Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact

Abstract

Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.

Lysergic Acid Diethylamide, Psilocybin and Dimethyltryptamine in Depression Treatment: A Systematic Review

“…No clinical studies of DMT use alone in depression treatment were found, as all of the included studies dosed ayahuasca, and it should be remembered that ayahuasca is administered with monoamine oxidase inhibitors, which may have an effect on mood themselves. It should also be remembered that ayahuasca contains other alkaloids, such as harmine or harmaline, and since it is a decoction of the plants themselves, it is difficult to estimate the dose of alkaloids consumed [ 34 , 35 ].…”

Ayahuasca as a Decoction Applied to Human: Analytical Methods, Pharmacology and Potential Toxic Effects

“…It becomes orally active when ingested in the presence of a MAO inhibitor such as β-carbolines. This allows DMT to cross the blood-brain barrier intactly and exert its effect in the central nervous system [14][15][16][17][18][19]. Following the administration of ayahuasca, DMT and β-carboniles are present in the human organism and are metabolized and excreted in the urine [20,21].…”

“…DMT is metabolized to the oxidative deamination product 3-indole-acetic acid obtained by the MAO pathway, and to the oxidative product DMT-N-oxide (DMT-NO) mediated by cytochrome P-450. Further N-demethylation produces N-methyltryptamine (NMT), which later turns to 2-methyl-1,2,3,4-tetrahydroβ-carboline (2-MTHBC) [19]. Harmine and harmaline are demetylated into harmol and harmalol and hydroxylized by the CYP450 enzyme complex.…”

Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects

“…From a pharmacological and chemical point of view, salvinorin A is quite unique due to two main features: (i) it is the only known non-alkaloidal hallucinogen, and (ii) it is the first naturally occurring non-nitrogenous compound that acts as an efficacious and potent κ-opioid receptor (KOP)-selective agonist [8][9][10][11]. Although not having affinity for the 5-HT 2A receptors known to mediate the hallucinogenic properties of the classic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin [12], mescaline [13], and N,N-dimethyltryptamine (DMT) [14], salvinorin A induces similar psychoactive effects, including perceptual distortions, alterations in affect, behaviour, and cognition, and out-ofbody experiences, with such effects being intense and short-lived [3,15]. The consumption of this substance has been associated with minimal or no health risks, thus being conceded as a safe hallucinogen [3].…”