Zalsupindole

Not to be confused with DLX1.
Zalsupindole
Clinical data
Other namesZAL; DLX-001; DLX-1; DLX001; DLX1; AAZ-A-154; AAZ; (R)-5-Methoxy-N,N-dimethyl-α-methylisotryptamine; (R)-5-MeO-α-methyl-isoDMT; (R)-5-MeO-N,N-dimethyl-isoAMT
Routes of
administration		Oral[1][2][3]
Drug classNon-hallucinogenic serotonin 5-HT2A receptor agonist; Psychoplastogen
ATC code
  • None
Identifiers
  • (2R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine
CAS Number
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H20N2O
Molar mass232.327 g·mol−1
3D model (JSmol)
  • CN(C)[C@H](C)Cn1ccc2cc(ccc21)OC
  • InChI=1S/C14H20N2O/c1-11(15(2)3)10-16-8-7-12-9-13(17-4)5-6-14(12)16/h5-9,11H,10H2,1-4H3/t11-/m1/s1
  • Key:KHEUWLQKCXGVEL-LLVKDONJSA-N

Zalsupindole, also known by its code names DLX-001 and AAZ-A-154 and as (R)-5-methoxy-N,N-dimethyl-α-methylisotryptamine ((R)-5-MeO-α-Me-isoDMT), is non-hallucinogenic serotonin receptor agonist and psychoplastogen of the isotryptamine family related to psychedelic tryptamines such as dimethyltryptamine (DMT).[4][1][2][5][6][7] It is under development for the treatment of major depressive disorder and other central nervous system disorders.[2][5] The drug is taken orally.[4][1][2][3]

It acts as a partial agonist of the serotonin 5-HT2A receptor and also interacts with other serotonin receptors.[4][1] The drug activates the serotonin 5-HT2A receptor with sufficiently high efficacy to promote neuroplasticity but not with adequate efficacy to cause psychedelic effects.[4][1] It does not produce psychedelic-like effects in animals or humans but does produce antidepressant-like effects in animals.[4][1][3]

Zalsupindole was first described in the scientific literature by 2021.[4][8] It was developed by David E. Olson and colleagues at the University of California, Davis and Delix Therapeutics.[4][2][5] As of January 2026, it is in phase 1 clinical trials and a phase 2 trial is being planned.[2][4][9]

Use and effects

A phase 1 dose-ranging clinical trial found that zalsupindole is non-hallucinogenic in humans across a dose range of 2 to 360 mg orally.[4][1][3][9] Nonetheless, it produced changes in brain function as measured by quantitative electroencephalography (qEEG).[4][3][9]

Side effects

Side effects of zalsupindole include dose-dependent nausea, headache, and dizziness.[3][9]

Pharmacology

Pharmacodynamics

Zalsupindole is a non-selective serotonin receptor modulator including of the serotonin 5-HT2A receptor.[4][1][10] It acts as a low-potency, low-efficacy partial agonist of the serotonin 5-HT2A receptor, with an EC50Tooltip half-maximal effective concentration of 8,200 nM and an EmaxTooltip maximal efficacy of 17%.[4][1] The drug is also a moderate-efficacy partial agonist of the serotonin 5-HT2C receptor, with an EC50 of 3,300 nM and an Emax of 70%.[4][1] Other activities have also been reported.[4][1] It is selective for the serotonin 5-HT2 receptors over a number of other receptors, including the serotonin 5-HT1A receptor, dopamine receptors, adrenergic receptors, and the κ-opioid receptor, among others.[4][1][10] The drug is a silent antagonist of the serotonin 5-HT2B receptor, with an IC50Tooltip half-maximal inhibitory concentration of 27,600 nM.[4][1][7]

Zalsupindole is orally bioavailable and centrally penetrant in animals.[4][7] It is a psychoplastogen via activation of the serotonin 5-HT2A receptor and rapidly and persistently increases neuroplasticity in preclinical research.[4][1][11][6][7] The serotonin 5-HT2A receptor antagonist ketanserin abolishes the psychoplastogenic effects of zalsupindole.[4] Zalsupindole produces comparable psychoplastogenic effects to serotonergic psychedelics like psilocin and dimethyltryptamine (DMT) as well as to the dissociative ketamine.[4] Animal studies have found that the drug produces antidepressant-like effects without causing psychedelic-like effects such as the head-twitch response.[4][1][8][12][6][7][13] It does not produce hyperlocomotion at therapeutically relevant doses.[1] In accordance with its serotonin 5-HT2B receptor antagonism, zalsupindole showed no cardiovascular safety signals in animals.[4][7]

Pharmacokinetics

The pharmacokinetics of zalsupindole have been studied.[4][1][3]

Chemistry

Zalsupindole, also known as (R)-5-methoxy-N,N-dimethyl-α-methylisotryptamine, is a substituted isotryptamine derivative.[4][14][15] It is a combined derivative of 5-methoxy-N,N-dimethylisotryptamine (5-MeO-isoDMT) and α-methylisotryptamine (isoAMT).[14][15] Another related compound is 6-methoxy-N,N-dimethylisotryptamine (6-MeO-isoDMT).[14] Zalsupindole is a close isotryptamine analogue of α,N,N,O-tetramethylserotonin (α,N,N,O-TMS or 5-MeO-α,N,N-TMT).[15]

Synthesis

The chemical synthesis of zalsupindole has been described.[4][12]

History

Zalsupindole was first described in the scientific literature by David E. Olson and colleagues in 2021.[4][8] It was developed by Olson's lab at the University of California, Davis and at his company Delix Therapeutics.[4][2][5] The drug wasfirst synthesized in 2019.[4] It was initially described under the name AAZ-A-154 and then by the name DLX-001 before receiving the name zalsupindole.[4][2][5][1]

Society and culture

Names

Zalsupindole is the generic name of the drug and its INNTooltip International Nonproprietary Name.[4][16] It is also known by its developmental code names DLX-001 and AAZ-A-154.[4][2][5]

Research

Zalsupindole, as well as related drugs such as tabernanthalog (TBG; DLX-007), DLX-159, DLX-2270, and JRT, are licensed by Delix Therapeutics and are being developed for treatment of neuropsychiatric disorders such as depression and schizophrenia.[4][11][2][5] As of January 2026, zalsupindole is in phase 1 clinical trials for major depressive disorder and other central nervous system disorders.[2][5] Phase 1a and 1b trials have been completed and results reported.[4][2][5][9] A phase 2 trial is being planned and has been cleared by the FDA for at home administration.[2][4][9]

See also

References

  1. ^ a b c d e f g h i j k l m n o p q r Agrawal R, Gillie D, Mungenast A, Chytil M, Engel S, Wu MC, et al. (October 2025). "Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics". ACS Chem Neurosci acschemneuro.5c00667. doi:10.1021/acschemneuro.5c00667. PMID 41078264.
  2. ^ a b c d e f g h i j k l m "DLX 1". AdisInsight. 11 December 2023. Retrieved 2 November 2024.
  3. ^ a b c d e f g Koenig A, van der Aa L, Pelletier N, Patat A, Viardot G, Olson D, et al. (2024). "ACNP 63rd Annual Meeting: Poster Abstracts P1-P304: P163. Phase I Results for DLX-001, a Novel Neuroplastogen Under Development for the Treatment of Major Depressive Disorder" (PDF). Neuropsychopharmacology. 49 (S1): 65–235 (157–158). doi:10.1038/s41386-024-02011-0. ISSN 0893-133X. PMC 11627186. PMID 39643633. Retrieved 31 January 2025.
  4. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah Salfiti M, Kyriazis M, Mikellides G (January 2026). "Zalsupindole: A Non-Hallucinogenic Psychoplastogen Advancing Psychedelic-Inspired Therapeutics". ACS Chem Neurosci. doi:10.1021/acschemneuro.5c00707. PMID 41493772.
  5. ^ a b c d e f g h i "Delving into the Latest Updates on DLX-001 with Synapse". Synapse. 1 November 2024. Retrieved 2 November 2024.
  6. ^ a b c Rasmussen K, Chytil M, Agrawal R, Leach P, Gillie D, Mungenast A, et al. (2024). "14. Preclinical Pharmacology of DLX-001, a Novel Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases". Biological Psychiatry. 95 (10). Elsevier BV: S80. doi:10.1016/j.biopsych.2024.02.192. ISSN 0006-3223.
  7. ^ a b c d e f Rasmussen K, Engel S, Chytil M, Koenig A, Meyer R, Rus M, et al. (December 2023). "ACNP 62nd Annual Meeting: Poster Abstracts P251 - P500: P361. Preclinical Pharmacology of DLX-001, a Novel Non-Hallucinogenic Neuroplastogen With the Potential for Treating Neuropsychiatric Diseases". Neuropsychopharmacology. 48 (Suppl 1): 211–354 (274–275). doi:10.1038/s41386-023-01756-4. PMC 10729596. PMID 38040810.
  8. ^ a b c Dong C, Ly C, Dunlap LE, Vargas MV, Sun J, Hwang IW, et al. (May 2021). "Psychedelic-inspired drug discovery using an engineered biosensor". Cell. 184 (10): 2779–2792.e18. doi:10.1016/j.cell.2021.03.043. PMC 8122087. PMID 33915107.
  9. ^ a b c d e f Meyer R, Koenig A, Nijhuis J, Tiessen R, Gillie D, Stam M, et al. (2026). "ACNP 64th Annual Meeting: Poster Abstracts P1-P291: P231. A Phase Ib study to evaluate the pharmacodynamics, safety, and tolerability of the novel neuroplastogen Zalsupindole (DLX-001), dosed daily and intermittently in participants with major depressive Disorder". Neuropsychopharmacology. 51 (S1): 74–242. doi:10.1038/s41386-025-02279-w. ISSN 0893-133X. Retrieved 9 January 2026.
  10. ^ a b Dunlap LE (2022). Development of Non-Hallucinogenic Psychoplastogens (Thesis). University of California, Davis. Retrieved 18 November 2024.
  11. ^ a b "Can we take the high out of psychedelics?". Wired UK. ISSN 1357-0978. Retrieved 2022-07-07.
  12. ^ a b WO 2020176597, Olson DE, Dunlap L, Wagner FF, "N-substituted indoles and other heterocycles for treating brain disorders", published 3 September 2020, assigned to The Regents of the University of California 
  13. ^ Cross R (2021-09-27). "Delix raises $70 million to synthesize psychedelic-inspired drugs". cen.acs.org. Archived from the original on 2021-09-27. Retrieved 2022-01-14.
  14. ^ a b c Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chem Rev. 124 (1): 124–163. doi:10.1021/acs.chemrev.3c00375. PMID 38033123.
  15. ^ a b c "(2R)-1-(5-Methoxyindol-1-yl)-N,N-dimethylpropan-2-amine". PubChem. Retrieved 27 November 2024.
  16. ^ https://iris.who.int/bitstream/handle/10665/380497/9789240107038-eng.pdf "zalsupindolum zalsupindole (2R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine antidepressant"
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