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Harmala alkaloids are MAO-inhibiting beta-carbolines. The three most studied harmala alkaloids in the B. caapi vine are harmine, harmaline and tetrahydroharmine. Harmine and harmaline are selective and reversible inhibitors of monoamine oxidase A (MAO-A), while tetrahydroharmine is a weak serotonin reuptake inhibitor (SRI).

This inhibition of MAO-A allows DMT to diffuse unmetabolized past the membranes in the stomach and small intestine, and eventually cross the blood–brain barrier (which, by itself, requires no MAO-A inhibition) to activate receptor sites in the brain. Without RIMAs or the non-selective, nonreversible monoamine oxidase inhibition by drugs like phenelzine and tranylcypromine, DMT would be oxidized (and thus rendered biologically inactive) by monoamine oxidase enzymes in the digestive tract.

Individual polymorphisms in the cytochrome P450-2D6 enzyme affect the ability of individuals to metabolize harmine. Some natural tolerance to habitual use of ayahuasca (roughly once weekly) may develop through upregulation of the serotonergic system. A phase 1 pharmacokinetic study on ayahuasca (as Hoasca) with 15 volunteers was conducted in 1993, during the Hoasca Project. A review of the Hoasca Project has been published.

Several studies have shown the alkaloids in the B. caapi vine promote neurogenesis ^[1][2][3]. More specifically, in vitro studies showed that harmine, tetrahydroharmine and harmaline, stimulated neural stem cell proliferation, migration, and differentiation into adult neurons ^[1][3]. In vivo studies conducted on the dentate gyrus of the hippocampus noted an increase in the proliferation of BrdU positive cells in response to 100 μg of 5-MeO-DMT injected intravenously in the adult mouse brain ^[2].

The ingestion of ayahuasca can also cause significant but temporary emotional and psychological distress. Excessive use could possibly lead to serotonin syndrome(although serotonin syndrome has never been specifically caused by ayahuasca except in conjunction with certain anti-depressants like SSRIs). Depending on dosage, the temporary non-entheogenic effects of ayahuasca can include tremors, nausea, vomiting, diarrhea, autonomic instability, hyperthermia, sweating, motor function impairment, sedation, relaxation, vertigo, dizziness, and muscle spasms which are primarily caused by the harmala alkaloids in ayahuasca. Long-term negative effects are not known. A few deaths due to participation in the consumption of ayahuasca have been reported, although none have been linked specifically to ayahuasca itself and are usually said to be due to other factors. Some of the deaths may have been due to unscreened preexisting heart conditions, interaction with drugs, such as antidepressants, recreational drugs, caffeine (due to the CYP1A2 inhibition of the harmala alkaloids), nicotine (from drinking tobacco tea for purging/cleansing), or from improper/irresponsible use due to behavioral risks or possible drug to drug interactions.

In 2018, it was reported that a single dose of ayahuasca significantly reduced symptoms of treatment-resistant depression in a small placebo-controlled trial. More specifically, statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after ayahuasca administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS) ^[4].

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