Stereospecific effects of acetylcarnitine on the spontaneous activity of brainstem neurones and their responses to acetylcholine and serotonin.

Abstract
Acetylcarnitine is an endogenous substance, active in the CNS, but its exact role in neurotransmission is still unknown. The present study was made to analyze by means of iontophoretic administration on single neurones of the medullary-pontine reticular formation in the rat the effects of the D- and L-acetylcarnitine on spontaneous and glutamate-evoked firing and on responses to applications of some other putative transmitters, such as acetylcholine, 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA) and noradrenaline. L-Acetylcarnitine increased both spontaneous and evoked discharges, and potentiated cholinergic and serotonergic responses. The Disomer was found to be almost ineffective. Neuronal responses to L-acetylcarnitine were reduced by dihydro-beta-erythroidine and enhanced by eserine, while atropine was ineffective. L-Acetylcarnitine increased both excitatory and inhibitory responses to 5-HT and its effect on the increase in firing rate induced by serotonergic drugs was reduced by dihydro-beta-erythroidine, but not by atropine. L- and D-Acetylcarnitine did not affect GABAergic or noradrenergic transmission. These results suggest a stereospecific facilitatory action of acetylcarnitine on neuronal responses to acetylcholine and 5-HT. It is hypothesized that this action could be exerted at a presynaptic level, at least with regard to serotonergic-induced responses, and that nicotinic receptors may be involved in the synaptic mechanism of release or reuptake of both acetylcholine and 5-HT.

Acetyl-L-Carnitine (ALCAR)
L-Carnitine (-hydroxy-gammatrimethylammonium butylate) (CH3)3N+-CH2-CH(OH)-CH2-COO- is a nutrient normally obtained in the diet from

meat (muscle). It is synthesized in the liver from lysine and methionine. Carnitine promotes fatty acid oxidation (fat metabolism) in muscle, thereby promoting efficient energy production. Fats (fatty acids) cannot be metabolized unless they are transported into mitochondria by carnitine. Fat is a primary source of energy in muscle, notably in heart muscle. Once in the mitochondria fatty acid chains are broken into two-carbon acetyl-CoA units (a process known as -oxidation). (A modified -oxidation also occurs in peroxisomes.) Acetyl-CoA can then be converted to ATP via the citric acid cycle and oxidative phosphorylation. The acetylated version of carnitine, Actyl-L-Carnitine (ALCAR) is absorbed by the gastrointestinal tract, enters cells and crosses the blood-brain barrier more readily than unacetylated carnitine, and is therefore more suitable as a nutritional supplement. Carnitine acetyltransferase is the enzyme catalyst which reversibly converts acetylCoA and carnitine to acetylcarnitine and CoEnzyme A (CoA) thus allowing peroxisomal -oxidation and the transport of fatty acid acetyl groups into the mitochondria for -oxidation. Carnitine acetyltransferase binding-affinity and activity decreases with age due to protein modification by aldehydes from lipid peroxidation. Supplementation of old rats with ALCAR and/or lipoic acid restored carnitine acetyltransferase binding-affinity and activity to levels observed in young rats [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Liu, J; 99(4):1876-1881 (2002)]. L-Carnitine stabilizes membranes by interaction with cytoskeletal protein and the phospholipid bilayer, by protecting cysteine residues from oxidation in membrane-bound enzymes and by direct action agaiinst lipid peroxidation [JOURNAL OF ANTI-AGING MEDICINE; Rani,JP; 4(2):145-153 (2001)]. In addition to its anti-oxidant properties, ALCAR is neuroprotective by inhibition of excitotoxicity and by providing a source of acetyl-CoA to the Tricarboxylic Acid Cycle (TCA) to promote aerobic

metabolism [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1053:153-161 (2005)]. L-Carnitine administered to aged (over 22 months old) rats for 21 days reduced DNAprotein cross-links by about half, and reduced nuclear DNA oxidative damage (8OHdG) by about a third in the striatum, hippocampus and cerebral cortex. For the whole brain, 21 days of Lcarnitine reduced mitochondrian DNA oxidative damage (8OHdG) by about one quarter [EXPERIMENTAL GERONTOLOGY; Haripriya,D; 40(2):129-135 (2005)]. Experiments show that the content of carnitine in rat heart muscle declines with age, but can be restored with ALCAR. Cardiolipin (diphosphatidyl glycerol) is a key component in mitochondrial inner membranes. Cardiolipin reduces proton permeability while serving as a transport cofactor. Cardiolipin declines with age in liver & heart mitochondrial membranes, but ALCAR supplementation restores cardiolipin to youthful levels (by an unknown mechanism) [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 959:491-507 (2002)]. ALCAR supplementation also can restore mitochondrial rRNA & mRNA to youthful levels in rat brains & hearts [EUROPEAN JOURNAL OF BIOCHEMISTRY 187:501-506 (1990)]. ALCAR supplementation reverses the age-related loss of mitochondrial cristae and, in combination with lipoic acid, substantially restored spatial memory capacity in experimental rats [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Liu,J; 99(4):2356-2361 (2002)]. In addition to its actions on fat metabolism, L-carnitine can reduce muscle apoptosis (cell suicide) through actions on gene expression and actions on apoptosis-related proteins or cytokines. Congestive heart failure is associated with myopathy (death of heart muscle cells, often due to apoptosis). L-carnitine increases gene expression of Bcl-2 protein and reduces gene expression of caspases, thereby reducing apoptosis. Chronic inflammation associated with heart failure leads to high levels of the cytokine Tumor Necrosis Factor-alpha (TNF), which promotes apoptosis. L-carnitine results in

reduced serum TNF levels [AMERICAN JOURNAL OF PHYSIOLOGY, CELL PHYSIOLOGY; Vescovo,G; 283:C802-C810 (2002)]. ALCAR protects against ischemia-reperfusion injury in both the heart [PROGRESS IN CARDIOVASCULAR DISEASES 40(3):265-286 (1997)] and brain [ANNALS OF EMERGENCY MEDICINE 29(6):758-765 (1997)]. The neuroprotective properties of ALCAR are partly associated with its ability to reduce brain dependence upon glucose metabolism [BRAIN RESEARCH 526:108-112 (1990)]. ALCAR supplementation can maintain NMDA receptors in the hippocampus at youthful levels [EXPERIMENTAL GERONTOLOGY 28:537-548 (1993)]. At the same time as ALCAR supplementation improves mitochondrial function in rat livers, it increases free radical damage due to increased energy production through oxidative phosphorylation. But supplementation with both ALCAR and lipoic acid can provide the benefits of both improved metabolic function and reduced oxidative stress. Moreover, ALCAR has been shown to enhance the ability of lipoic acid to reverse oxidative stress arising from iron overload in human fibroblasts [REDOX REPORT; Lal,A; 13(1):2-10 (2008)]. An age-dependent accumulation of iron has been demonstrated in the cerebral cortex of rats [REDOX REPORT; Suh,JH; 10(1):52-60 (2005)].

I would not take ALA. There is evidence that ALA may have irreversible harmful side effects (i.e., that cannot be reversed by stopping supplementation). See for example, the thread

http://www.imminst.o...showtopic=23646

where ALA was actually shown to be life-shortening when combined with a specific CR regime in rats. The full paper whose PDF is downloadable in that thread is interesting reading that I personally find scary (e.g., the specific life-shortening side effect of ALA can essentially last half a (rat's) life after stopping it). To me this suggests that if indeed there are negative side effects in humans discovered tomorrow, you might not be able to recover from them quickly if at all by stopping ALA.

However, you can take ALCAR without ALA. The original motivation for adding the ALA became obsolete with newer research that found that the oxidative stress found in earlier ALCAR studies on rats was due to overdosing. Lower doses were found to avoid the oxidative stress side effect and to be more effective. Some of this is discussed in the threads

http://www.imminst.org/forum/index.php?sho...55&hl=ALCAR

http://www.imminst.org/forum/index.php?sho...48&hl=ALCAR

Back to the OP, I took Alcar for about 6 months and really noticed very little. Then I stopped and suddenly...nothing - it really hadn't made any discernable change. However I have never heard of anyone harming themselves with their Alcar intake (the who ALA/RALA thing is completely different and TBH is off topic for this thread) so I would not worry about taking it.

Even if I didn't feel it in the way many others do, based on the research and anecdotal account, its probably going about its business making me slightly healthier.

Yeah, I'd really like to hear something about this. It seems to be helpful in making older people feel younger. (It also has positive cognitive effects even in younger people.) The question is, is it kind of like legalized speed for oldsters that's akin to "burning the candle at both ends", or does it actually make people live longer? I can at least say that if nothing else, it improves one's ability to exercise, and in my experience the combination of exercise and alcar seems to have helped me to mobilize fat. This was also the observation in a study on centenarians using LCarnitine. This is a thread on it with ref to the study and discussion of the effects of various forms of carnitine.

I think the stuff made me drop 5 pounds, which is surprising because I am already pretty light with an efficient metabolism. Although, that might have been from exercising as well. Main question is that people on here encourage ALA or R-Lipoc acid supplementation when taking ALCAR -- something to do with free radical production. That's what makes me ask if ALCAR has

an overall pro-aging or anti-aging benefit when taken alone, and if taken with ALA are there any drawbacks.

Acetyl L-Carnitine (aka ALCAR) or plain old L-Carnitine, is my best workout supplement. Take about 3 grams pre-workout and add 4-5 grams to my gallon of sports drink and I can tackle a 5hour running session. It gives me intensely sharp vision, I can hear a LOT better (so I have to turn my music way down) and it's a great antioxidant. It makes you look younger (anti-aging stuff) and it makes cardio days a breeze. On a tight budget, I'd stock up on ALCAR and forget the rest.

Piracetam is my second runner-up. I take 3 servings a day and it enhances my focus and concentration, especially if I'm listening to music. The other 'racetams' out there - Oxy, Ani, and Pramiracetam - been there, done that, and I'm back with good old Piracetam. Everyone's different, so I think you have to try all the 'racetams and find the one that works best for you. ALCAR Nootropics can really help you with your dependence on caffeine. There are about a half a dozen good threads here on caffeine dependence/withdrawal/replacement. ALCAR is usually mentioned; it's great for mental focus, but won't really make you feel physically stimulated.

Let us know how things work out! ALCAR, this is the best supplement in my regimen. Caffeine (always in moderation). I don't think piracetam fits in the "long term" category as I haven't heard of that many success stories of piracetam constantly performing. I've found in the past week that my daily dosage isn't really doing anything for me anymore and I'm going to take a 3 week break or so and see if I can get back on the horse after wards. I know some people report that piracetam constantly performs for them but there are many threads on here attempting to solve the "adaptation" issue. Lion's Mane, not necessarily cheap but long term is a necessity. Not a motivator, just NGF stimulator. I really think one of the best things is a good diet, good sleep, and good exercise. Make sure

you're getting all your vitamins either from what you eat or from supps (I really noticed the effects when I started supplementing Vitamin D). Living a healthy lifestyle is prolly the most beneficial thing you can do. Melatonin is helpful if you're a restless sleeper but I find the standard dosage too much (headaches) and it also leaves me really groggy in the morning upon waking.

I've also come to nootropics to hopefully stimulate my energy and motivation and I can't really say much other than ALCAR and caffeine really stimulate me (ALCAR not so much stimulating just a real fog clearer in the morning) . Piracetam gives me the ability to concentrate more but doesn't motivate me at all.

Mechanisms of ischemic neuroprotection by acetyl-L-carnitine.

Zanelli SA, Solenski NJ, Rosenthal RE, Fiskum G. Department of Pediatrics, University of Virginia School of Medicine, Charlottesville 22908, USA.

Abstract
Acetyl-L-carnitine is a naturally occurring substance that, when administered at supraphysiologic concentrations, is neuroprotective in several animal models of global and focal cerebral ischemia. Three primary mechanisms of action are supported by neurochemical outcome measures performed with these models and with in vitro models of acute neuronal cell death. The metabolic hypothesis is based on the oxidative metabolism of the acetyl component of acetyl-L-carnitine and is a simple explanation for the reduction in postischemic brain lactate levels and elevation of ATP seen with drug administration. The antioxidant mechanism is supported by reduction of oxidative stress markers, for example, protein oxidation, in both brain tissue and cerebrospinal fluid. The relatively uncharacterized mechanism of inhibiting excitotoxicity could be extremely important in both acute brain injury and chronic neurodegenerative disorders. New experiments performed with primary cultures of rat cortical neurons indicate that the presence of acetyl-L-carnitine significantly inhibits both acute and delayed cell death following exposure to NMDA, an excitotoxic glutamate antagonist. Finally, several other mechanisms of action are possible, including a neurotrophic effect of acetyl-L-carnitine

and inhibition of mitochondrial permeability transition. While the multiple potential mechanisms of neuroprotection by acetyl-L-carnitine limit an accurate designation of the most important mode of action, they are compatible with the concept that several brain injury pathways must be inhibited to optimize therapeutic efficacy.

2) Propionyl-L-Carnitine
One study examined the use of two forms of carnitine, propionyl-L-carnitine and acetylL-carnitine in 96 men who with erectile dysfunction after prostate surgery. One group were given a placebo, another group took propionyl-L-carnitine (2 grams per day) plus acetyl-L-carnitine (2 grams per day) and sildenafil (Viagra) when needed, and the third group used Viagra alone.

Propionyl-L-carnitine and acetyl-L-carnitine were found to enhance the effectiveness of sildenafil, and result in improved erectile function, sexual intercourse satisfaction, orgasm, and general sexual well-being compared to Viagra alone.

Another study examined the effectiveness of propionyl-L-carnitine supplements plus sildenafil in men with erectile dysfunction and diabetes who were previously unresponsive to Viagra alone.

Participants in the study received either propionyl-L-carnitine (two grams per day) plus Viagra (50 milligrams twice a week) or Viagra alone. After 24 weeks, propionyl-Lcarnitine plus Viagra was significantly more effective than Viagra alone.

Acetyl-L Carnitine - Is It an Alternative to Testosterone?

Summarized by Robert W. Griffith, MD July 16, 2004

Introduction Many men, as they get older, lose their sex drive; this may be associated with increased fatigue and sometimes depression. If their testosterone level is low, they are often treated with this hormone, in one form or another. But there are some risks (real or apparent) to the use of testosterone, so an alternative effective treatment would be very welcome. A group of Italian researchers have studied carnitine as a possible substitute, and have reported their findings in the journal Urology. Propionyl-l-carnitine and acetyl-l-carnitine are powerful antioxidants that have proved beneficial in diseases typical of aging (e.g. Alzheimer's, peripheral artery disease), according to some reports. Here's a summary of their study.

What was done A total of 150 men aged 60 to 74 (average age: 66) were allocated randomly to one of three groups. They had to have decreased libido and erectile quality, depressed mood and ability to concentrate, irritability, fatigue, and a free testosterone level below 6 pg/mL. They were not accepted if they had prostatic enlargement, a raised PSA (prostate-specific antigen, a marker for prostate cancer), smoked or drank alcohol, had diabetes, a previous MI, or other possibly relevant diseases. The first group was given testosterone undecanoate (160 mg/day), the second group propionyl-l-carnitine plus acetyl-l-carnitine (2 g/day of each), and the third group was given starch tablets (as a placebo). The treatment period was 6 months. A battery of lab tests and questionnaires were conducted before, during (at 3 and 6 months) and 6 months after the treatment. They covered cardiovascular strength, sex drive, sexual satisfaction, hormone levels in the blood, prostate size, PSA level, mood (using the Hamilton Depression Scale), and fatigue. Twelve men dropped out before treatment started, when they learned that they might receive a placebo; 8 others dropped out during the study, but this was not due to any side effect of treatment. This left 130 men in the study - 40 on testosterone, 45 on carnitine, and 45 on placebo.

What was found Both testosterone and carnitine improved sexual performance, as shown by nocturnal penile tumescence measurements1 and the International Index of Erectile Function score; carnitine was found to be more effective than testosterone in this respect. Both treatments improved the blood flow through the arteries supplying the penis to an equal extent; these measurements had returned to baseline levels at 6 months after the end of treatment. Testosterone has the reputation of increasing prostate size. This was confirmed here - the testosterone treatment group had increased prostatic volume at 3 and 6 months, which returned to normal after 6 months' off treatment. At the same time, LH (luteinizing hormone) levels were lowered. PSA levels were unchanged. Carnitine had no effect on prostate volume, LH, or PSA levels.

Both testosterone and carnitine significantly improved the symptoms of depression and fatigue, as measured by questionnaires. The side effects reported were negligible, and were the same in each treatment group.

What does this mean? In this study design, both testosterone and carnitine were effective in improving the symptoms reported by some aging males. Carnitine was superior to testosterone in their action on early symptoms of impotence, but otherwise their effects were roughly equal. Testosterone was associate some degree of prostate enlargement, but carnitine was not. Does this mean aging men should consider carnitine rather than testosterone for their problems? There are reasons for caution. First, the mechanism of action of carnitine is not clear. The authors of the report state that the reason other antioxidants (such as vitamin E, tocopherol, or glutathione) don't work in aging men - while carnitine does - is because they have a different point of attack in the biochemical processes. The rationale for using testosterone, on the other hand, is clear.

Second, carnitines (acetyl-l- and propionyl-l-carnitine) have been investigated for several years in several conditions: poor semen quality leading to infertility, Peyronie's disease (bent shaft of penis), peripheral arterial disease, and Alzheimer's disease. In none of these conditions has carnitine proved to be an effective treatment in "adequate, well-controlled clinical studies" - the FDA criterion for efficacy and safety of a new drug. See the third link below, which takes a cool look at the likely benefits of carnitine.

Clearly we need another well-controlled study, rather than basing a new treatment on the results of this study alone. We can hope that this will be done soon, and that the results confirm carnitine's superiority to the potentially risky use of testosterone in older men. Otherwise, we must conclude that this study is just another false alarm in the history of carnitine research.

Propionyl-L-Carnitine, Acetyl-L-Carnitine, and Lipoic Acid

CarnitinesBetter Than Testosterone for Impotence

Propionyl and acetyl carnitine derivatives beat

sex hormone at its own game and enhance Viagras benefits By Will Block I kissed my first woman and smoked my first cigarette on the same day. I have never had time for tobacco since. Arturo Toscanini taliansyou gotta love em. Warm, passionate, ebullient, and full of the joy of life and love. What fun they are to be with, and what a marvelous country and culture they have: the timeless beauty of the land and sea, the inspiring historical heritage, the magnificent art and architecture, the brilliant science and engineering, the glorious music, the fabulous food and wine, the sophisticated fashions, the sexy cars, and Sophia Loren! And, oh, the languagewas there ever a more seductively beautiful tongue than Italian? It seems made for music and made for love. Madonna (full name: Madonna Louise Veronica Ciccone) once said, You dont have to have a language in common with someone for a sexual rapport. But it helps if the language you dont understand is Italian. Your partner could be reciting the tax code, for all you knew, and it would still sound deliciously sexy. Men, Stand Up and Fight! The Italians, it could be said, are in love with amore. Where theres love, of course, there tends to be sex, so it seems fair to say that Italians have more than a passing interest in mankinds favorite pastime. All of which may or may not have anything to do with the fact that some recent studies on the subject of sexual function (dysfunction, actually) were conducted by a team of Italian researchers in Ferrara, Bologna, Fermo (Ascoli Piceno), and Rome. Two of the scientists are the inventors of a patented process involving the combined use of two chemical compounds, propionylL-carnitine (PLC) and acetyl-L-carnitine (ALC), for the therapy of symptoms associated with partial androgen deficiency of the aging male.1

By androgen they mean the male sex hormones, especially testosterone. The primary symptoms in question are impotence, depressed mood, and fatigue. Its no surprise that impotence (aka erectile dysfunction) does a mans mood no good, and fatigue seems to be a natural part of aging in any case. But should a man simply accept all this as an inevitability of the aging process? Certainly not! He should stand up and fight for what is rightfully his: a degree of vigor that, while it might not match that of his youth, still far exceeds what a stingy Mother Nature doles out to those who fail to grab the bull by the horns. In other words, a man should behave like an Italianlike Toscanini, for example, who clearly had his priorities straight. Whether the aging Maestro (he lived to be 89) ever felt the need for some pharmacological enhancement for his amorous pursuits, we do not know, and its none of our business anyway. What we do know is that todays man has available a variety of prosexual boosters that men of earlier generations could only have dreamed about (some dreams do come true). Prescription Remedies Carry Risks Breathes there a man who hasnt heard of Viagra, Levitra, and Cialis? These are the Big Three sexual enhancers of the pharmaceutical world (they enhance performance, but not libidothats still the mans responsibility). We hear about their benefits all the time, but what we seldom hear is that these wonder drugs have some less than wonderful side effects (especially in older men), including headache, flushing, dyspepsia, nasal stuffiness, painful urination, diarrhea, and visual disturbances. Its even possible for users of these drugs to experience sudden blindness; this prompted the FDA to issue a warning about all three of them in 2005. A more traditional therapy for male sexual problems is testosterone, which enhances both libido and performance, as well as muscle mass and strength, bone density, mood, and overall energy. Testosterone, however, is generally recommended only for men with unusually low levels of it, and, like most other steroid hormones, it is not without its dangers. It can, e.g., increase the risk for stroke, aggravate sleep apnea, increase PSA

(prostate-specific antigen) levels, and cause enlargement of the prostate gland. Although it probably does not cause prostate cancer, it may enhance the growth of an existing prostate cancer. (Testosterone is also used, by the way, to treat women for breast cancer and low libido.) Carnitine DerivativesAn Attractive Alternative Is there anything that can simulate testosterones prosexual effects, but without the risks? The Italian researchers mentioned above think there is. Italy has long been in the forefront of studying and using the amino acid carnitine and its derivatives (see the sidebar) for boosting energy metabolism, as well as for other therapeutic purposes. Thus it was natural to think of these compounds as potential prosexual supplements. [For more information on this subject, see Acetyl L-Carnitine Can Help Straighten Your Penis (October 2001) and Testosterone Is Life, If Youre a Man (February 2002).]

Acetyl-L-Carnitine and Propionyl-L-Carnitine

Both acetyl-L-carnitine (ALC) and propionyl-L-carnitine (PLC) are natural substances that help boost our energy metabolism by acting as sources of their parent compound, carnitine, an unusual type of amino acid.* Carnitine in our cells facilitates the transport of fatty acid molecules across the mitochondrial membranes. Without these fuel molecules, our mitochondria (the cells chemical powerhouses) would sputter and dieand so would we. Our carnitine levels tend to decline with age, so maintaining a healthy supply of this compound is a good idea.

*Acetyl is pronounced ahSEEtl, and propionyl is pronounced PROpeeohneel. The acetyl group (CH3CO) comes from acetic acid (CH3COOH), and the propionyl group (CH3CH2CO) comes from propionic acid (CH3CH2COOH).

For energy metabolism, ALC is more important than PLC, because it acts as a delivery system for both carnitine molecules and acetyl groups. The latter are extremely important in many of lifes biochemical processes, such as the production of acetyl coenzyme A (the most important intermediary in the generation of energy from amino acids, fats, and carbohydrates) and acetylcholine (the neurotransmitter whose depletion in the brain is a hallmark of Alzheimers disease). ALCs role in boosting energy metabolism may explain in part why it improves memory and other cognitive functions in people with mild cognitive impairment and early Alzheimers disease. [See Acetyl L-Carnitine Protects Memory and Intellectual Functions (August 2005).] ALC also exerts a neuroprotective effect, which may help explain its tendency to inhibit the peripheral neuropathies that often accompany diabetes. And ALCs methyl-group-donating action helps to prevent eye damage caused by a harmful, age-related process called glycation, which degrades the proteins in our lenses. Cardioprotective properties have been attributed to ALC, and to PLC as well. There is evidence suggesting that PLC, in particular, may be helpful in treating such cardiovascular disorders as congestive heart failure, angina pectoris, and intermittent claudication (pain upon walking, owing to peripheral arterial disease). Whether for therapeutic purposes or as a nutritional supplement, its generally more effective to take PLC than carnitine itself; the same is true of ALC. Contrary to some claims, ALC and PLC are not antioxidants. In fact, they tend to have an indirect pro-oxidant effect because of their enhancement of cellular energy metabolism, which is the primary source of free radicals in our bodies. This tendency can be offset, however, with the potent antioxidant lipoic acid, which should therefore always be taken along with ALC and PLC. [See Can Acetyl L-Carnitine and Lipoic Acid Slow the Aging Process? (October 2004).]

The researchers conducted a randomized, double-blind, placebo-controlled trial of the effects of propionyl-L-carnitine and acetyl-L-carnitine, taken together, versus those of testosterone undecanoate (a commonly used chemical derivative that well refer to simply as testosterone).1 They recruited 150 generally healthy men, aged 6074 (average 64), whose chief complaints were those typical of older men who feel that theyre slowing down in various ways. These symptoms include decreased libido, partial to complete impotence, depressed mood, and a reduced ability to concentrate, as well as irritability and fatigue. All the men had very low serum testosterone levels.

The carnitine derivatives PLC and ALC produced improvements in virtually all the measures used in this study, and greater improvements than testosterone in several of them.

Of the 150 men, 130 completed the 12-month trial. They had been divided into three groups: Group 1 received 160 mg/day of testosterone; Group 2 received 2 g/day of PLC and 2 g/day of ALC; and Group 3 received a placebo (a 500-mg starch tablet). The men were examined at the outset of the trial and again at 3 months and 6 months, after which the treatments were halted; the final examination was performed 6 months later. The following variables were measured:

Total PSA PSA is a glycoprotein whose elevated levels in the blood can indicate prostate cancer. The PSA test routinely administered to aging men is useful but usually not definitive; it must be used in conjunction with the familiar digital rectal examination and any other tests the physician deems appropriate.

Prostate volume This can be measured by ultrasonography (ultrasound). It provides a clue to testosterone activity, which tends to enlarge the prostate gland.

Peak systolic velocity This is the maximum rate of blood flow, measured by Doppler ultrasonography (a special technique for measuring flow rates) within the cavernosal arteries of the penis during systole (the hearts contraction).

End diastolic velocity This is the minimum rate of blood flow, measured at the end of diastole (the hearts resting period between contractions). Resistive index (RI) This is a useful number calculated from the two measured blood velocities. The higher the RI, the better, in terms of erectile function. Nocturnal penile tumescence (NPT) This is measured using an ingenious device that monitors the peniss size and rigidity while the patient is asleep; it records the number and duration of erections that meet certain minimum criteria.

Total and free testosterone Much of a mans testosterone is chemically bound to proteins in the blood and is thus not bioavailable (free) for hormonal action. Thus the most important measure is that of free testosteroneespecially in aging men, in whom it continually declines as a percentage of the total.

Lutropin Also called luteinizing hormone, this pituitary hormone stimulates the production of testosterone by the testes; it also stimulates estrogen production and ovulation in women. (All the sex hormones, and the hormones that stimulate their production, have roles to play in both sexes.)

Prolactin This is a pituitary hormone that stimulates and maintains the secretion of breast milk. Its relevance in men is that an age-related increase in prolactin can inhibit the release of gonadotropins, which are hormones that stimulate the growth and function of the gonads in both sexes. Thus, excessive prolactin levels would suppress testosterone production.

Testosterone Increased Prostate Volume Regarding the results of this trial, lets get the placebo group out of the way first: these men showed no significant changes in any measurewhich is surprising, considering how strong the placebo effect usually is. In any case, it means that the effects found in the two treatment groups were real as measured and did not require the subtraction of a placebo effect.

Both Group 1 (testosterone) and Group 2 (PLC/ALC) benefited significantly from their respective treatments, with Group 2 faring better overall. First of all, neither treatment increased PSA levels (which is good). The testosterone group showed a significant increase in prostate volume (not good), which was to be expected. After 12 months (i.e., 6 months after treatment had ceased), prostate volume had decreased significantly, but not to the baseline level. By contrast with the testosterone group, the PLC/ALC group showed no increase in prostate volume. Bigger and Better Things to Come with PLC/ALC Both groups showed similar, significant increases in the resistive index at 3 months, and these improvements were maintained at 6 months. After 6 more months without treatment, however, the RI had reverted to baseline values in both groups. The same pattern was observed with nocturnal penile tumescence, except that here the PLC/ALC group had significantly better results: whereas the total duration of NPT increased by 48% in the testosterone group, it increased by 88% in the PLC/ALC group. (I know what youre thinking: Big dealwhat good does more NPT do me? I sleep right through it anyway. But its a sign of bigger and better things to come when youre awake!)

The men who took PLC plus sildenafil had significantly better results in virtually all respects than the men who took only sildenafil.

As expected, testosterone treatment increased both total and free testosterone levels in Group 1, and it reduced the levels of lutropin (via a negative feedback mechanism); it had no effect on prolactin levels. In Group 2, by contrast, treatment with PLC/ALC produced no changes in any of the hormone levelsmeaning no undesirable consequences from any such changes.

PLC/ALC Outperforms Testosterone Leaving the realm of laboratory tests, the researchers also evaluated the mens sexual function, using the International Index of Erectile Function (IIEF), a standardized set of questionnaires in five categories. Following are the categories and the results observed:

Erectile function Both testosterone and PLC/ALC produced significant improvement at 3 months, with further improvement at 6 months. The improvement with PLC/ALC was significantly better than that with testosterone at both time points.

Satisfaction with sexual intercourse With both treatments, there was significant improvement at 6 months. Orgasm There was no improvement with testosterone, but PLC/ALC produced significant improvement at 3 months, with further improvement at 6 months. Sexual desire Both treatments produced significant improvement at 3 months, but no further improvement at 6 months. General sexual well-being There was no improvement with testosterone, but PLC/ALC produced significant improvement at 3 months, with no further improvement at 6 months.

Depression and Fatigue Are Both Improved Leaving no stone unturned, the researchers also evaluated the mens mood, using a standardized test called the Hamilton Depression and Melancholia Scale. Both treatment regimens produced significant mood improvement at 3 months, with no further improvement at 6 months. At both time points, the scores for the PLC/ALC group were significantly lowermeaning better moodthan those for the testosterone group. Finally, the researchers also measured the mens fatigue level, again using a standardized test. The fatigue scores dropped significantlymeaning more energyfor both groups at both time points, by roughly the same amounts. Throughout the trial, there were no significant side effects in either group.

In summary, the combined carnitine derivatives, PLC and ALC, produced improvements in virtually all the measures used in this study, and greater improvements than testosterone in nocturnal penile tumescence, in three of the five measures of erectile function (per the IIEF questionnaires), and in moodall without altering hormonal levels or enlarging the prostate gland. PLC/ALC Enhances Benefits of Sildenafil The prosexual benefits of PLC and ALC are supported by the results of another recent study by the same research group, this one on 96 men (average age 61) who had undergone a prostatectomy of the kind that largely spares the nerves required for erections to occur.2 Many such men experience erectile difficulties and find help in products such as Viagra (sildenafil). The researchers surmised that PLC and ALC would enhance sildenafils efficacy in restoring or improving sexual activity after the operation, and they found that this was true. The men who took PLC/ALC (2 g/day of each) in addition to sildenafil (as required) for 4 months had significantly better results in virtually all areas of sexual function than the men who took only sildenafil (as required).

Bottling up our emotions is bad for us in many ways. Now we have learned that this tendency is also associated with impotence.

Another Italian research group studied the effects of PLC in combination with sildenafil in 40 diabetic men (average age 64) who suffered from impotence, which is a common consequence of that disease.3 (To make matters worse, many of the drugs used to treat diabetes can, in certain cases, contribute to impotence, and they can reduce sildenafils efficacy.) In this 6-month study, the men who took PLC (2 g/day) plus sildenafil (twice

weekly) had significantly better results in virtually all respects than the men who took only sildenafil (twice weekly). Lipoic Acid Also Gives Men an Erectile Boost Its worth noting that another natural supplement found to be helpful for diabetic men with impotence is the potent antioxidant lipoic acid, a compound widely used in Europe for the treatment of diabetes. [See Lipoic Acid, the Antioxidants Antioxidant (July 2001), Lipoic Acid Helps Fight Diabetes (December 2003), and Can Lipoic Acid Fight Diabetes-Induced Impotence? (April 2006).] Its advisable for those taking a carnitine derivative to take lipoic acid as well (see the sidebar). Men, Let It All Hang Out (Emotionally, That Is) No one ever accused the Italians of being shy about expressing themselves openly and volubly. Luckily for them, their unabashedly emotional nature may help to keep them healthy. Doctors have long known that bottling up our emotions something that many men are accused of by their long-suffering wives or girlfriendsis bad for us in many ways. Now we have learned (from yet another group of Italian researchers, naturally) that this tendency is also associated with impotence.4 In studying 100 men (average age 40) with psychogenic impotence, i.e., impotence not caused by organic disease, the researchers found an unusually high prevalence (34%) of alexithymia, the psychiatric term for a difficulty in recognizing, acknowledging, and communicating emotions openly (those men were not behaving like proper Italians!). The lesson here is that, when it comes to love and sex, our emotions do not want to be bottled upthey want to be free, so that we can well, you know. Bottles are good, however, for containing nutritional supplementsand if some of those might help revitalize your sex life, well then, hit the bottle!
References

1. Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology 2004;63:641-6. 2. Cavallini G, Modenini F, Vitali G, Koverech A. Acetyl-L-carnitine plus propionyl-Lcarnitine improve efficacy of sildenafil in treatment of erectile dysfunction after bilateral nerve-sparing radical retropubic prostatectomy. Urology 2005;66:1080-5. 3. Gentile V, Vicini P, Prigiotti G, Koverech A, Di Silverio F. Preliminary observations on the use of propionyl-L-carnitine in combination with sildenafil in patients with erectile dysfunction and diabetes. Curr Med Res Opin 2004;20:1377-84. 4. Michetti PM, Rossi R, Bonanno D, Tiesi A, Simonelli C. Male sexuality and regulation of emotions: a study on the association between alexithymia and erectile dysfunction. Int J Impot Res 2006;18:170-4.

Increases in VO2max and metabolic markers of fat oxidation by caffeine, carnitine, and choline supplementation in rats.
Sachan DS, Hongu N. Department of Nutrition and Agricultural Experiment Station, University of Tennessee, Knoxville, TN 37996-1900, USA.

Abstract

We have previously shown that the combination of caffeine, carnitine, and choline supplementation decreased body fat and serum leptin concentration in rats and was attributed to increased fat utilization for energy. As a result, it was hypothesized that the supplements may augment exercise performance including physiological and biochemical indexes. Twenty 7-week-old male Sprague-Dawley rats were given free access to a nonpurified diet with or without supplementation of caffeine, carnitine, and choline at concentrations of 0.1, 5, and 11.5 g/kg diet, respectively. One half of each dietary group was exercised on a motor-driven treadmill for 3 weeks and maximal aerobic power (VO(2)max) was determined on the 18th day of exercise. Rats were killed 24-hr postexercise, and blood, regional fat pads, and skeletal muscle were collected. The VO(2)max was increased (P < 0.05) in the supplemented/exercised group; however, the respiratory quotient (RQ) was not affected. Postexercised concentrations of serum triglycerides were decreased but beta-hydroxybutyrate, acylcarnitine, and acetylcarnitine were increased in the supplemented animals. The changes in serum metabolites were complemented by the changes in the muscle and urinary metabolites. The magnitude of increase in urinary acylcarnitines (34-45-fold) is a unique effect of this combination of supplements. Cumulative evidence indicates enhanced beta-oxidation of fatty acids without a change in the RQ because acetyl units were excreted in urine as acetylcarnitine and not oxidized to carbon dioxide. For this phenomenon, we propose the term "fatty acid dumping." We conclude that supplementation with caffeine, carnitine, and choline augments exercise performance and promotes fatty acid oxidation as well as disposal in urine.

Choline is also a sterol-1 factor inducer of AP-1. AP-1 induces retinoic receptor RXR and the tocopherol receptive receptor, PPAR-gamma, the first is involved with repair processes and the second with fatty acid oxidation.

Note that in the first two recent citations, using exercised

female test cohorts using carnitine and choline, circulating vitamins A and E were increased, despite there being no change in diet (not supplemented).

These two compounds are powerful inflammation control agents, via their nuclear receptor action. Anti-inflammatory activity is a natural reaction to elevated oxidative stress - and that is curtailed by NAC, glutathione and other antioxidants, but only if they are regenerated.

Regeneration requries methyl group donation, Choline is a major source of methyl donors and is widely represented among food groups.

It has, however, other actions, neurochemical among them (also serves an important role in phospholipid synthesis).

Thus, the caveat on dose that Vlad mentions. Sensitivity to ALCAR is direcetly dependend on methyl donor availability and glutathione and NAC regeneration in membranes.

Yeah but trouble hit the nail on the head with ALCAR producing much acetylcholine in his system, which depletes choline levels, consequentaly causing him to get headaches. Some

people reported to get neck cramps, etc if they don't supplement choline or lecithin. ALA will provide great antioxidant support and I personally don't take ALCAR without ALA (rarely) but that's slightly off topic.

I am still curious as to how conclusive it is that ALCAR causes increased fat storage around the waistline for certain phenotypes.

Kim, how much are you using again?

Yeah but trouble hit the nail on the head with ALCAR producing much acetylcholine in his system, which depletes choline levels, consequentaly causing him to get headaches. Some people reported to get neck cramps, etc if they don't supplement choline or lecithin. ALA will provide great antioxidant support and I personally don't take ALCAR without ALA (rarely) but that's slightly off topic.

I am still curious as to how conclusive it is that ALCAR causes increased fat storage around the waistline for certain phenotypes.

Kim, how much are you using again?

I'm confused I thought ALCAR was good for fatloss. Under what circumstances is it not?

If you use too much, and if you can't proper counter oxidative stress damage from increased fatty acid oxidation in mito membranes (hence, the prudent suggestion of ALA, as either RALA or GXR).

Coenzyme Q, vitamin E, and glutathione (via synthesis with NAC) have been shown to protect against mitochondrial oxidation / lipid peroxidation in cultured cells. In vivo studies remain to be conducted that definitively support use of these supplements as mitochrondrial membrane

protectants.

A useful recent reference that discusses mechanisms and novel choline derivatives:

Mitochondria-Targeted Peptide Antioxidants: Novel Neuroprotective Agents Hazel H. Szeto. Department of Pharmacology, Joan and Sanford I. Weill Medical College of Cornell University. AAPS Journal. 2006; 8(3): E521-E531.

See:http://www.aapsj.org...art=aapsj080362

BTW, I posted about ALCAR heaches a long time ago. I used lecithin and choline bitartrate to eliminate it. In the process, I used too much choline bitartrate. As it turns out, unprocessed choline bitartrate causes one's body to smell like fish. My wife didn't like that.

If you take a high dose of ALCAR when you are hungry, you should be able to feel slight pain in each side of your jaw, slightly below your ears. It can last about 15-30 min, but it is somewhat interesting.

A full blown ALCAR headaches are painful. I had it for 3 days.

Leadfoot Problem
With R(+)-lipoic acid, in short, the old animals got back their get-upand-go. But there's another possible solution to the problem of fading energy production with age, in the form of the compound acetyl-Lcarnitine (ALCAR).

ALCAR is a better-absorbed form of carnitine, an amino-acid-like substance involved in shuttling energy from fat into the mitochondria.

More: ALCAR supplements also boost levels of cardiolipin in mitochondria. Cardiolipin is a fatty substance found only in mitochondria. It's needed for the functioning of several of the energy transporters and "pumps" that help create the ion "reservoir" whose force drives ions through Complex V turbines to create energy.

As a result, adding ALCAR to the diets of old animals increases the activity of several mitochondrial energy transporters and ion pumps 78, 79 , 80, 81 and the mitochondria of old animals fed ALCAR supplements produce as much energy as those of young. 80, 82 And, again as is seen with R(+)-lipoic acid, 73 old animals fed ALCAR double the amount of distance they cover when running around in their cages. 82.

Results in humans show that this isn't just a lab-rat result. Many shortterm studies using even "standard" L-carnitine supplements have shown improvements in exercise performance in people with cardiomyopathy (weakened and structurally abnormal hearts), vascular disease, 83 heart failure, 84 or whose hearts have been damaged by a heart attack 85.

But if this makes it sound as if you should rush out to buy ALCAR supplements for mitochondrial function, there's just two little details you'll want to know. The first has nothing to do with science, and everything to do with the right of the individual to make decisions about his or her own health: "Health" Canada has decided that you can't have ALCAR or standard L-carnitine supplements.

But the second, and more important, problem is that, while ALCAR

increases the transport of fuel into the mitochondria - thereby increasing mitochondrial energy production - it doesn't improve the efficiency with which that energy is produced. In fact, old animals receiving ALCAR actually produce 30% more free radicals for every unit of energy that they produce. 82

We've already seen how much aging itself makes the mitochondria of young animals burn "dirtier" than those of young ones. 73, 74 Making the mitochondria even more polluting using ALCAR can be expected to have a serious impact on the cell, and the long-term health of the organism. Indeed, we've seen how the age-related increase of free radical production impacts the levels of vitamin C and reduced glutathione in these animals. 73, 74, 75 Well, giving old animals ALCAR supplements actually lowers antioxidant defenses even further, slashing vitamin C by an additional 50% and cutting an extra 30% off of their reduced glutathione supplies!

In other words, giving old animals ALCAR is like flooring the gas pedal on a worn-out old Cadillac: sure, the car goes faster but it also belches out more pollution. And the harder you push the engine, the dirtier its exhaust.

By contrast, you'll recall, R(+)-Lipoic Acid not only increases old animals' energy production, but also reduces the amount of free radical waste created in the process, and restores more youthful antioxidant defenses. 73, 74 So what would happen if you combined the two supplements, creating (one might expect) a vehicle which both runs more cleanly and powerfully per unit of fuel consumed (as with R(+)lipoic acid), and is running more fuel through the engine (as in

ALCAR)?

The study has been done 73, 82, 86 although the actual numbers have yet to be properly published. The results: supplementing old animals' diets with a combination of ALCAR and R(+)-Lipoic Acid simultaneously gives a boost to mitochondrial metabolism, while resulting in no increase in free radical stress. (To find out just how much more energy the mitochondria of old animals receiving both supplements produce, as compared to the extra juice they get from either supplement alone, we'll have to wait for the full publication of their results).

And crucially, free radical researcher Dr. Bruce Ames of UC Berkeley, who has been a leading force in the ALCAR research from the beginning, has recently revealed that only R(+)-Lipoic Acid has these effects. In his words, "Lipoic acid sold in a health food store is a synthetic mixture, a racemic mixture. And R[+]- is the natural form and S[-]- is an unnatural one ... And in our hands R[+]- works and S[-]doesn't." 86

Astonishing results. Results that force us to ask daring, even radical questions about the role of this orthomolecule in the fundamental processes of life and death.

It would be best to keep the phenibut for sleep and utilize the ALCAR and Sulbtiamine for an addition to a pre-workout supplement, or for focus or something.

ALCAR stimulates the growth of neurites within the brain. These neurites directly effect thought processing, reaction time, ect.

Acetylcholine synthesis is also adressed by ALCAR. This is key for proper neurotransmissions. I believe ALCAR increases dopamine production as well.

Most importantly.... ALCAR directly increases mitochondrial ENERGY production. It allows for fatty acid transport into the mitochondria.

Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-Lcarnitine therapy.
Ruggenenti P, Cattaneo D, Loriga G, Ledda F, Motterlini N, Gherardi G, Orisio S, Remuzzi G. Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, Bergamo, Italy. Comment in:

Hypertension. 2010 Feb;55(2):e13. Hypertension. 2009 Sep;54(3):462-4.

Abstract
Insulin resistance, a key component of the metabolic syndrome, is a risk factor for diabetes mellitus and cardiovascular disease. Acetyl-L-carnitine infusion acutely ameliorated insulin sensitivity in type 2 diabetics with insulin resistance. In this sequential off-on-off pilot study, we prospectively evaluated the effects of 24-week oral

acetyl-L-carnitine (1 g twice daily) therapy on the glucose disposal rate (GDR), assessed by hyperinsulinemic euglycemic clamps, and components of the metabolic syndrome in nondiabetic subjects at increased cardiovascular risk a priori segregated into 2 groups with GDR < or =7.9 (n=16) or >7.9 (n=16) mg/kg per minute, respectively. Baseline GDR and systolic blood pressure were negatively correlated (n=32; P=0.001; r=-0.545), and patients with GDR < or =7.9 mg/kg per minute had higher systolic/diastolic blood pressure than those with higher GDR. Acetyl-L-carnitine increased GDR from 4.89+/-1.47 to 6.72+/-3.12 mg/kg per minute (P=0.003, Bonferroniadjusted) and improved glucose tolerance in patients with GDR < or =7.9 mg/kg per minute, whereas it had no effects in those with higher GDRs. Changes in GDR were significantly different between groups (P=0.017, ANCOVA). Systolic blood pressure decreased from 144.0+/-13.6 to 135.1+/-8.4 mm Hg and from 130.8+/-12.4 to 123.8+/10.8 mm Hg in the lower and higher GDR groups, respectively (P<0.05 for both; P<0.001 overall) and progressively recovered toward baseline over 8 weeks posttreatment. Total and high molecular weight adiponectin levels followed specular trends. Diastolic blood pressure significantly decreased only in those with higher GDRs. Treatment was well tolerated in all of the patients. Acetyl-L-carnitine safely ameliorated arterial hypertension, insulin resistance, impaired glucose tolerance, and hypoadiponectinemia in subjects at increased cardiovascular risk. Whether these effects may translate into long-term cardioprotection is worth investigating.

Acetyl-L-carnitine supplementation differently influences nutrient partitioning, serum leptin concentration and skeletal muscle mitochondrial respiration in young and old rats.

Iossa S, Mollica MP, Lionetti L, Crescenzo R, Botta M, Barletta A, Liverini G. Department of General and Environmental Physiology, University of Naples Federico II, Italy I-80134.

Abstract
Variations in energy balance, body composition, and nutrient partitioning induced by acetyl-L-carnitine (ALCAR) supplementation were studied in young (2 mo) and old (24 mo) Wistar rats. Changes in skeletal muscle metabolism as well as in serum free triiodothyronine and leptin levels were also evaluated. Rats were administered 0 (control) or 15 g/L ALCAR in their drinking water for 1 mo. ALCAR treatment significantly decreased body lipid percentage in young rats and significantly increased body protein percentage in old rats. The percentage of metabolizable energy (ME) intake stored as lipid was lower in ALCAR-treated young rats, whereas the percentage of ME intake stored as protein was greater in ALCAR-treated old rats compared with their age-matched controls. In addition, ALCAR supplementation significantly decreased serum leptin levels in old rats. Elevated skeletal muscle respiration was found in old rats treated with ALCAR, due to an increase in mitochondrial protein mass. In conclusion, ALCAR supplementation decreases efficiency of lipid deposition in young rats and increases efficiency of protein deposition in old rats. In addition, ALCAR supplementation partly reduces the leptin resistance that occurs in old rats, and improves ATP production in skeletal muscle mitochondria through an increase in mitochondrial protein content.

Neuroprotective activity of acetyl-Lcarnitine: studies in vitro.

Forloni G, Angeretti N, Smiroldo S.

Unit of Neurobiology of Alzheimer, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

Abstract
The neuroprotective properties of acetyl-L-carnitine (ALCAR) were investigated in primary cell cultures from rat hippocampal formation and cerebral cortex of 17-day-old rat embryos. Chronic exposure to ALCAR (10-50 microM for 10 days) reduced the cell mortality induced by 24 hr fetal calf serum deprivation. Protection was partial when the neuronal cells, chronically treated with ALCAR (50 microM), were exposed to glutamate (0.25-1 mM) and kainic acid (250-500 microM) for 24 hr. The neurotoxicity induced by N-methyl-D-aspartate (NMDA, 250 microM) was attenuated by the acute co-exposure with ALCAR (1 mM), the chronic treatment with ALCAR (50 microM) significantly reduced the neuronal death induced by NMDA (0.25-1 mM). Cell mortality was also investigated in ALCAR-treated hippocampal cultures chronically treated with betaamyloid fragment 25-35. ALCAR appeared to have neuroprotective activity. This suggests an explanation of the positive results obtained with ALCAR in the treatment of Alzheimer's disease.