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.

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 [8]). 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.

Neuroprotection

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).