A Brief History of the MAOIs
The enzyme monoamine oxidase (MAO) is responsible for the destruction of various monoamine neurotransmitters including serotonin, noradrenaline, and dopamine. As humans age, levels of monoamine oxidase increase, reducing the availability of neurotransmitters and theoretically increasing the risk of disorders such as depression and Parkinson’s disease (10). Drugs that inhibit MAO increase concentrations of monoamines and can treat depression (11). In order to gain an appreciation of where l-deprenyl fits within the grand scheme of psychopharmacology, it’s important to look at the origins of the MAOIs.
In 1952, Crane reported the “psychiatric side-effects” of the tuberculosis drug, iproniazid (1). Iproniazid, which was later found to inhibit the enzyme monoamine oxidase (MAO), produced“psychic energizing” euphoria in tuberculosis patients (2, 3). This led to considerable interest in the use of monoamine oxidase inhibitors (MAOIs) for the treatment of depression, narcolepsy, social phobia, and schizophrenia.
With regard to schizophrenia, Lauer observed that when patients were given iproniazid along with the serotonin precursor L-tryptophan, they became livelier and more willing to engage interpersonally. It appeared that by inhibiting the breakdown of serotonin while simultaneously increasing its production with precursors enabled a more robust response
(4). Such an observation had relevance to Parkinson’s disease, where patients suffer from a deficit of dopamine. If the breakdown of dopamine could be slowed with the use of an MAOI, the effects of the precursor drug L-dopa might be enhanced. While MAOI’s appeared to have weak anti-Parkinson’s effects on their own due to their dopamine sparing activity, when combined with L-dopa, a hypertensive crisis often ensued (6).
Besides being contraindicated with L-dopa, the MAOIs had another very serious blemish. It was discovered (sometimes under fatal circumstances) that the trace amine tyramine also produced hypertensive crisis when ingested concurrently with MAOIs (7). Because tyramine is found in high concentrations in aged foods such as wine and cheese, this phenomenon became known as the “cheese effect.”
It wasn’t until the development of two novel MAOIs that the mechanisms behind the cheese effect became elucidated. In 1964, Knoll developed l-deprenyl, a potent and irreversible MAOI (5). Unlike traditional MAOIs, deprenyl selectively inhibited the deanimation of only certain amines, most notably dopamine, phenylethylamine and benzylamine. What made l-deprenyl particularly remarkable was its freedom from tyramine interactions. Not only was it free from such interactions, but l-deprenyl also had the ability to block the hypertensive effects of tyramine (8). How could it be that some MAOIs potentiated the effects of tyramine while others, like deprenyl, prevented it?
Four years after Knoll’s discovery, Johnston developed another MAOI, clorgyline. Clorgyline differed from deprenyl in two respects: 1) clorgyline selectively inhibits the deanimation of serotonin as opposed to phenylethylamine and 2) clorgyline potentiated tyramine induced hypertension (9). Because of these observations, Johnston proposed that there are two forms of MAO: type A and type B. Type A, found mainly in the gut and other organs outside the brain, is preferentially inhibited by clorgyline. Type A is responsible for the deanimation of serotonin and noradrenaline. Type B, found in the brain and platelets and preferentially inhibited by l-deprenyl, deanimates phenylethylamine. Tyramine and dopamine can be broken by either form. Despite the nonselective degradation of dopamine and tyramine, the location of the two subtypes is important to consider when making reference to the cheese effect or l-dopa induced hypertensive crisis. It is because of the fact that MAO-A is found in the gut (and not MAO-B) that deprenyl does not cause hypertension when co-administered with l-dopa or tyramine.
What Joseph Knoll was initially trying to achieve with the creation of l-deprenyl can probably best be summarized in his own words:
It has been known since 1933 that â-phenylisopropylamine or amphetamine is a psychostimulant. Its effect is accompanied by an intense sympathetic activation and a slight decrease of the cerebral monoamine-oxidase activity. In recent years potent MAOIs have been introduced into therapy, which do not provoke an acute excitation of the central nervous system but possess clinically useful psycho-energizing, antidepressant effects. In the past few years we tried to find compounds possessing both the amphetamine-like psychostimulant effect and the psycho-energetic effect characteristic of the potent MAOI. (12)
In other words, Knoll wanted to discover a more stimulating antidepressant. As time went on it was found that while l-deprenyl definitely had a stimulant effect, it wasn’t as powerful as d-amphetamine. And while it did inhibit MAO-B and showed some promise as an antidepressant, deprenyl didn’t have the antidepressant efficacy of the nonselective MAOIs. Re-formulating his ideas, Knoll coined the term “catecholaminergic activity enhancer” or CAE to describe the mechanism of deprenyl. Knoll noticed that like the endogenous substance phenylethylamine, deprenyl caused an enhancement of “impulse propagation mediated release.” That is, when treated with l-deprenyl, neurons exhibited enhanced release of catecholamines in response to stimuli (13).
Knoll extrapolated the CAE concept to the idea of “high performers” and “low performers”:
Or another example: the rabbit is feeding on cabbage and is very relaxed. An eagle comes. The relaxed rabbit has less than a second to change from that relaxed state to the highest activity, to get running with all his power because his life is at stake. That’s the problem. What happens in the brain and why is it that one animal can run so fast that it escapes, but the eagle catches the other and eats him? Why is one animal a high performer, and the other a lower performer? This activation and what underpins it was the problem I have worked on day and night for years. (14)
It’s been observed that from weaning to sexual maturity, rats have enhanced catecholaminergic activity which then slowly declines with age. Deprenyl can maintain a rat’s enhanced activity into late life (15). The young rats would be termed “high performers” while the untreated old rats are “low performers.” Thus, Knoll’s theory behind deprenyl is that by enhancing the activity of catecholaminergic neurons, and returning them closer to a state found in early life, deprenyl has the ability to inhibit aspects of the aging process and turn low performers into high performers.
L-deprenyl, (-)-N,1-dimethyl-N-propragylphenylethylamine, belongs to the family of chemicals known as the propargylamines. They are most closely related to the phenylethylamines. The only difference between the two classes of drugs is the attachment of a propargyl group (three carbons with a triple bond between the second and third carbon) to the nitrogen. Specifically, deprenyl is the N-propargyl analogue of methamphetamine. From a structure activity relationship, it is this propargyl group that causes l-deprenyl to lack the catecholamine releasing effect of methamphetamine. It is also the propargyl group that enables covalent bonding to MAO-B (14). If a second propargyl group is added to the nitrogen, thereby giving it a positive charge, the resulting compound will be more potent at MAO-A instead of MAO-B When the propargyl group is replaced by a propyl group, PPAP is formed which retains l-deprenyl’s CAE effect, but lacks its MAO-B inhibiting action (13).
As we’ve seen with other phenylethylamine related drugs, chirality is often of prime importance in determining the effects of the drug. In general with phenylethylamine derivatives, the “d” enantiomers have more potent stimulating effects than the “l” enantiomers. Deprenyl is no exception. Unlike l-deprenyl, d-deprenyl is a potent dopamine re-uptake inhibitor and is more liable to cause abuse and dependence (16).
The effects of l-deprenyl on dopamine are largely variable and seem to be dependent upon dose. For example in rats, acute treatment with .02mg/kg, .2mg/kg and 2mg/kg of l-deprenyl will decrease, have no effect, and increase dopamine levels, respectively (21). On the other hand, rats treated for 21 days with .25mg/kg of l-deprenyl show increased levels of dopamine (25). A 10mg/kg acute dose in rats leads to increased dopamine levels and decreased dopamine turnover. Repeated treatment with the 10mg/kg dose leads to increasing locomotor activity which is indicative of behavioral sensitization (a phenomenon that occurs with cocaine and amphetamines). An interesting aspect of this study was that unlike cocaine and the amphetamines, the behavioral sensitization to l-deprenyl was not accompanied by increases in dopamine concentrations (20). This idea that deprenyl exerts dopaminergic effects without changing dopamine concentrations could be supported by the observation that low doses of deprenyl (.02 and .2mg/kg but not 2mg/kg in rats) decrease methamphetamine-induced mortality without influencing methamphetamine-induced dopamine depletion (21).
Because l-deprenyl is approximately 160 times less potent at inhibiting the dopamine transporter (DAT) compared to d-methamphetamine (22), it’s no surprise that humans receiving 10mg/day of l-deprenyl do not experience dopamine re-uptake inhibition characteristic of cocaine or amphetamine (28). However, it does appear that l-deprenyl induces a reversible inhibition of the DAT by increasing endogenous phenylethylamine, a substrate for both MAO-B and the DAT (26). Low dose l-deprenyl (.25mg/kg) can attenuate amphetamine induced increases in dopamine most likely due to two reasons: 1) l-deprenyl treatment increases competition for DAT binding and 2) while l-deprenyl up-regulates DAT expression, these new pumps do not appear functional (26).
L-deprenyl increases levels of the enzyme L-amino acid decarboxylase, a necessary enzyme for monoamine synthesis (23). Its effect on tyrosine hydroxylase, the rate limiting factor for dopamine synthesis, is variable. 2mg/kg of l-deprenyl given 3 times a week for 2 months increases tyrosine hydroxylase expression (27). However, repeated dosages of 10mg/kg of l-deprenyl decreased tyrosine hydroxylase (28). Chronic treatment with .25mg/kg for 21 days reduced tyrosine hydroxlase activity to 60% of the control group (31). Another group of researchers showed .1mg/kg for 21 days caused reduced tyrosine hydroxylase activity at first, but activity recovered by day 14 and increased after day 21 (32). While these results seem contradictory, it does appear that low, chronic doses of l-deprenyl are more likely to increase tyrosine hydoxylase activity than higher acute doses.
Potentiation of neuronal response to dopamine and dopamine agonists has been observed following l-deprenyl treatment (29,30). This would indicate an increase in dopamine receptor sensitivity. However, Timar and Knoll (33) have demonstrated that long term treatment with .25mg/kg of l-deprenyl leaves dopamine receptor sensitivity unchanged, and others (31) have corroborated his results.
Formed from the decarboxylation of phenylalanine, PEA is a naturally occurring trace amine found in the brain that has amphetamine-like activity. Patients with major depression often have low levels of PEA metabolites in the urine, while manic and schizophrenic patients demonstrate elevated levels (36). While the intake of phenylalanine can improve depression, supposedly by increased PEA formation (35), PEA is rapidly metabolized by MAO-B, limiting its effect. However, when MAO-B is inhibited with l-deprenyl, PEA levels rapidly and substantially increase (37). When PEA is administered along with l-deprenyl to humans, there is a potent and rapid antidepressant effect on par with amphetamine, but without tolerance (38).
Like its close structural relative, amphetamine, PEA induces the release of dopamine (39). The mechanism behind this release probably lies in PEA’s role as a fast acting dopamine agonist (40). When combined with l-deprenyl, PEA induces decreases in cortical beta 1 and beta 2 adrenoreceptor density, as well as D1 receptor density (41).
The oral bioavailability of a 10mg oral dose of l-deprenyl is approximately 10% and increases 3 fold with the presence of food (42). Peak plasma levels are reached within 30-90 minutes and the half-life is anywhere from 70-90 minutes (42,43). L-deprenyl is rapidly metabolized to l-desmethyldeprenyl, l-amphetamine, and l-methamphetamine (43). Chronic administration will cause the accumulation of both l-deprenyl and its metabolites, and can increase the half-life of l-deprenyl up to four-fold (42). Approximately 80% of an l-deprenyl dose can be recovered in the urine as l-amphetamine and l-methamphetamine (44).
So what’s the significance of having amphetamine metabolites? We’ll cover that, as well as the neuroprotective effects and potential clinical uses of l-deprenyl in Part II.
Many special thanks to Matt, Ted, Clay and Colleen for continued support, friendship and inspiration.
“Good art and true science keeps the noble human values alive, no matter how the struggle for power and money corrupts the world.” Joseph Knoll
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