The clinical pharmacology and potential therapeutic applications of 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT)

Abstract

5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT) is a naturally occurring tryptamine that primarily acts as an agonist at the 5‐HT1A and 5‐HT2A receptors, whereby affinity for the 5‐HT1A subtype is highest. Subjective effects following 5‐MeO‐DMT administration include distortions in auditory and time perception, amplification of emotional states, and feelings of ego dissolution that usually are short‐lasting, depending on the route of administration. Individual dose escalation of 5‐MeO‐DMT reliably induces a “peak” experience, a state thought to be a core predictor of the therapeutic efficacy of psychedelics. Observational studies and surveys have suggested that single exposure to 5‐MeO‐DMT can cause rapid and sustained reductions in symptoms of depression, anxiety, and stress. 5‐MeO‐DMT also stimulates neuroendocrine function, immunoregulation, and anti‐inflammatory processes, which may contribute to changes in mental health outcomes. To date, only one clinical trial has been published on 5‐MeO‐DMT, demonstrating the safety of vaporized dosing up to 18 mg. Importantly, the rapid onset and short duration of the 5‐MeO‐DMT experience may render it more suitable for individual dose‐finding strategies compared with longer‐acting psychedelics. A range of biotech companies has shown an interest in the development of 5‐MeO‐DMT formulations for a range of medical indications, most notably depression. Commercial development will therefore be the most important resource for bringing 5‐MeO‐DMT to the clinic. However, fundamental research will also be needed to increase understanding of the neurophysiological and neural mechanisms that contribute to the potential clinical effects of 5‐MeO‐DMT and its sustainability and dissemination over time. Such studies are less likely to be conducted as part of drug development programs and are more likely to rely on independent, academic initiatives.

3,4-Methylenedioxy methamphetamine, synthetic cathinones and psychedelics: From recreational to novel psychotherapeutic drugs

“…Also, 5-MeO-DMT is the main psychoactive component of the venom of the Sonoran Desert toad ( Bufo alvarius ) and can also been found in fungi such Amanita citrina and Amanita porphyria [see refs. ( 187 ) and ( 188 ) for reviews]. Moreover, it has been speculated that 5-MeO-DMT might also be endogenously produced in humans, although the existing reports are controversial ( 188 ).…”

“…The 5-MeO-DMT experience contrasts with the DMT experience, as the latter is known to produce particularly vivid and complex visual imagery rather than marked ego- dissolution ( 187 ). 5-MeO-DMT is a potentially useful addition to the psychedelic pharmacopeia because of its short duration of action, relative lack of visual effects and putatively higher rates of ego-dissolution and mystical experiences.…”

“…5-MeO-DMT is not devoid of adverse effects, which include fear, sadness, anxiety, confusion, fatigue, crying, paranoia, trembling, vomiting, nausea, headache, pressure on the chest or abdomen and loss of body perception [reviewed by Reckweg et al ( 187 )]. Subacute effects include flashbacks, i.e., short re-experiencing of some of the subjective 5-MeO-DMT effects and reactivations, i.e., brief (seconds) sensory disturbances such as flashes of light, especially during the week after 5-MeO-DMT exposure.…”

“…Another affected hormone can be prolactin (PRL). Ayahuasca increases blood cortisol and prolactin (PRL) levels ( 247 , 248 ) and 5-MeO-DMT also strongly promotes the release of PRL in rats ( 249 ) which is followed by a decrease and is consequence of hypothalamic 5-HT receptors activation, resulting in systemic anti-inflammatory and immunomodulatory effects through prolactin receptor-expressing immune cell types ( 187 ). Furthermore, such increases were higher than those induced by its tryptamine analogs, bufotenin and DMT.…”

5-MeO-DMT modifies innate behaviors and promotes structural neural plasticity in mice

“…The copyright holder for this preprint this version posted November 3, 2022. ; https://doi.org/10.1101/2022.11.03.515044 doi: bioRxiv preprint useful for treating psychiatric disorders, with an advantage of brief acute action that is more compatible with use in the clinic. 5-MeO-DMT, a compound found naturally in the Sonoran Desert toad, has been noted for its unusual pharmacological properties and clinical significance (reviewed in [16,17]). As a tryptamine psychedelic like psilocybin, 5-MeO-DMT targets a similar set of serotonin receptors including the 5-HT1A and 5-HT2A subtypes [18,19], although 5-MeO-DMT has a higher affinity preference for 5-HT1A receptors, relative to 5-HT2A, receptors than psilocybin [20].…”