Ayahuasca, a hallucinogenic botanical mixture from the Amazon, is now used globally. Its main constituents are DMT, a hallucinogen, and harmine, a monoamine oxidase inhibitor that prevents DMT's rapid breakdown. Recent developments include online sales and substitution with related botanical or synthetic compounds. Ayahuasca use appears to improve mental health and reduce recidivism to alcohol and cocaine misuse. This review discusses ayahuasca's pharmacology, focusing on harmine, and suggests mechanisms for reduced recidivism, including MAOI effects, actions at 5-HT(2A) and imidazoline receptors, and inhibition of DYRK1A and the dopamine transporter. The therapeutic potential of harmine in other CNS conditions is also speculated upon.
Harmine, a key component of the psychoactive tea ayahuasca, increases dopamine efflux in a specific region of the rat brain's nucleus accumbens (the shell) through a novel mechanism independent of its known monoamine oxidase inhibition. Using fast cyclic voltammetry in rat brain slices, harmine (300 nM) boosted dopamine efflux to 148% of baseline in the shell, and this effect was additive with cocaine (260% of baseline). The increase was blocked by the 5-HT2A/2C antagonist ketanserin, while the MAO inhibitor moclobemide had no effect. Harmine did not alter dopamine efflux in the accumbens core or reuptake in either subregion. These findings suggest harmine acts via a presynaptic 5-HT2A receptor-dependent mechanism, potentially supporting an agonist therapy approach for cocaine dependence.
Diphenidine (DPH), a dissociative novel psychoactive substance, binds to the dopamine transporter in rat brain tissue and increases electrically-evoked dopamine efflux in the nucleus accumbens, indicating potential for addiction. In contrast, methoxphenidine (MXP) shows no significant effect on dopamine transporter binding or dopamine release. Computational modeling of five dissociative compounds confirms these differences and explains the atomic-level interactions within the dopamine transporter. Despite their chemical similarity, DPH, but not MXP, may have addictive liability through stimulant-like actions on dopamine systems.