[7][9] Tyramine has been shown to act as a MAE of norepinephrine, dopamine, and serotonin in the rat brainstem in vitro similarly to β-phenylethylamine.
[11] β-Phenylethylamine and tyramine additionally act as potent monoamine releasing agents of norepinephrine and dopamine at higher concentrations.
[12][11] The MAE and monoamine releasing agent actions of these compounds are mechanistically distinct and they have been referred to as "mixed-acting" monoaminergic potentiators.
[5][7][9][13] β-Phenylethylamine, tryptamine, and tyramine when administered to animals are ineffective as MAEs in vivo due to very rapid breakdown by monoamine oxidase (MAO).
[15][16][17][18] Tyramine, unlike β-phenylethylamine and tryptamine, is unable to cross the blood–brain barrier, which additionally limits its capacity for centrally mediated effects.
[1][19] Selegiline (L-deprenyl) (a phenylethylamine derivative) is used as an antiparkinsonian agent and antidepressant and exhibits CAE effects independent of its monoamine oxidase inhibition.
[20] The psychostimulants amphetamine (both levoamphetamine and dextroamphetamine) and methamphetamine (both levomethamphetamine and dextromethamphetamine) are CAEs like selegiline, but these drugs are also potent monoamine releasing agents and these actions overshadow the former activities.
[20] Besides acting as CAEs, levomethamphetamine and dextromethamphetamine diminish serotonergic activity, similarly to selegiline, whereas levoamphetamine and dextroamphetamine do not do so.
[7][3][26] It shows some selectivity for serotonin, with its maximal impact on this neurotransmitter occurring at 10-fold lower concentrations than for norepinephrine or dopamine.
[3][28][29] In addition, recent findings have suggested that known synthetic MAEs like BPAP and selegiline may exert their effects via TAAR1 activation.
[3][4] However, in an older study of MAO-B knockout mice, no non-MAO binding of radiolabeled selegiline was detected in the brain, suggesting that this agent might not act directly via a macromolecular target in terms of its MAE effects.
[42] However, there appears to be no dose–effect ceiling with this agent and it can maximally increase striatal dopamine levels by more than 5,000% of baseline at higher doses.
[47] Knoll answered that other monoaminergic agents create an artificial, unphysiological, and abnormal situation in the brain that has substantial accompanying side effects and problems, for instance triggering of homeostatic compensation mechanisms.
[47] In contrast, Knoll maintained that MAEs simply augment normal and physiological monoaminergic signaling by increasing the amount of monoamine neurotransmitter released per action potential.
[47] On the basis of these arguments, Knoll claimed that MAEs are theoretically better-tolerated, safer, and less tolerance-forming than other monoaminergic drugs.
[1] The enhancer regulation system has been theorized to play an important role in dynamically controlling innate and acquired drives and mediating age-related changes in goal-directed behavioral activity.
[9][7] The concept of this system was created and advanced by the developers of selegiline, including József Knoll and Ildikó Miklya.
[7][12] Accordingly, brain monoamine release was found to be significantly higher in prepubertally castrated rats at 3 months of age compared to non-castrated controls.
[7][50] In addition, treatment of 3-week-old prepubertal rats for 2 weeks with exogenous sex hormones, including the androgen testosterone or the estrogen estrone, though not progesterone, significantly and rapidly reduced brain monoamine release relative to untreated controls.
[9] However, the key endogenous actors of the enhancer regulation system have been theorized to be more potent than phenethylamine but have yet to be identified.
[9][7] It has been hypothesized that highly potent enhancer substances may exist that may be able to rapidly modulate the activity of brain catecholaminergic neurons by as much as 5- to 10-fold to quickly control time-dependent motivational states.
[51][11][12][1][7] Rodent studies have found that exogenous MAEs like selegiline and BPAP augment brain monoamine release, slow monoaminergic neurodegeneration, and help to preserve behavioral activity with age.
[7][52] It has been proposed that exogenous MAEs like selegiline might be able to modestly slow the age-related decay of brain monoamine release in humans, although such hypotheses have yet to be tested.
[1][9][56][13][24] There has also been theoretical interest in MAEs as potential antiaging agents that might help to oppose age-related catecholaminergic neurodegeneration and prolong lifespan, though such ideas have not been tested.