In Part I, we reviewed the theory, history, and overall pharmacology of l-deprenyl. Part II will discuss the possible applications of l-deprenyl, including its role as a neuroprotectant, antidepressant, and anti-addiction medication. But to continue where we left off last time is, as promised, let us first discuss l-deprenyl’s amphetamine metabolites.
L-deprenyl has three main metabolites: l-nordeprenyl, l-amphetamine, and l-methamphetamine, with nordeprenyl and l-methamphetamine being the most prominent (1). This is controversial because amphetamines (especially methamphetamine) are widely used drugs of abuse. Deprenyl even shares a similar discriminative stimulus with cocaine and amphetamine, although only at dosages that are above clinical relevance (9).
Furthermore, it is the d-amphetamines (and not the l- amphetamines) that are most often used recreationally. L-amphetamine and L-methamphetamine are approximately 10 times less potent at inhibiting the dopamine and norepinephrine re-uptake pumps compared to the d-isomers (2,3). L-methamphetamine requires a concentration of 4mg/kg in rats to elicit dopaminergic response. Concentrations of l-methamphetamine reach only .4mg/kg during a high dosage l-deprenyl regimen (10mg/kg compared to the therapeutic .25mg/kg ). The lack of potency of the l-amphetamines combined with the low dosage of deprenyl used clinically probably makes the abuse potential of l-deprenyl moot. Studies have failed to demonstrate l-deprenyl’s ability to maintain self-administration in animals at dosages even well above the therapeutic range (4).
The low dose amphetamines that are formed via metabolism might even have properties that contribute to l-deprenyl’s efficacy. Since patients on 10mg of l-deprenyl a day can excrete up to 7mg of l- (meth)amphetamine in 24 hours. Some authors have theorized that amphetamine metabolites are responsible for the beneficial effects of l-deprenyl treatment (5,6). In rats, inhibiting the formation of l-methamphetamine from l-deprenyl prevents acute behavioral effects such as increases in locomotor activity (7). L-amphetamine can increase EEG theta rhythms (which are associated with learning and memory) while d-amphetamine decreases them (10). Comparable with those derived from l-deprenyl therapy, low doses of l-amphetamine in rats can also prevent the age-related decline in learning ability (11).
L-methamphetamine’s role is more controversial given the neurotoxic potential of d-methamphetamine. High concentrations of l-methamphetamine can promote apoptosis (programmed cell death), but then again, so can high concentrations of l-deprenyl (12). At least one study found that l-methamphetamine prevented the neuroprotective actions of l-deprenyl (13). More encouraging is l-deprenyl’s ability to reduce the negative cardiovascular effects of d-methamphetamine use (14).
What conclusion can we draw from all of this? While metabolism of l-deprenyl into l-methamphetamine might potentially take away from some of the neuroprotective effects, the concentrations that are reached in the clinical situation are probably too low to cause much worry. Metabolism into l-amphetamine, on the other hand, has potential benefits for increasing cognition.
Those using l-deprenyl should be aware that treatment could cause a positive drug test for amphetamines. While an oral dose of 10mg is almost totally excreted within 24 hours (15), amphetamine metabolites can be found in the hair of l-deprenyl users for up to 4 weeks after a single oral dose (16). In an attempt to differentiate the urine content of therapeutic l-deprenyl use from methamphetamine abuse, Kim et al. found that the l-deprenyl users had a much higher ratio of amphetamine: methamphetamine in their urine (17). However, unforgiving and ethically flawed drug testing organizations are unlikely to pay attention to such a study. Thus, it’s probably best for athletes subject to drug testing to avoid l-deprenyl use.
The neuroprotective effect of l-deprenyl seen in Parkinson’s patients was originally thought to be related to MAO-B inhibition. By preventing the breakdown of dopamine, l-deprenyl can increase dopaminergic tone as well as prevent the formation of free radicals. However, it soon became apparent that much of l-deprenyl’s neuroprotective effect had nothing to do with MAO-B inhibition. L-deprenyl can protect DNA from the oxidizing effects of peroxynitrite even in neuronal cells that only contain MAO-A (18). MPTP is metabolized by MAO-B into MPP+, a dopaminergic toxin. Even when MPP+ is administered directly, deprenyl is still neuroprotective, proving that MAO-B inhibition is not a requirement (19). Lastly, deprenyl’s neuroprotection is not limited to dopaminergic neurons, but also noradrenergic (34) and cholinergic neurons (35).
The mechanism behind such effective neuroprotection lies in deprenyl’s upregulation of important antioxidant enzymes, such as superoxide dismutase (21). By increasing antioxidant enzymes, L-deprenyl, as well as its metabolite L-nordeprenyl, protects neurons from excitotoxicity and glutathione depletion (20). L-deprenyl also enhances nerve growth factor and reduces neuronal apoptosis (22,23).
The ultimate benefit of increasing antioxidant enzymes and reducing things like neuronal apoptosis is a longer, healthier life. L-deprenyl has been documented to increase the life expectancy of both rats (24) and dogs (25). In humans, l-deprenyl at dosages of 5-10mg per day can increase the life expectancy of Parkinson’s patients when combined with L-dopa (26). However, l-deprenyl’s longevity enhancing properties were questioned when another study demonstrated a slight excess in mortality rate in Parkinson’s patients taking the drug (27). A 2000 study published in Neurology failed to corroborate this excess mortality, reporting no significant difference in mortality between l-deprenyl and other Parkinson’s drugs (28).
L-deprenyl’s life-extension effects are particularly noticeable in immunosuppressed animals (29,30). Besides upregulating antioxidant enzymes involved in immunity, deprenyl increases cytokine synthesis, particularly IL-1beta and IL-6 (31). It also enhances other immunofactors such as interferone-gamma, tumor necrosis factor alpha, and natural killer cells (33). L-deprenyl also has an anti-tumor effect in mammary cancer in rats (32). The anti-tumor effect is attributed to two mechanisms: 1. Increases in dopamine, which normalizes prolactin secretion (prolactin encourages the growth of mammary tumors) 2. Increases in norepinephrine in the spleen, which leads to the production of immunofactors.
Memory, Alzheimer’s and ADHD
L-deprenyl has been found to improve memory in both animals and humans. Improvements in spatial short-term memory have been noted in old dogs (36) and male rats (37). In female rats, l-deprenyl had a synergistic effect with estradiol in increasing spatial learning, also demonstrating a significant effect on its own (38). In humans, l-deprenyl improves memory in Alzheimer’s dementia (39) and can also aid in recovery from stroke (40).
In a trial comparing 5-10mg/day of l-deprenyl to 1mg/kg methylphenidate (Ritalin) in children with attention deficit hyperactivity disorder (ADHD), the l-deprenyl group experienced similar improvements in ADHD parameters with fewer side effects and drop-outs (41). A similar study found l-deprenyl effective in treating both children with ADHD and Tourette’s syndrome (42).
Given the intimate relationship between dopamine and sexual function, l-deprenyl can act as an aphrodisiac in male rats (62), turning sexually low performing rats into high performing ones (63). Male rats on l-deprenyl also experience increased erectile potency (64) probably due to enhancement of nitric oxide, which can dilate blood vessels (65).
Hypersexuality is not uncommon in Parkinson’s patients receiving l-deprenyl and other dopaminergic drugs (66), and there is at least one case of a patient on l-deprenyl who developed transvestic fetishism (67). The man’s impulse to wear women’s clothing ceased when the drug was discontinued.
Atypical Drugs for Atypical Depression
The atypical subtype of major depressive disorder is defined by mood reactivity, interpersonal/rejection sensitivity, overeating, oversleeping, and leaden paralysis (a heavy feeling in the muscles). Atypical depression has also been called “neurotic depression” or “non-endogenous depression”, as the patient’s mood and symptoms are responsive temporarily to external factors (59). L-deprenyl has particular relevance to atypical depression, as atypical patients respond better to MAOIs than other antidepressants (60). Even moderate dosages of l-deprenyl in the range of 10-20mg/day have been shown to relieve atypical depressive symptoms in 59% of patients (61).
MAO-B, Stress and Cigarettes
While l-deprenyl’s neuroprotective effects do not rely on its ability to inhibit MAO-B, its antidepressant effects probably do. Why? Recently, the quest for the “true” antidepressant mechanism has shifted towards investigating the effects of hormones on the brain—particularly cortisol (43). It has been demonstrated that dexamethasone, a cortisol derivative, can increase the activity of MAO-B (44). We can infer that depressed individuals or others with high levels of stress hormones will display increased activity of MAO-B and subsequently lower dopamine and trace amine concentrations. This might partially explain the popularity of MAO-B inhibition by cigarette smoke in highly stressed people. Obviously, low dose l-deprenyl is a much healthier way to get the same effect.
Unfortunately, MAO-B inhibition by itself isn’t enough to treat most depressions. L-deprenyl at a dose of 10mg/day is not significantly better than placebo in relieving depressive symptoms (45). A more effective approach is exploiting deprenyl induced MAO-B inhibition and supplementing with phenylethylamine (PEA) or PEA precursors. Depressed subjects usually exhibit low levels of PEA. Deprenyl can be used to potentiate the effects of oral PEA that would not usually be bioavailible. When deprenyl is administered along with PEA, a rapid antidepressant response ensues, on par with that of amphetamine but without tolerance (46). Substantial antidepressant effect is even seen when deprenyl is combined with l-phenylalanine, which is enzymatically converted to PEA via the enzyme L-Amino Acid Decarboxylase (47).
It appears that in most cases, inhibition of both MAO-B and MAO-A is needed for an antidepressant response, as L-deprenyl is the most consistent and effective when administered at dosages of 30-60mg/day (48,49). At these dosages, it is likely that MAO-A is (at least partially) inhibited and dietary precautions would be necessary. What’s interesting about the 30mg/day dose is that no tyramine interactions were noted, suggesting that l-deprenyl even in non-selective dosages might have benefits over other MAOIs.
A particularly intriguing combination for depression is a MAO-B selective dose of l-deprenyl combined with the reversible MAO-A inhibitor moclobemide. Since neither of these drugs provokes the tyramine reaction, one can inhibit both MAO-A and MAO-B without following a low-tyramine diet. This combination has been found effective in treating Parkinson’s patients with depression (50).
MAO-B selective dosages of l-deprenyl can also potentiate the antidepressant effect of the serotonin precursor, 5-HTP (51). Since this is case, can a low dose of l-deprenyl be used to augment other antidepressants? In theory, yes. In reality, it’s a little risky.
The rationale for l-deprenyl augmentation is sound. By inhibiting MAO-B, there is increased availability of neurotransmitters and trace amines. Also, the “catecholamine enhancing” effect of l-deprenyl, along with the low doses of amphetamine metabolites would probably be useful in treating depression as well. Furthermore, l-deprenyl has been found to increase imipramine binding sites and downregulate central beta-adrenergic receptors, two markers of effective antidepressant treatment (52). So what’s the problem?
Besides the tyramine reaction, another problem with MAOIs is serotonin syndrome, particularly when combined with serotonin re-uptake inhibitors. Since MAO-B is not responsible for the deamination of serotonin, l-deprenyl should be theoretically safe with an SSRI. However, the results have been fatal at least once when fluoxetine was combined with l-deprenyl (53). This was probably due to the mild MAO-A and MAO-B inhibiting effects of fluoxetine (54,55). In other instances, fluoxetine and l-deprenyl were combined safely (56.57). “Cleaner” SSRI’s that lack MAOI properties such as sertraline might be better in combination with l-deprenyl. However, caution should still be taken and a conservative dose of l-deprenyl used (2.5-5mg/day) in order to prevent possible MAO-A “spillover.”
L-deprenyl is safest when used with antidepressants that do not block the serotonin transporter. These include bupropion, trazodone, reboxetine, and the tricyclics (58). Within the tricyclic category, greater caution should be taken with imipramine and clomipramine due to their higher affinity for the serotonin transporter.
L-Deprenyl and Addiction
While l-deprenyl itself probably has little abuse potential in humans at therapeutic dosages, some have theorized that because it inhibits the breakdown of dopamine, and drugs of abuse often work through dopaminergic pathways, then l-deprenyl can increase the abuse liability of other drugs (68). In rats, chronic low dose l-deprenyl treatment can potentiate cocaine-induced increases in dopamine (69). Other studies with humans have failed to find any significant interaction between cocaine and l-deprenyl in terms of the reported “high” (70).
There’s even evidence that deprenyl has anti-addictive properties. In humans, 7 days of continuous deprenyl therapy at 10mg/day reduces the subjective euphoria of cocaine by 40% and prevented the decrease in glucose utilization that normally accompanies cocaine administration (71). Memory circuits in the hippocampus can trigger memories of drug euphoria and cause cocaine relapse (72). Deprenyl normalization of brain metabolism can interfere with these conditioned memory responses. In this case, deprenyl’s nootropic and anti-addictive qualities are one in the same. The possibility of a relation between drug addiction and lapses in cognitive function is intriguing. By becoming “smarter” (at least biochemically by normalizing cerebral glucose metabolism), we simultaneously lower addictive potential. In a related study, a combination of piracetam and gingko biloba was ineffective at treating cocaine dependence (73). However, the role of nootropics in an overall treatment for addiction should not be ignored.
Besides being possibly effective for cocaine addiction, there is direct evidence that l-deprenyl can aid in smoking cessation. 10mg of l-deprenyl combined with a nicotine patch was found to be more effective than the patch alone (74). Similarly, in another study, 10mg of l-deprenyl was found to decrease cravings for cigarettes during abstinence as well as decrease the satisfaction received from cigarettes (75). The MAO-B inhibition of cigarette smoke is probably responsible for some of its pleasurable effects (76). Not only will l-deprenyl inhibit MAO-B without the unhealthy effects of cigarettes, its antioxidant activity could be especially beneficial to smokers and ex-smokers.
L-deprenyl has also been shown to preserve dopaminergic function during withdrawal from opiates (77). While l-deprenyl presents a promising adjunct to drug addiction therapy, controlled studies are definitely lacking.
Finding the Right Dose
Dosages of l-deprenyl will vary depending upon the reason for use. In general, low dosages (1-5mg/day) are best for neuroprotective, antioxidant, and life extension purposes. Moderate MAO-B selective dosages (5-15mg) are better suited for mild depression, ADHD, and general dopaminergic enhancement. Dosages higher than 15mg are only probably applicable to more serious depressive episodes.
In terms of the right dosage for neuroprotection, Carrillo and colleagues have conducted several animal studies to determine the best deprenyl dosage in order to increase life span. The neuroprotective effect of deprenyl vs. deprenyl dosage is a bell-shaped curve, meaning that more is not necessarily better. High dosages of deprenyl in rats can reduce rather than increase antioxidant enzymes (78). In male mice, there is a need to reduce the dosage of l-deprenyl over time in order to maintain the antioxidant effect (79). Females on the other hand require a lower dose than males, which increases as they get older (80).
While converting from dosages in animals to dosages in humans is rather tricky, deprenyl’s creator Joseph Knoll has admitted that the 10mg dose used in Parkinson’s is probably excessive for providing neuroprotection. Knoll himself (who is probably well into his 70s or beyond and still publishes multiple papers a year) takes 1mg a day (81).
According to Knoll, it is the post-developmental phase of life when deprenyl is most useful. Increased action of sex hormones with the onset of sexual maturity coincides with a dampening of monoamine activity enhancement (82). Thus, deprenyl is probably most useful after the completion of puberty in humans. Using the animal data from Carrillo et al, we can make some educated guesses on the dosages needed for life-extension and neuroprotection. Males in their 20s would probably benefit most from a dose of 2.5-5mg/day, while males above 30 probably don’t need more than 2.5mg per day. With females, dosages should start lower (2.5mg or less in the 20s) and increase slightly (up to 5mg/day) overtime. In females, estrogen probably works synergistically with l-deprenyl to provide neuroprotection (38). Females on birth control probably need an even lower dose due to pharmacokinetic interactions (83).
Enhancing an Enhancer Drug
There are many compounds that can have positive synergistic (or at least additive) effects when combined with l-deprenyl. Already mentioned have been l-dopa (Parkinson’s), PEA (depression), l-phenylalanine (depression), and estradiol (spatial learning). Melatonin acts synergistically with l-deprenyl to protect against MPTP toxicity (84). Both Vitamin E (86) and lipoic acid (85) have been studied either combined or head to head with deprenyl without any statistical benefit in measurements of Parkinson’s and life-extension. The acetylcholinesterase inhibitor tacrine showed increased effectiveness when combined with l-deprenyl in an animal model of Alzheimer’s disease (87).
Since the development of l-deprenyl in the 1960s, Joseph Knoll and researchers have made breakthroughs in propargylamine pharmacology and the science of neuroprotection, monoamine enhancement and life-extension. Venturing away from phenylethylamines and into tryptamines, Knoll and colleagues developed R- (-)-1-(benzofuran-2-yl)-2-propylaminopentane (BPAP), which appears 130 times more potent than l-deprenyl in measures of catecholamine (and serotonin) enhancement and neuroprotective benefits (88,89). Because prevailing medical practice dictates that we treat rather than prevent, drugs like BPAP may be slow to reach the public. For now, l-deprenyl represents a unique and effective option for not only those suffering from various illnesses, but also those just wishing to live a longer, healthier life.
Special thanks goes to David Pearce, author of The Good Drug Guide(http://www.biopsychiatry.com) and The Hedonistic Imperative (http://www.hedweb.com/hedethic/hedonist.htm). His work has been an invaluable resource to me in writing these articles.
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