Chemistry:4-AcO-DMT

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4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT or 4-acetoxy-DMT), also known as O-acetylpsilocin or psilacetin, is a psychedelic drug of the tryptamine family related to psilocybin and psilocin.[1][2][3][4] It is a synthetic derivative of psilocin (4-HO-DMT) in which the hydroxyl group has been acetylated, and is the analogue of psilocybin (4-PO-DMT) in which the phosphate ester has been replaced with an acetate ester.[1][2][3] The drug is a prodrug of psilocin and is used orally similarly to psilocybin.[1][2][5][6][7]

As a prodrug of psilocin, 4-AcO-DMT acts as a non-selective serotonin receptor agonist, including of the serotonin 5-HT2A receptor.[1][8] The hallucinogenic effects of psilocin are thought to be mediated by activation of this receptor, although other receptors also contribute to its effects.[9][10][1] 4-AcO-DMT's effects are reported to be similar to those of psilocybin and psilocybin mushrooms.[2][5][1] However, it has been said to have reduced side effects such as nausea and body load that can be caused by ingestion of whole psilocybin mushrooms.[2][5][1] It is also said to have a faster onset and shorter duration than psilocybin.[5] The drug is not expected to differ from psilocybin or psilocin in terms of safety.[1] 4-AcO-DMT is modestly less potent by weight than psilocybin in animals when they are given at equimolar doses.[2]

4-AcO-DMT was first described in a patent by Albert Hofmann in 1963 and its chemical synthesis was improved by David E. Nichols and colleagues in 1999.[2][8][3] It was suggested by Nichols as a more economical and accessible alternative to psilocybin for use in scientific research, as the synthesis of psilocybin is more challenging and as psilocybin is a controlled substance.[2][8][3] 4-AcO-DMT was first detected as a designer drug in Europe in 2009.[8] It became increasingly prevalent as a recreational drug in the 2010s and has been the most commonly used novel tryptamine.[2][5] In the 2020s, 4-AcO-DMT became widely encountered in the form of mushroom edibles in the United States as an alternative to psilocybin.[11][12][13][14] Relatedly, it has sometimes been referred to as "synthetic shrooms".[4] Mushrooms edibles may contain 4-AcO-DMT, Amanita muscaria mushroom constituents, or non-mushroom drugs such as bath salts, and have been linked to poisonings and deaths.[15][4][14][11]

4-AcO-DMT is not scheduled under United States law or any international drug schedules, including the United Nations 1971 Convention on Psychotropic Substances, making it a potentially more accessible alternative to psilocybin for research.[2] It can be imported and possessed for research in the United States if labeled “not for human consumption,” but using it in vivo is illegal and violates the Federal Analogue Act.[1]

Use and effects

In his book TiHKAL (Tryptamines I Have Known and Loved), Alexander Shulgin lists the same dose range of 10 to 20 mg orally and duration of 3 to 6 hours for psilocin, psilocybin, and 4-AcO-DMT.[6] Another publication gave a 4-AcO-DMT dose range of 10 to 15 mg orally, with a typical dose of 12.5 mg orally, and a duration of about 5 to 8 hours.[7] A further source gave a dose range for the drug of 5 to 30 mg orally, an onset of 15 to 40 minutes, and a duration of 4 to 7 hours.[16] 4-AcO-DMT is a prodrug of psilocin similarly to psilocybin and its effects are reported to be similar or identical to those of psilocybin and psilocybin-containing mushrooms.[2][5][16] However, it is said to produce less nausea and body load than psilocybin-containing mushrooms.[2][5][1] The drug is also often described as having a faster onset and shorter duration than psilocybin.[5] 4-AcO-DMT is modestly less potent by weight than psilocybin in animals when they are given at equimolar doses.[2]

Specific effects of 4-AcO-DMT have been reported to include psychedelic visuals, closed-eye imagery, synesthesia, insights, disembodiment, euphoria, feelings of bliss and unity, oceanic boundlessness, ego dissolution, sedation, cognitive impairment, and spiritual experiences, among others.[7][16] Adverse effects have been reported to include psychological side effects such as anxiety, paranoia, and low mood as well as gastrointestinal side effects such as nausea and vomiting.[7]

Contraindications

Side effects

4-AcO-DMT, as a prodrug of psilocin, is not expected to differ from psilocybin or psilocin in terms of safety.[1]

Interactions

Pharmacology

Pharmacodynamics

Template:Psilocin activities

4-AcO-DMT is a prodrug of psilocin (4-HO-DMT).[2] As a prodrug of psilocin, 4-AcO-DMT acts as a non-selective agonist of serotonin receptors, including of the serotonin 5-HT2A receptor.[1] The psychedelic effects of 4-AcO-DMT are mediated specifically by activation of the serotonin 5-HT2A receptor.[1]

Similarly to psilocybin, psilocin, and other serotonergic psychedelics, 4-AcO-DMT produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.[2][8][4][17] In addition, like psilocybin and other psychedelics, 4-AcO-DMT fully substitutes for the psychedelic DOM in rodent drug discrimination tests.[18] 4-AcO-DMT produces effects such as hypolocomotion and hypothermia in rodents as with psilocin as well.[2]

Pharmacokinetics

There are no clinical studies of the pharmacokinetics of 4-AcO-DMT as of 2024.[2] However, the pharmacokinetics of 4-AcO-DMT have been studied in rodents.[2] The drug was confirmed to act as a prodrug of psilocin similarly to psilocybin (4-PO-DMT).[2] However, given by intraperitoneal injection at equimolar doses, 4-AcO-DMT showed only 70% of the relative bioavailability or total exposure of psilocybin.[2] Hence, 4-AcO-DMT results in modestly lower psilocin levels than psilocybin even when the drugs are given at equivalent doses with adjustment for differences in molecular weight.[2] Along similar lines, the psilocin concentrations with 4-AcO-DMT 15 minutes after administration were 75 to 90% of those of an equimolar dose of psilocybin.[2] The elimination half-life of psilocin was approximately 30 minutes and did not differ between 4-AcO-DMT and psilocybin.[2] Psilocin ester prodrugs like 4-AcO-DMT are cleaved into psilocin by esterase enzymes.[19]

A 2025 in-vitro study examined the stability and metabolism of several psilocin ester prodrugs, including 4-AcO-DMT.[20] The results showed that 4-AcO-DMT was rapidly broken down into psilocin by esterase enzymes, with over 99.9% of the prodrug converted within 5 minutes under conditions mimicking the human body (i.e., in human plasma).[20] These findings support the idea that 4-AcO-DMT is quickly and efficiently converted into psilocin before it enters the bloodstream, and that the prodrug itself likely contributes little to the overall pharmacological effect.[20]

Chemistry

4-AcO-DMT shown in powder form.

Synthesis

Stability

Given enough time in unfavorable conditions, 4-AcO-DMT can sometimes turn into a degraded form which is brown in color and can even progress into a brown/black tar-like substance. Researchers hypothesize this is a polymerization reaction and is said to have no effect on the potency of the substance. Preliminary GCMS analysis of the closely related homologue 4-AcO-DET suggests that this degraded form of 4-AcO-DMT consists mainly of the hydroxy form of the parent molecule.[21]

Analogues

4-AcO-DMT is closely related to psilocin (4-HO-DMT) and psilocybin (4-PO-DMT).[6] It is a lower homologue of 4-AcO-MET, 4-AcO-DET, 4-AcO-MiPT, and 4-AcO-DiPT.[6] Other analogues of 4-AcO-DMT include 4-AcO-DPT, 4-MeO-DMT, and 4-PrO-DMT (O-propionylpsilocin).[6][22] Other related prodrugs of psilocin besides 4-AcO-DMT, 4-PrO-DMT, and psilocybin include CT-4201, EB-002, RE-109 (4-GO-DMT), and MSP-1014.

History

4-AcO-DMT and several other esters of psilocin were patented on January 16, 1963 by Sandoz via Albert Hofmann and Franz Troxler.[2][8][23][24] The drug's chemical synthesis was improved by David E. Nichols and colleagues in 1999 and it was suggested as a more economical and accessible alternative to psilocybin for use in scientific research.[2][8][3] 4-AcO-DMT was first detected as a designer drug in Europe in 2009.[8] It became increasingly prevalent as a recreational drug in the 2010s and has been the most commonly used novel tryptamine.[2][5] In the 2020s, 4-AcO-DMT became widely encountered in the form of mushroom edibles in the United States as an alternative to psilocybin and psilocybin-containing mushrooms.[11][12][13][14]

Society and culture

International

4-AcO-DMT is not scheduled under any international drug schedules, including the United Nations 1971 Convention on Psychotropic Substances, making it a potentially more accessible alternative to psilocybin for research.[25]

Australia

4-AcO-DMT can be considered an analog of psilocin making it a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[26] A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.[26]

Canada

4-AcO-DMT is not a controlled substance in Canada as of 2025.[27]

Czech Republic

4-AcO-DMT is prohibited in Czech Republic except strictly limited research and therapeutical purposes.[28]

Germany

4-AcO-DMT is banned in Germany according to the BtMG since it is an ester of psilocin.[29]

Israel

Italy

Sweden

The Riksdag added 4-AcO-DMT to Narcotic Drugs Punishments Act under swedish schedule I ("substances, plant materials and fungi which normally do not have medical use" ) as of January 25, 2017, published by Medical Products Agency (MPA) in regulation HSLF-FS 2017:1 listed as "4-acetoxi-N,N-dimetyltryptamin".[30]

United Kingdom

4-AcO-DMT, being an ester of psilocin, is a Class A drug in the United Kingdom under the Misuse of Drugs Act 1971.[31]

United States

4-AcO-DMT is not an explicitly controlled substance in the United States.[32][1][33] However, it may be considered an analogue of psilocin and psilocybin under the Federal Analogue Act, but only if intended or used for human consumption.[1][33] Conversely, if not intended for human consumption, for instance if used only for research purposes, it may be considered legal.[1][33]

While not controlled at the federal level, 4-AcO-DMT is listed as a controlled substance at the state level in multiple states in the United States, including in Alabama which has made it a schedule I at the state level on March 18, 2014, along with several other tryptamine analogues.[34]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 "DARK Classics in Chemical Neuroscience: Psilocybin". ACS Chem Neurosci 9 (10): 2438–2447. October 2018. doi:10.1021/acschemneuro.8b00186. PMID 29956917. https://shaunlacob.com/wp-content/uploads/2020/12/DC-PSILO.pdf. "A chemically modified psilocin precursor, known as psilacetin (20), O-acetylpsilocin, or 4-acetoxy-N,N-dimethyltryptamine, which replaces the phosphoryloxy group found on psilocybin with an acetoxy group, is also readily available. The substituted acetoxy group is believed to be metabolized in an equivalent manner to the phosphoryloxy group, both producing psilocin during first-pass metabolism.37 This simple modification skirts written laws in the United States when the product is clearly designated “not for human consumption,” allowing pseudolegal import and possession for research purposes only; however, if it were to be used in vivo, the user would be in violation of the Federal Analogue Act.38 Although psilacetin has been hypothesized to act as an identical pharmacological substitute for psilocybin, many users report a small, yet significant, difference in the effects of each drug.39 Psilacetin is often described as having a faster onset of action without the anxiety and nausea associated with psilocybin-containing mushroom ingestion (which could be due to avoiding the ingestion of the significant amounts of chitin usually found in these mushrooms) and to have a shorter duration of action with a more peaceful experience throughout, leaving most users with a positive afterglow.37,39". 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 "In vivo validation of psilacetin as a prodrug yielding modestly lower peripheral psilocin exposure than psilocybin". Front Psychiatry 14. 2024. doi:10.3389/fpsyt.2023.1303365. PMID 38264637. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Improvements to the Synthesis of Psilocybin and a Facile Method for Preparing the O-Acetyl Prodrug of Psilocin". Synthesis 1999 (6): 935–938. 1999. doi:10.1055/s-1999-3490. http://www.erowid.org/archive/rhodium/pdf/nichols/nichols-psilocin.pdf. Retrieved 17 January 2012. 
  4. ↑ 4.0 4.1 4.2 4.3 "4-AcO-DMT Is the Most Accessible (and Mysterious) Drug on the Market Right Now". 24 June 2024. https://doubleblindmag.com/4-aco-dmt/. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 "A qualitative descriptive analysis of effects of psychedelic phenethylamines and tryptamines". Human Psychopharmacology 35 (1). January 2020. doi:10.1002/hup.2719. PMID 31909513. "4-AcO-DMT (4-acetoxyN,N-dimethyltryptamine, O-acetylpsilocin, or psilacetin) was the most prevalent tryptamine reported with 30.8% of the sample reporting use and two thirds (66.7%) of tryptamine users reporting use. 4-AcO-DMT—often pronounced as “4-akko-DMT”—was reported by most users as producing similar effects as psilocybin mushrooms with less nausea. One participant referred to this compound as “silly pills,” which is a play on the name psilocybin. This particular compound was often preferred over natural mushrooms due to the lack of adverse side effects such as nausea, which the natural mushroom tends to produce. Thus, participants often suggested that 4-AcODMT allows one to achieve the same high as psilocybin without adverse physical effects such as nausea and heavy body load. One participant did complain of dry mouth and mentioned that although 4-AcO-DMT feels similar to psilocybin, he said it lacks the “organic” feel produced by psilocybin. [...] Of the most common tryptamines used by this sample, the majority of these compounds were first discovered or first synthesized as early as the 1930s (e.g., 5-MeO-DMT), 1950s (e.g., 4-AcO-DMT), or in the 1970s (e.g., 4-HO-MET and 5-MeO-DIPT). [...] 4-AcO-DMT was the most commonly used tryptamine by participants, and this compound also appears to be among the most prevalent novel tryptamines in recent years (Palamar & Le, 2019; PalmaConesa et al., 2017). [...] 4-AcO-DMT is often described as having a faster onset of action than psilocybin with a high of shorter duration, and as many of our participants noted, use allows them to avoid the nausea commonly associated mushroom ingestion (Geiger et al., 2018). Despite 4-AcO-DMT being among the most prevalent tryptamines, and having been discovered in the 1950s, little academic research has focused on recreational use of this compound.". 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. http://www.erowid.org/library/books_online/tihkal/tihkal.shtml.  https://www.erowid.org/library/books_online/tihkal/tihkal18.shtml
  7. ↑ 7.0 7.1 7.2 7.3 Cite error: Invalid <ref> tag; no text was provided for refs named MallaroniMasonVinckenbosch2022
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 "Investigation of the Structure-Activity Relationships of Psilocybin Analogues". ACS Pharmacol Transl Sci 4 (2): 533–542. April 2021. doi:10.1021/acsptsci.0c00176. PMID 33860183. 
  9. ↑ "Recent advances in the neuropsychopharmacology of serotonergic hallucinogens". Behav Brain Res 277: 99–120. January 2015. doi:10.1016/j.bbr.2014.07.016. PMID 25036425. 
  10. ↑ "The neural basis of psychedelic action". Nat Neurosci 25 (11): 1407–1419. November 2022. doi:10.1038/s41593-022-01177-4. PMID 36280799. 
  11. ↑ 11.0 11.1 11.2 "Magic mushroom chocolates are having a moment. But do they even contain mushrooms?". 9 August 2024. https://www.latimes.com/california/story/2024-08-09/magic-mushroom-chocolates-are-having-a-moment-but-do-they-even-contain-mushrooms. 
  12. ↑ 12.0 12.1 "Psychedelic mushroom edibles promise health benefits. Be wary, experts say.". Washington Post. 4 July 2024. https://www.washingtonpost.com/health/2024/07/03/mushrooms-psychedelic-edible-harmful/. 
  13. ↑ 13.0 13.1 "Mushroom edibles are rising in popularity. It's hard to say what's in them.". 18 July 2024. https://www.nbcnews.com/health/health-news/mushroom-edibles-are-rising-popularity-s-hard-say-s-rcna162408. 
  14. ↑ 14.0 14.1 14.2 "Are Mushroom Edibles Safe and Legal?". TIME. 4 October 2024. https://time.com/7032706/are-mushroom-edibles-safe-legal/. Retrieved 1 February 2025. 
  15. ↑ "What we know about microdosing candy illnesses as death investigation underway". 5 July 2024. https://arstechnica.com/science/2024/07/authorities-investigating-death-possibly-linked-to-toxic-microdosing-candies/. 
  16. ↑ 16.0 16.1 16.2 "4-AcO-DMT (Ацетилпсилоцин)" (in ru). https://aipsin.com/newsubstance/671/. 
  17. ↑ "Effect of Hallucinogens on Unconditioned Behavior". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. 36. 2018. pp. 159–199. doi:10.1007/7854_2016_466. ISBN 978-3-662-55878-2. 
  18. ↑ "Discriminative Stimulus Effects of Substituted Tryptamines in Rats". ACS Pharmacol Transl Sci 4 (2): 467–471. April 2021. doi:10.1021/acsptsci.0c00173. PMID 33860176. 
  19. ↑ "Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders". J Med Chem 67 (2): 1024–1043. January 2024. doi:10.1021/acs.jmedchem.3c01225. PMID 37983270. 
  20. ↑ 20.0 20.1 20.2 "Synthesis and In Vitro Profiling of Psilocin Derivatives: Improved Stability and Synthetic Properties". J Med Chem 68 (7): 7153–7165. March 2025. doi:10.1021/acs.jmedchem.4c02612. PMID 40108981. 
  21. ↑ "Erowid 4-Acetoxy-DET Vaults : 4-Acetoxy-DET / Ethacetin Degradation". 4 July 2003. https://erowid.org/chemicals/4_acetoxy_det/4_acetoxy_det_article1.shtml. 
  22. ↑ "Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy-N,N-dimethyltryptamine in Mice". ACS Pharmacol Transl Sci 6 (4): 567–577. April 2023. doi:10.1021/acsptsci.2c00222. PMID 37082754. 
  23. ↑ Hofmann A, Troxler F, "Esters of indoles", US patent 3075992, assigned to Sandoz Ltd.
  24. ↑ US patent 3075992
  25. ↑ "In vivo validation of psilacetin as a prodrug yielding modestly lower peripheral psilocin exposure than psilocybin". Front Psychiatry 14. 2024. doi:10.3389/fpsyt.2023.1303365. PMID 38264637. 
  26. ↑ 26.0 26.1 "Poisons Standard October 2015". Federal Register of Legislation. Australian Government. 30 September 2015. https://www.comlaw.gov.au/Details/F2015L01534. 
  27. ↑ "Controlled Drugs and Substances Act". https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html. 
  28. ↑ "Government regulation of the list of the addictive substances". Federal Register of Legislation. Czech Government. https://www.zakonyprolidi.cz/cs/2013-463#p1-1-d. 
  29. ↑ "Anlage I BtMG" (in de). https://www.gesetze-im-internet.de/btmg_1981/anlage_i.html. 
  30. ↑ "Föreskrifter om ändring i Läkemedelsverkets föreskrifter (LVFS 2011:10) om förteckningar över narkotika" (in sv). https://lakemedelsverket.se/upload/lvfs/HSLF-FS_2017_1.pdf. 
  31. ↑ "Misuse of Drugs Act 1971". Schedule 2 Part I, Act of 1971. http://www.legislation.gov.uk/ukpga/1971/38/schedule/2. 
  32. ↑ Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026), United States: U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division, January 2026, https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf 
  33. ↑ 33.0 33.1 33.2 "Prodrugs of New Psychoactive Substances (NPS): A New Challenge". J Forensic Sci 65 (3): 913–920. May 2020. doi:10.1111/1556-4029.14268. PMID 31943218. "In a review about psilocybin, Geiger et al. (58) also discussed the modified psilocin precursor, O-acetylpsilocin (4-acetoxy-N,N-dimethyltryptamine also known as psilacetin) which is available for purchase online having been mentioned in drug forums and to a limited extent in the literature (59,60). Chemically, an acetoxy group replaces the phosphoryloxy group found on psilocybin and is believed to be metabolized to produce psilocin during first-pass metabolism (58). The authors report that this modification obfuscates written laws in the United States when the product is designated “not for human consumption,” allowing pseudo-legal import and possession for research purposes only; however, if it were to be used in vivo, the user would be in violation of the Federal Analogue Act (58).". 
  34. ↑ "Controlled Substances List". Alabama State Board of Health. 22 February 2024. p. 50. https://www.alabamapublichealth.gov/blog/assets/controlledsubstanceslist.pdf. 

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