5-DM-DOM

Last updated

5-DM-DOM
Clinical data
Other names5-O-Desmethyl-DOM; 5-DES-Me-DOM; 5-OH-DOM; 5-Hydroxy-DOM; 5-HMMP; 5-Hydroxy-2-methoxy-4-methylamphetamine; 2-Methoxy-5-hydroxy-4-methylamphetamine
Drug class Serotonin receptor modulator; Serotonin 5-HT2 receptor modulator; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Identifiers
  • 5-(2-aminopropyl)-4-methoxy-2-methylphenol
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C11H17NO2
Molar mass 195.262 g·mol−1
3D model (JSmol)
  • CC1=CC(=C(C=C1O)CC(C)N)OC
  • InChI=1S/C11H17NO2/c1-7-4-11(14-3)9(5-8(2)12)6-10(7)13/h4,6,8,13H,5,12H2,1-3H3
  • Key:UVEGZSXIBVSOJB-UHFFFAOYSA-N

5-DM-DOM, also known as 5-O-desmethyl-DOM, 5-OH-DOM, or 5-hydroxy-2-methoxy-4-methylamphetamine (5-HMMP), is a psychedelic drug of the phenethylamine and amphetamine families related to the DOx psychedelic DOM (2,5-dimethoxy-4-methylamphetamine; STP). [1] [2] [3] [4] [5] It has been identified as an active metabolite of DOM in animals. [1] [3] [6] [7] The drug is one of two possible O-demethylated analogues and metabolites of DOM, the other being 2-DM-DOM (2-O-desmethyl-DOM; 2-OH-DOM; 2-HMMP). [1] [3] [6]

Contents

Use and effects

The properties and effects of 5-DM-DOM in humans have not been reported and are unknown. [8]

Pharmacology

5-DM-DOM shows affinity for the serotonin 5-HT2A and 5-HT2C receptors (Ki = 210 nM and 500 nM, respectively). [1] [9] [3] Its affinity for the serotonin 5-HT2A receptor was about 1.75-fold lower than that of DOM. [9] [3] In another earlier study, the drug's affinity (Ki) was 200 nM for the serotonin 5-HT2 receptor, with this being about 2-fold lower than that of DOM. [10] Conversely, in another later study, its affinity (K0.5) was 4.8 nM for the serotonin 5-HT2A receptor and was about the same as that of DOM (which was 4.4 nM). [11] In addition, 5-DM-DOM was shown to be an agonist of the serotonin 5-HT2A receptor, with an EC50 Tooltip half-maximal effective concentration (Emax Tooltip maximal efficacy) of 18.1 nM (101%), relative to 19.3 nM (95%) in the case of DOM. [11]

5-DM-DOM fully generalized to (–)-DOM (the more active psychedelic enantiomer of DOM) and LSD in rodent drug discrimination tests. [9] [3] It produced 87.5% (–)-DOM-appropriate responding at a dose of 0.3 mg/kg and 94% LSD-appropriate responding at a dose of 3.0 mg/kg. [3] For comparison, the training dose of (–)-DOM was 0.6 mg/kg. [3] The drug's substitution was inhibited by the selective serotonin 5-HT2A receptor antagonist volinanserin (MDL-100907). [9] [3] An earlier study on the other hand found that 5-DM-DOM across a dose range of 1.0 to 3.0 mg/kg failed to substitute for racemic DOM at a training dose of 1.0 mg/kg, with 5-DM-DOM at 1.0 to 2.0 mg/kg producing insignificant substitution (3–12%) and the 3.0 mg/kg dose producing behavioral disruption. [5] The drug's ED50 Tooltip median effective dose could not be calculated nor compared with that of DOM or (–)-DOM in this study. [5]

DOM shows an unusually delayed onset of effects in animals and humans compared to other psychedelics like LSD and mescaline. [1] [3] [12] In rats, DOM produces peak interoceptive effects after 60 minutes, whereas LSD and mescaline do so after only 15 minutes. [1] [3] This cannot be explained by delayed uptake of DOM into the brain, as maximal brain levels of (–)-DOM in rats occur after 15 to 30 minutes. [1] [3] Based on these findings, it was theorized that DOM's delayed onset of effects might be due to formation of active metabolites such as 2-DM-DOM and 5-DM-DOM. [1] [3] [13] As a result of their free hydroxyl group and consequent greater polarity, these metabolites are expected to cross the blood–brain barrier more slowly than DOM. [1] [9] [5] The hypothesis was tested, but it could not be unequivocally accepted nor rejected. [3] Both metabolites were said to be less potent than DOM itself. [1] [3] [5] [2] In any case, the metabolites showed a delayed time to peak interoceptive effects similarly to DOM in rats. [1] [9] [3]

There have been concerns that 5-DM-DOM might be neurotoxic. [9] This is because DOM has been found to undergo bis-demethylation into 2,5-DDM-DOM followed by subsequent oxidation to a reactive alkylating para-quinone and/or cyclic iminoquinone. [9] [14] The properties of the hydroquinone DOM metabolite have been said to parallel those of the monoaminergic neurotoxin 6-hydroxydopamine. [14]

Chemistry

The predicted log P of 5-DM-DOM is 1.9 [15] and of DOM is 2.2. [16]

History

5-DM-DOM was first described in the scientific literature as a DOM metabolite the mid-1970s. [3] [6] [17] [7] Subsequently, its pharmacology was described by Richard Glennon and colleagues in the early-to-mid 1980s [5] and in the early 2000s. [4] [3]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Trachsel D, Lehmann D, Enzensperger C (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. pp. 813–814. ISBN   978-3-03788-700-4. OCLC   858805226. Archived from the original on 21 August 2025.
  2. 1 2 Glennon RA, Young R (5 August 2011). "Role of Stereochemistry in Drug Discrimination Studies". Drug Discrimination. Wiley. pp. 129–161. doi:10.1002/9781118023150.ch4. ISBN   978-0-470-43352-2 . Retrieved 1 February 2026. Examination of 2-HMMP, the 2-desmethyl metabolite of DOM (also called 2-DM DOM), and 5-HMMP, the 5-desmethyl metabolite (also called 5-DM DOM) (Figure 4-5), a positional isomer of 2-HMMP, showed that DOM-stimulus generalization occurred to 2-HMMP (ED50 = 1.71 mg/kg), but that administration of low doses of 5-HMMP produced only saline-like responding followed, at a higher dose, by disruption of the animals' behavior [7]. With a different training drug [i.e., (+)LSD], pre-session injection interval, and strain of rat (Fischer 344 rather than Sprague-Dawley), the (+)LSD stimulus generalized to both metabolites with the 5-desmethyl metabolite 5-HMMP being approximately twice as potent as its positional isomer [8]. [...] Figure 4-5. Chemical structures of the hallucinogen DOM, [...] its 2-desmethyl analog 2-HMMP (also known as 2-DM-DOM) and its positional isomer 5-HMMP (also known as 5-DM-DOM).
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Eckler JR, Chang-Fong J, Rabin RA, Smith C, Teitler M, Glennon RA, et al. (July 2003). "Behavioral characterization of 2-O-desmethyl and 5-O-desmethyl metabolites of the phenylethylamine hallucinogen DOM". Pharmacology, Biochemistry, and Behavior. 75 (4): 845–852. doi:10.1016/s0091-3057(03)00159-x. PMID   12957227.
  4. 1 2 Eckler JR (20 December 2002). Stimulus Control by Hallucinogens: SSRI Interactions (PhD thesis). State University of New York at Buffalo.
  5. 1 2 3 4 5 6 Glennon RA, Young R, Rosecrans JA (April 1982). "Discriminative stimulus properties of DOM and several molecular modifications". Pharmacology, Biochemistry, and Behavior. 16 (4): 553–556. doi:10.1016/0091-3057(82)90413-0. PMID   7071088.
  6. 1 2 3 Castagnoli N (1978). "Drug Metabolism: Review of Principles and the Fate of One-Ring Psychotomimetics". Stimulants. Boston, MA: Springer US. pp. 335–387. doi:10.1007/978-1-4757-0510-2_7. ISBN   978-1-4757-0512-6 . Retrieved 1 February 2026. The metabolism of [DOM (111)] has been examined in some detail. [...] FIG. 9. Metabolic pathways for amine 111 (DOM). [...] The third general metabolic pathway for 111 is oxidative O-demethylation of the methyl phenyl ether groups. All three possible O-demethylated metabolites, compounds 118-120, have been characterized in rabbit liver homogenates (Zweig and Castagnoli, 1975, 1977). [...]
  7. 1 2 Zweig JS, Castagnoli N (March 1977). "In vitro O-demethylation of the psychotomimetic amine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane". Journal of Medicinal Chemistry. 20 (3): 414–421. doi:10.1021/jm00213a020. PMID   845874.
  8. ↑ Shulgin A, Manning T, Daley P (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley: Transform Press. ISBN   978-0-9630096-3-0.
  9. 1 2 3 4 5 6 7 8 Glennon RA (April 2017). "The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse". Journal of Medicinal Chemistry. 60 (7): 2605–2628. doi:10.1021/acs.jmedchem.7b00085. PMC   5824997 . PMID   28244748. Another strategy was to unmask one of the two methoxy groups of DOB to provide a polar phenolic group – phenolic groups being known to decrease BBB permeability. We had already examined the two des-methyl analogs of DOM: 2-des-methyl DOM (2-DM-DOM; 26) and 5-des-methyl DOM (5-DM-DOM; 27) (Figure 8).43 Both compounds displayed affinity at 5-HT2A receptors, their affinities being approximately one-fifth and one-half, respectively, that of DOM. Furthermore, both compounds substituted in R(-)DOM-trained and LSD-trained animals, suggesting agonist action, and stimulus effects were antagonized by pretreatment of the animals with the selective phenylalkylamine-based 5-HT2A receptor antagonist M100907 (MDL-100,907; volinanserin, 28).43 Stimulus generalization was demonstrated to be time-dependent, with the phenolic compounds having a longer onset of action time (decreased ability of the agents to penetrate the BBB?). Both of these agents were potential candidates for further investigation. However, there was some concern that 2-DM-DOM and 5-DM-DOM might undergo further O-demethylation in vivo to a hydroquinone. It had been shown years earlier that DOM can undergo metabolic bis-demethylation to a hydroquinone, and that the hydroquinone undergoes oxidation to a para-quinone (and/or a cyclic iminoquinone) that reacts irreversibly with various proteins.44 As a consequence, this approach was not pursued because of potential risks of neurotoxicity.
  10. ↑ Lyon RA, Titeler M, Seggel MR, Glennon RA (January 1988). "Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens". European Journal of Pharmacology. 145 (3): 291–297. doi:10.1016/0014-2999(88)90432-3. PMID   3350047.
  11. 1 2 McCorvy JD (16 January 2013). Mapping the binding site of the 5-HT2A receptor using mutagenesis and ligand libraries: Insights into the molecular actions of psychedelics (Ph.D. thesis). Purdue University. Archived from the original on 15 May 2025. Retrieved 27 May 2025– via Purdue e-Pubs.{{cite thesis}}: CS1 maint: bot: original URL status unknown (link)
  12. ↑ Shulgin A, Shulgin A (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN   0-9630096-0-5. OCLC   25627628. https://www.erowid.org/library/books_online/pihkal/pihkal068.shtml
  13. ↑ Trout K, Daley PF (December 2024). "The origin of 2,5-dimethoxy-4-methylamphetamine (DOM, STP)". Drug Testing and Analysis. 16 (12): 1496–1508. doi:10.1002/dta.3667. PMID   38419183. The lengthy duration may additionally involve the formation of two active metabolites, 1-(2-hydroxy-5-methoxy4-methylphenyl)propan-2-amine and 1-(5-hydroxy-2-methoxy4-methylphenyl)propan-2-amine.35,36 These have been suggested to have greater effectiveness at behavioral disruption in rats than DOM.35 Their effects would be perceived of as a second intensity peak beginning when a user would typically anticipate a drug to be wearing off. This suggestion may be supported by the metabolism of DOM reported in rats by Zweig and Castagnoli36 and Eckler35 but is presently remains unproven for humans due to scant and inadequate studies of DOM's metabolism in humans. Shulgin also voiced suspicions of DOM producing an active metabolite in humans.4 Snyder observed that only between 5% and 10%34 or 5–20%14 of an administered dose of DOM was excreted unchanged, suggesting that significant levels of metabolism may occur in humans.
  14. 1 2 Jacob P, Kline T, Castagnoli N (June 1979). "Chemical and biological studies of 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine". Journal of Medicinal Chemistry. 22 (6): 662–671. doi:10.1021/jm00192a011. PMID   458821.
  15. ↑ "5-(2-Aminopropyl)-4-methoxy-2-methylphenol". PubChem. Retrieved 1 February 2026.
  16. ↑ "2,5-Dimethoxy-4-Methylamphetamine". PubChem. Retrieved 1 February 2026.
  17. ↑ Zwieg JS, Castagnoli N (1975). "Metabolic O-demethylation of the psychotomimetic amine 1-(2, 5-dimetroxy-4-methylphenyl)-2-aminopropane". Psychopharmacology Communications. 1 (4): 359–371. PMID   1224005.
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