Chemistry:Norpsilocin

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Norpsilocin, also known as 4-hydroxy-N-methyltryptamine (4-HO-NMT), is a tryptamine alkaloid recently discovered in 2017 in the psychedelic mushroom Psilocybe cubensis.[1][2] It is hypothesized to be a dephosphorylated metabolite of baeocystin.[2]

Pharmacology

Norpsilocin was found to be a near full agonist of the 5-HT2A receptor and was found to be more potent than psilocin.[3][4] It also has affinity for other serotonin receptors.[5] Moreover, it has been found to cross the blood–brain barrier in animals and to have good metabolic stability similarly to psilocin.[5]

Norpsilocin has shown psilocin-related peripheral effects in animals, including decreased spinal reflexes such as knee jerk response (opposite effect to psilocin), antiserotonergic activity (14% of that of psilocin), and pressor activity (70% of that of psilocin).[6][7] Surprisingly however, in spite of its serotonin 5-HT2A receptor agonism and psilocin-like effects, norpsilocin failed to induce the head-twitch response, a behavioral proxy of psychedelic effects, in animals.[5] Likewise, norbaeocystin and aeruginascin failed to induce the head-twitch response.[5] Only psilocybin was effective in this regard.[5] In any case, norbaeocystin showed antidepressant-like activity (forced swim test) similarly to psilocybin and fluoxetine in spite of its putative non-hallucinogenic nature.[5] Norpsilocin itself was not tested in this assay.[5]

A 2025 animal study found that both baeocystin and norpsilocin are peripherally selective with very limited ability to cross the blood–brain barrier.[8]

Research

Norpsilocin is being evaluated under the developmental code name PLZ-1017 for the possible treatment of pervasive developmental disorders in children.[9]

See also

References

  1. ↑ "Identification of ω-N-Methyl-4-hydroxytryptamine (Norpsilocin) as a Psilocybe Natural Product". Journal of Natural Products 80 (10): 2835–2838. October 2017. doi:10.1021/acs.jnatprod.7b00407. PMID 28929753. Bibcode: 2017JNAtP..80.2835L. 
  2. ↑ 2.0 2.1 "Two New Crystalline Forms of Norpsilocin". Psychedelic Science Review. 23 April 2020. https://psychedelicreview.com/two-new-crystalline-forms-of-norpsilocin/. 
  3. ↑ "Study Finds Norpsilocin is More Potent Than Psilocin at 5-HT2A". Psychedelic Science Review. 16 March 2020. https://psychedelicreview.com/event/study-finds-norpsilocin-is-more-potent-than-psilocin-at-5-ht2a/. 
  4. ↑ "Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin". Journal of Natural Products 83 (2): 461–467. February 2020. doi:10.1021/acs.jnatprod.9b01061. PMID 32077284. Bibcode: 2020JNAtP..83..461S. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Pharmacological and behavioural effects of tryptamines present in psilocybin-containing mushrooms". Br J Pharmacol 181 (19): 3627–3641. October 2024. doi:10.1111/bph.16466. PMID 38825326. 
  6. ↑ Keeper of the Trout and Friends (2007). "4-Hydroxy-MMT". Some Simple Tryptamines (2 ed.). Austin, Texas: Mydriatric Productions. p. 56. ISBN 978-0-9770876-5-5. OCLC 948674100. https://bitnest.netfirms.com/external/SST/56. "4-Hydroxy-MMT [...] Activity: Ott 1996 notes Cerletti 1968 reported psychotropic effects in animals. In comparison to psilocin, Cerletti et al. 1968 determined that 4-Hydroxy-N-methyltryptamine decreased spinal reflexes such as knee jerk response (instead of increasing it as psilocin does), had 14% as much antagonism of serotonin as psilocin, and showed 70% as much pressor activity. [...] In comparison to psilocin, Cerletti et al. 1968 determined it had increased spinal reflexes, such as knee jerk response, had around 11% as much antagonism of serotonin activity, and showed as much pressor activity as psilocin.) [...] Cerletti, A. et al. (1968) Advances in Pharmacology 6B: 233-246. "Pharmacologic Studies on the Structure-Activity Relationship of Hydroxyindole Alkylamines." (A. Cerletti, M. Taeschler & H. Weidmann) [...] Ott, Jonathan (1996) Pharmacotheon. Entheogenic Drugs, their Plant Sources and History. Second Edition Densified. Natural Products Co., Kennewick, WA 639 pp. ISBN 0-9614234-8-x (Hardcover)/ 0-9614234-9-8 (paperback)" 
  7. ↑ Pharmacologic studies on the structure-activity relationship of hydroxyindole alkylamines. Advances in Pharmacology. 6. 1968. 233–246. doi:10.1016/s1054-3589(08)60322-1. ISBN 978-0-12-032906-9. "TABLE III: INFLUENCE OF SUBSTITUTION IN POSITION 3 OF INDOLE AND 4-HYDROXYINDOLE: [...] Substituent: R3: CH2—CH2—N(—H,—CH3). R4: OH. [(Norpsilocin/4-HO-NMT).] Knee Jerk: ↓ 20–50 [μg/kg i.v.]. Serotonin antagonism: 14[% of psilocin]. Pressure activity: [+]35 [mm Hg]. [...]" 
  8. ↑ "Behavioural and pharmacological evaluation of the psilocybin analogue baeocystin in Wistar rats". Prog Neuropsychopharmacol Biol Psychiatry 140. July 2025. doi:10.1016/j.pnpbp.2025.111439. PMID 40619050. 
  9. ↑ "Norpsilocin - Pilz Bioscience". 19 January 2021. https://adisinsight.springer.com/drugs/800061882. 



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