5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), also known as O-methylbufotenin or mebufotenin (INNTooltip International Nonproprietary Name), is a naturally occurring psychedelic of the tryptamine family.

[2] 5-MeO-DMT was first synthesized in 1936 by Toshio Hoshino[9] (ja), professor of Tokyo Institute of Technology, and was first isolated from a natural source in 1959.

[12] Effects vary and can range from radical perspective shifting and perception of new insights, euphoria, immersive experiences, dissociation and non-responsiveness, sensual/erotic enhancement, to dysphoria, fear, terror, panic, and ego death.

[14][15] The Church of the Tree of Life, founded in California in 1971 by John Mann but now defunct, declared the use of 5-MeO-DMT to be a sacrament.

While most common psychedelics are believed to primarily elicit psychological effects through agonism of serotonin 5-HT2A receptors, 5-MeO-DMT shows 1,000-fold greater affinity for 5-HT1A over 5-HT2A;[26] In line with its affinity for 5-HT1A receptors, 5-MeO-DMT is extremely potent at suppressing the firing of dorsal raphe 5-HT neurons.

[29] A 2019 European study with 42 volunteers showed that a single inhalation produced sustained enhancement of satisfaction with life, and easing of anxiety, depression, and post-traumatic stress disorder (PTSD).

[2] In contrast to most serotonergic psychedelics however, it has been said that it is unclear that the hallucinogenic effects of 5-MeO-DMT are principally mediated by activation of the serotonin 5-HT2A receptor.

[2] In accordance with the preceding findings, 5-MeO-DMT is reported to produce notably distinct subjective effects compared DMT and other psychedelics in humans.

[5][25][24] In contrast to certain other tryptamines, 5-MeO-DMT is inactive as a monoamine releasing agent, including of serotonin, norepinephrine, and dopamine.

[22] Similarly to DMT, but in contrast to most other psychedelics, like LSD and psilocybin,[33][34] there appears to be very little development of tolerance with 5-MeO-DMT.

[2] In addition, peripherally formed bufotenin may not be able to exert significant central effects due to its limited ability to cross into the brain.

[2] The metabolism of 5-MeO-DMT can be dramatically reduced and its levels markedly augmented and prolonged by monoamine oxidase inhibitors (MAOIs).

First described in 1983 by Ken Nelson (writing under the pseudonym of Albert Most), smoking the parotoid secretions of the animal produces a powerful and short-lived psychedelic experience.

[49] Concerned with the ecological impacts of the growing use of I. alvarius secretions as a source of 5-MeO-DMT, Ken Nelson would later advocate for the use of synthetic 5-MeO-DMT and conservation of the Colorado River Toad.

[50] As a structural analog of N,N-dimethyltryptamine (DMT), 5-MeO-DMT is a Schedule 9 prohibited substance under the Poisons Standard.

[51] 5-MeO-DMT is legal for personal use and possession in Canada,[52] though sale, distribution, and other activities involving the substance are illegal under Canadian federal law.

[56] 5-MeO-DMT is being developed and evaluated for potential therapeutic effects in patients with treatment-resistant depression (TRD).

[60] Beckley Psytech in collaboration with King's College London is evaluating the safety and tolerability of intranasal 5-MeO-DMT in healthy subjects, in a phase 1 study.

[61][62] Beckley Psytech CEO Cosmo Feilding-Mellen sees a potential in the short-acting nature of 5-MeO-DMT compared to psilocybin: "Requiring one or two therapists to sit in a room with a single patient for the entire duration of an MDMA or psilocybin experience, which is essentially a whole working day, is probably going to be very resource-intensive and expensive.