological marvels - and the supposed Darwinian dominance-battles of their science-
fictional inhabitants - rather than on odysseys into the inner depths of their souls. Yet the design of
long-acting entactogens - and their neurological analogues - should allow introspective depth and a
capacity for higher-order self-reflection to be fabulously enriched as well. Tomorrow's counterparts
of today's bunch of furtive adolescent introspectionists won't have to shuffle around faint little
tickles of thought. Drugs to enrich self-insight and heighten self-reflection may eventually become
commonplace. They may be distributed as freely as aspirin if not smarties; and prove safer in
excess than either.

This prospect is some way off. Full-blooded pharmacological and genetic emancipation is still
decades away. Even so, we are poised to acquire a literally life-transforming technology - a toolkit
for enlightenment powerful enough to implement Heaven-On-Earth and beyond - yet we balk at the
sorts of public health policy decision needed to accelerate the transition. An enriched conception of
mental health is blocked by entrenched elites who've never sampled what they outlaw - whether
designer genes or utopian pharmacology. In the jaundiced eyes of (most of) the older generation,
Ecstasy and rave-culture are an aberration, not a portent. "Peace, Love, Understanding and
Respect" sounds like a hollow slogan. Today, in the wider world, the words can't be anything else.
Ecstasy itself is too short-acting, unsustainable and neurotoxic at high doses to form part of
anyone's global health plan. But a permanent distillation of the MDMA magic, if feasible, offers an
extraordinary if unorthodox vision of one post-Darwinian paradise to come.

Beyond MDMA : mental superhealth?

Moore's Law in computing is named after semiconductor engineer and Intel co-founder Gordon
Moore. It states that processing power in computers doubles every eighteen months or so. Moore's
Law has roughly held good since 1965 when it was first propounded. It's a rule-of-thumb about how
many transistors we can cram onto successive generations of chip rather than a fundamental truth
about Nature. Yet the trend it captures seems set to continue, at least until chip designers run up
against the physical constraints of the nanoscale later next decade, or perhaps until quantum
computers allow calculations orders of magnitude more powerful than today's toys.
 Unfortunately, the dizzying rate of technical progress that Moore's law quantifies hasn't been
matched by an analogous law of progress for generations of human mental health. On average, we
are probably no happier than our malaise-ridden hominid ancestors. We aren't noticeably fonder of
each other. By way of consolation, we can take refuge in the pre-scientific notion that happiness is
unquantifiable. Yet if such quasi-objective indices of mental health as suicide rates are anything to
go by, then we would probably be psychologically better off as hunter-gatherers. Over 800,000
people in the world took their own lives last year. The World Health Organisation (WHO) estimates
that this figure will rise to around 1.5 million by the year 2020. Here in the UK, suicide is the most
common cause of death for men under 35 years old. Globally, several hundred million people are
clinically or "sub-clinically" depressed; and a spectrum of chronic anxiety disorders afflicts further
hundreds of millions more. Even as we progressively conquer physical disease as conventionally
defined, the toll of psychological distress is still rising. Admittedly, "mental illness" and "mental
health" are value-laden, ideologically contested terms. Even the new scientific discipline of biological
psychiatry is inescapably culture-bound. Yet "Progress" that doesn't leave us emotionally better off
would seem something of a misnomer.

Not merely has there been no discernible growth in average mental health to match the tempo
of scientific advance, technophobes claim there never will be such a mental health revolution. As
long as we rely on the same legacy wetware to animate our lives, the neo-Luddites and religious
fundamentalists may even be right. Our levels of well-being - and ill-being - compute fitness
functions that served the inclusive fitness of our DNA in our ancestral environment in Africa. Our
genes didn't design us with the emotional welfare of their throwaway vehicles in mind. So the
genetically adaptive hedonic treadmill - for many of us better named the dolorous treadmill -
ensures that average levels of well-being/ill-being of Darwinian life remain stagnant. Six months
after winning the national lottery or becoming quadriplegic in a catastrophic accident, the
winner/victim statistically reverts to his or her average level of ill-being/well-being before the
win/trauma. Hence such affirmations as Rajinder Johar's "The Joy of Quadriplegia". Illustrating the
hedonic treadmill at its most extreme, "locked-in syndrome" leaves its victims paralysed. The
subject is fully conscious but unable to move any extremities, talk, or make horizontal eye
movements. Yet in the words of James Hall, longest surviving (2002) American victim of a midbrain
pontine stroke: "In some ways, my stroke was a blessing....Since my stroke, I've published books,
articles, poems. I'm busier and happier than I've ever been." Completely paralysed, Mr Hall
communicates by focusing on particular letters that his computer picks up from his limited eye-
motions.

Such triumph-of-the-human-spirit stories are comforting, up to a point. The downside of the

emotional homeostasis they reflect is that millions of temperamentally depressive and dysthymic
people would feel gloomy in the Garden of Eden. Again, this hypothesis isn't easy to test rigorously.
The more dramatic manifestations of emotional homeostasis at work are hard to investigate
ethically in well-controlled prospective studies. Anecdotes and impressions aren't science. Yet the
cumulative evidence for a genetically constrained "set-point" in our pleasure-pain axis is compelling.
The dismally low dial-setting doesn't bode well for any utopian project based around mere social
reform.

Fortunately there is no reason, in principle, why an analogue of Moore's law can't be

implemented in successive generations of the reward circuitry of organic life-forms. The affective,
aesthetic, intellectual, interpersonal (and spiritual?) well-being of neurochemical robots like us can
be genetically pre-coded. If rationally redesigned, our enlightened successors may view today's
"natural" rewards as poor surrogates for genetically underwritten happiness. When the mechanisms
underlying bliss and its gradients are understood, the molecular machinery of the sublime can be
modulated - and amplified indefinitely. Within a few decades at most, we will be scientifically
enlightened enough to redesign the neurochemical pathways of emotion. Meanwhile our pleasure
centres are too small for us to flourish; and their functional architecture is inefficient. They needn't
be either: our normal homeostatic "set-point" of well-being can be genetically ratcheted up to a far
higher plane; and archaic Darwinian notions of mental "illness" and "wellness" consigned to oblivion.
Gradients of indescribable happiness can potentially animate our lives no less powerfully than
gradients of ill-being. Until this fabulous era dawns, then - to borrow the words of Oscar Wilde - "we
are all in the gutter, but some of us are looking at the stars".

Critically, such gradients of celestial bliss can also be lucid, serene, entactogenic and
empathetic - i.e. MDMA-like and better, not manic or vulgarly hedonistic. The godlike powers of
tomorrow's biotechnologists will allow the neurological substrates of empathy and self-insight to be
permanently up-regulated. Aesthetically, the mundane ugliness of life in the present epoch can be
replaced by gradations of hitherto unimaginable beauty. Potentially again, an E-like magic can
imbue the texture of normal waking consciousness. If we so wish, our emotional palette can be
genetically enriched, mixed and then pharmacologically refined in ways that transcend the crude
primary colours of our Darwinian past.

Counter-intuitively, yet indispensably for the long-term evolutionary stability of a ecstatic

society of redesigned post-humans, allelic combinations that promote blissful empathy can also
potentially be fitness-enhancing - in the technical Darwinian as well as in the popular sense of
"fitness". The dawning reproductive era of "designer-babies" promises to be empowering because
the capacity for parental love and nurture can be genetically and pharmacologically enhanced, not
just levels of personal happiness, health and superintelligence. The age-old scourge of child-neglect
(and worse) can be relegated to evolutionary history. Very speculatively, our future offspring may
not merely be more loved by their caregivers, but much more "loveable" too. For if given the
[genetic] freedom to choose, then parents-to-be may understandably want their offspring to be
loving as well as smart and happy.

The prospect of unleashing such parental freedom is disturbing to most of us. Why not leave
babymaking, as before, either to the mysterious workings of Providence or the blind shufflings of
selfish DNA? Yet now we're imminently free to choose, there is nothing self-evidently morally
admirable about playing genetic Russian-roulette with the lifeforms we create. Many of the nastier
behaviours and modes of consciousness that so often proved fitness-enhancing in the ancestral
environment will cease to be adaptive if the alleles that promote them tend to be shunned by
prospective parents intent on creating the children of their dreams. The "nastier" alleles may well
get out-competed. Selection pressure will tend to favour a very different range of heritable adaptive
traits once evolution is no longer "blind" i.e. when genotypes are parentally chosen or designed in
anticipation of their likely effects on a child's behavioural phenotype. If we want to, we can
systematically redesign ourselves and choose the traits of our offspring. The details, for sure, are
sketchy. Reproductive science and genetic engineering are in their infancy. But Homo sapiens is
poised to bootstrap its way out of the cruel Darwinian abyss.

Inevitably, talk of treating humans like organic robots, and then mooting a baseline of mental
health orders of magnitude richer than the Darwinian mind can contemplate, sounds fantastical
today. In the context of our traditional conceptual framework, the idea of an analogue of Moore's
law for successive generations of human mental health evokes thoughts of cloud-cuckoo-land, not a
global health-plan. Set against the daily messiness of our ecstasy-impoverished lives, the prospect
of using biotechnology to abolish suffering, and a post-Darwinian transition to paradise-engineering,
strikes most of us as fanciful, its liberatory potential just a mirage. At best, such heady words fall
lifelessly off the page or screen. Yet a major discontinuity - a momentous evolutionary transition in
the development of life on earth - is imminent as the biotechnology revolution unfolds. The advent
of genomic medicine is set to challenge the old Darwinian regime of natural selection and the
emotionally crippled minds it spawned.
 In the long run, genomic medicine can underwrite mental and physical superhealth for
everyone. For in principle, lifelong well-being can be genetically hardwired from conception. In the
short run, better-designed research tools and therapeutic agents can probe, and then repair, our
damaged minds. As chemical stopgaps go, MDMA is a magical revelation. It's perhaps the best aid
to insight-oriented psychotherapy ever synthesized. Tragically, when MDMA is used to excess the
outcome can be harmful, not healing. So as a weekend club drug, MDMA is seriously flawed. Today,
of course, empathogens and entactogens are outlawed for any purpose. The altered states of
consciousness they induce are criminalised. People who take such agents are stigmatised as "drug
abusers". Yet some MDMA users feel, rightly or wrongly, they've been granted a tantalising glimpse
of what true mental health may be like in centuries to come; and an insight into what the rest of us
are missing.

David Pearce
(last updated 2010)

"Faster, faster, until the thrill of speed overcomes the fear of death."
Hunter S. Thompson

The amphetamines are potent psychomotor stimulants. Their use causes a release of the
excitatory neurotransmitters dopamine and noradrenaline (norepinephrine) from storage
vesicles in the CNS. Amphetamines may be sniffed, swallowed, snorted or injected. They
induce exhilarating feelings of power, strength, energy, self-assertion, focus and
enhanced motivation. The need to sleep or eat is diminished. The release of dopamine
typically induces a sense of aroused euphoria which may last several hours: unlike
cocaine, amphetamine is not readily broken down by the body. Feelings are intensified.
The user may feel he can take on the world.

The euphoria doesn't last. There follows an intense mental depression and fatigue.
Amphetamine depletes the neuronal stores of dopamine in the mesolimbic pleasure
centres of the brain.

More than any other illegal drug, speed is associated with violence and anti-social
behavior. Occasional light and infrequent use is probably relatively harmless; but heavy
chronic use can lead to stereotypies of behavior, depressive disorders, "meth bugs" akin
to cocaine-induced formication, strain on the cardiovascular system, increasing
behavioral disintegration, and outright "amphetamine psychosis".

Amphetamine is structurally related to ephedrine, a natural stimulant found in plants of

the genus Ephedra. It is also structurally related to adrenaline, the body's "fight or flight"
hormone. Amphetamine was first synthesised by Edeleano in Germany in 1887, but it only
entered clinical medicine in the late 1920s when its psychostimulant effect was
recognised. The US medical and pharmaceutical establishment was worried that supplies
of ephedra in faraway China would be exhausted. Amphetamine promised a cheap and
synthetic substitute. Like ephedrine, amphetamine dilates the bronchial small sacs of the
lungs, a great blessing for sufferers from breathing disorders. So in 1932, Smith, Kline
and French introduced the famous Benzedrine Inhaler.
 Amphetamine sulphate was aggressively marketed for asthmatics, hay-fever
sufferers and anyone with a cold. Amphetamine was soon available in pill form too. "Pep
pills" were sold over the counter for all manner of ailments. Doctors prescribed
amphetamine for depression, Parkinson's disease, epilepsy, travel-sickness, night-
blindness, hyperactive disorders of children, obesity, narcolepsy, impotence, and apathy
in old age.

Soldiers on both sides in World War Two consumed millions of amphetamine tablets. This
practice sometimes caused states of quasi-psychotic aggression in the combatants.

From 1942, Hitler received daily methamphetamine injections from his quack doctor
Morell. This corrupted his judgement, undermined his health and probably changed the
course of the War.

'Ice' is recrystalised methamphetamine hydrochloride, a potent stimulant. Ice will

dissolve in water and break down to smaller particles. It generally takes the form of clear
crystallised chunks. Ice induces a profound sense of euphoria in the user by blocking the
reuptake, and stimulating the release, of dopamine and noradrenaline in the central
nervous system. Ice is a "power drug". Methamphetamine use is typically followed by
prolonged depression and fatigue. In contrast to base cocaine, smoking meth will extend
its effects for up to 24 hrs per ingestion. Smoked in a base form, meth is unappetisingly
known on the street as SNOT. It can only be smoked. SNOT gets its name on account of
its resemblance to the natural product of the same name. It is very addictive.

The effects of using methamphetamine may include:

• extreme elation
• wakefulness
• alertness
• enhanced self-confidence
• aggression
• talkativeness
• loss of appetite
• increased intiative
• increased physical activity

Withdrawal symptoms may include:

• severe craving
• deep depression
• fatigue
• inertia
• paranoia
• psychosis

Smokable methamphetamine is similar to smokable cocaine, crack. They may both

briefly be delightful. But they offer only a toxic and delusive short-cut to the biological
nirvana awaiting our descendants.
 http://amphetamines.com/refs/index.html

Abstract

A general synthesis of perfluoroalkylated amphetamines is presented. Initially, 1-aryl-1-iodo-2-

(perfluoroalkyl)ethylenes are prepared by radical addition of perfluoroalkyl iodides to arylacetylenes.
Key step of the reaction sequence is the following dehydroiodination in the presence of n-BuLi to give 1-
perfluoroalkyl-2-arylacetylenes in situ, which are reacted with secondary amines to produce
perfluoroalkylated enamines in a new one pot procedure. Final hydrogenation yields the desired products
in good yields. By using N,N-dibenzylamine or N-benzylamines the corresponding primary and
secondary perfluoroalkylated amines are easily available.

Graphical abstract

A general method for the synthesis of fluoroalkylated amphetamine derivatives is presented starting from
commercially available arylacetylenes. The method allows the preparation of primary, secondary, and
tertiary amines.

Introduction

First of all many thanks go to CHEM_GUY for his continuous urging of the Hive community to try
Urushibara Nickel reduction on phenylnitropene. This reduction turned out to be easier than any so far
encountered. This is not based on any of the excellent references pertaining to Urushibara that have been
mentioned on the hive, only chem_guys postings!

Procedure

Dissolve 4.0g Nickel Chloride hydrate (light green crystals) in 75 ml 95% ethanol w/ mag stirring and
warming to 50°C. After salt is dissolved remove stir bar and add 1ml water and 1ml conc. HCl. [1] While
solution at 50°C slowly add 5g regular Reynolds wrap torn up into 0.25 x 1.0in strips in 1g portions with
manual stirring. The aluminum will SLOWLY react with the nickel salt forming the metal Ni(s) through
metathesis as a dark grey chunky powder which settles to the bottom. A gentle effervescence of hydrogen
occurs during reaction. Add aluminum at a rate that maintains a steady effervescence and keeps
temperature roughly in the 50°C range. Note this may take up to two hours! At the end of Al addition all
green color from nickel salt should be discharged. If any color remains add another gram of aluminum
and wait for soln to clear. Precipitated Nickel powder was added to 100ml 20% NaOH soln and manually
stirred at 60°C for 30 min. Excess NaOH is decanted and nickel is washed with 5 x100ml aliquots of
distilled water to remove excess base. At this point Urishubara nickel catalyst is prepared and ready for
reduction.

Dissolve 5g pure phenylnitropropene in 50ml Ethanol and add to Ni solution [2]. Now slowly add 3ml
conc. HCl [3] and 1 gram shredded aluminum w/ manual stirring. Aluminum will slowly dissolve with a
more vigorous effervescence of hydrogen than the first step. Maintaining good stirring with a glass
stirring rod is essential in beginning. Attempted magnetic stirring will result in frustration because nickel
is ferromagnetic and will stick to stirbar preventing surface area exposure necessary for reduction. After
aluminum is dissolved add three more milliliters HCl and one more gram Al. Repeat adding acid and Al
until 10 grams Al and about 30ml HCl has been added. Aluminum reacts slowly. Expect addition to take
about six hours, longer if temp falls below 50°C. Constant stirring towards end is not necessary, just give
mix a good stir occasionally.

After all aluminum is added and mostly decomposed slowly pour in a soln of 30g NaOH in 100ml H20
with careful stirring. Wear goggles and be careful! Base neutralization is highly exothermic! In 30
minutes all aluminum sludge will solvate into bottom aqueous layer and a nice orange alcohol layer
reeking of amine will settle out on top. Nickel is not dissolved by the NaOH so it will remain floating
around between the two layers but this does not present a major problem. After all, it’s not poisonous like
mercury or anything! Now decant off the top orange organic layer and distill off alcohol down to a
orange stinky syrup completely different smelling than the P2NP. Dissolve these goodies in acetone and
slowly add sulfuric acid to precipitate the amine sulfate. Voila!!!!!! about 3 grams light yellow
amphetamine sulfate.

Notes

[1] Addition of water and acid found to be necessary to initiate rxn between NiCl2 and Al.

[2] When nitropropene was added to NiCl2 soln before conversion to Ni powder was complete some
polymerization occurred greatly reducing yield. It seems essential to add P2NP to rxn after Ni is fully
precipitated.

[3] Use of Sulfuric acid produced inferior results causing polymerization of P2NP to red tar.

Increasing Yield: Use overhead mechanical stirring to keep nickel catalyst better suspended during
reduction. Re-extract aqueous NaOH/Al layer w/ toluene and work up in standard manner. Use larger
amount of nickel catalyst and more aluminum for H2 generation.