Current drug metabolism
October 1, 2010
Hong-Wu Shen, Xi-Ling Jiang, Jerrold C Winter et al.
171 citations
5-MeO-DMT, a naturally occurring psychoactive drug, is metabolized by the enzyme CYP2D6 into the active metabolite bufotenine and is mainly inactivated by MAO-A. When taken with MAO-A inhibitors like harmaline, deamination is reduced, leading to prolonged exposure to both 5-MeO-DMT and bufotenine. These compounds act together on serotonin systems, potentially causing serotonin toxicity. CYP2D6 also metabolizes harmaline, and genetic variations in this enzyme may alter drug interactions and risks. This review covers the metabolism, pharmacokinetics, and drug-drug interactions of 5-MeO-DMT with harmaline, along with risks of intoxication.
Biochemical pharmacology
July 1, 2010
Hong-Wu Shen, Chao Wu, Xi-Ling Jiang et al.
40 citations
The metabolism and pharmacokinetics of the natural psychoactive compound 5-MeO-DMT are strongly influenced by both CYP2D6 genetic variation and monoamine oxidase inhibitors (MAOIs). Compared to the wild-type CYP2D6.1 enzyme, the CYP2D6.2 variant showed 2.6-fold lower catalytic efficiency and CYP2D6.10 showed 40-fold lower efficiency in producing the active metabolite bufotenine. In human liver microsomes treated with the MAOI pargyline, 5-MeO-DMT O-demethylation correlated strongly with CYP2D6 activity. In mice with the human CYP2D6 gene, systemic exposure to bufotenine was 60% higher than in wild-type mice. Pretreatment with the MAOI harmaline increased systemic exposure to 5-MeO-DMT by 3.6- to 4.4-fold and to bufotenine by 6.1- to 9.9-fold, depending on mouse genotype. MAOIs substantially alter 5-MeO-DMT processing and bufotenine formation, with CYP2D6 genotype determining the extent of these effects.
Drug metabolism and disposition: the biological fate of chemicals
May 1, 2013
Xi-Ling Jiang, Hong-Wu Shen, Donald E Mager et al.
29 citations
Coadministration of the MAO-A inhibitor harmaline sharply increases systemic and brain exposure to the designer drug 5-MeO-DMT and its active metabolite bufotenine in mice. The effect is stronger in wild-type mice than in CYP2D6-humanized mice, because CYP2D6 breaks down 5-MeO-DMT into bufotenine. Surprisingly, a higher harmaline dose (15 mg/kg) reduces bufotenine levels, an effect confirmed in vitro as harmaline also inhibits CYP2D6. A unified pharmacokinetic model describing these interactions was developed and may help predict drug interactions at various doses and in different CYP2D6 genotypes.
Drug metabolism and disposition: the biological fate of chemicals
July 1, 2011
Hong-Wu Shen, Xi-Ling Jiang, Ai-Ming Yu
29 citations
The psychedelic drug 5-MeO-DMT shows nonlinear pharmacokinetics in mice: as the dose increases, the drug's concentration in the body rises more than proportionally. After intravenous or intraperitoneal injections of 2, 10, and 20 mg/kg, dose-normalized blood levels were 1.5- to 2.7-fold higher at the two higher doses compared with the lowest dose. The drug also entered the brain, with brain concentrations increasing nonproportionally with dose. A two-compartment model with nonlinear (Michaelis-Menten) elimination and CYP2D6-dependent linear elimination described the data. These results suggest that the risk of intoxication may increase nonproportionally at higher doses.
Neuropharmacology
February 1, 2015
Xi-Ling Jiang, Hong-Wu Shen, Ai-Ming Yu
26 citations
Co-administration of the monoamine oxidase inhibitor harmaline with the serotonin agonist 5-MeO-DMT potentiates hyperthermia in mice, involving activation of both 5-HT1A and 5-HT2A receptors. Harmaline alone induced hypothermia, while higher doses of 5-MeO-DMT alone caused hyperthermia. The combination of harmaline and 5-MeO-DMT produced greater hyperthermia, which could be suppressed by antagonists of either receptor. CYP2D6 status influenced harmaline-induced hypothermia and the hyperthermic response at certain dose combinations. Stress-induced hyperthermia was attenuated by 5-HT2A but not 5-HT1A antagonists. These findings may inform strategies to relieve lethal hyperthermia in serotonin toxicity.
Pharmacological reports : PR
June 1, 2016
Xi-Ling Jiang, Hong-Wu Shen, Ai-Ming Yu
13 citations
Co-administering the monoamine oxidase inhibitor harmaline with a low dose of 5-MeO-DMT triggers excessive late-phase hyperactivity in mice, an effect that requires activation of both 5-HT1A and 5-HT2A serotonin receptors. High doses of either drug alone produce biphasic effects: early-phase hypoactivity mediated by 5-HT1A receptors and late-phase hyperactivity mediated by 5-HT2A receptors. Harmaline alone at 15 mg/kg causes early hypoactivity blocked by a 5-HT1A antagonist and late hyperactivity reduced by a 5-HT2A antagonist. The findings indicate that combining these drugs, as often done recreationally, can provoke prolonged overactivity through dual serotonin receptor mechanisms.
Pharmacology, biochemistry, and behavior
September 1, 2011
J C Winter, D J Amorosi, Kenner C Rice et al.
10 citations
In mice genetically modified to express human CYP2D6 (Tg-CYP2D6) and wild-type mice, the psychedelic 5-MeO-DMT produced similar rates of learning a drug discrimination task. Bufotenine did not substitute for 5-MeO-DMT, while its lipid-soluble analog acetylbufotenine produced intermediate substitution. Combining harmaline with 5-MeO-DMT significantly increased drug-appropriate responding in both mouse types, indicating harmaline enhances 5-MeO-DMT's stimulus effects. Harmaline alone also produced significant 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice, suggesting metabolic interactions. No differences between wild-type and Tg-CYP2D6 mice were found in acquisition or responses to bufotenine and acetylbufotenine.