Psychoplastogen

Psychoplastogen
Drug class
Class identifiers
SynonymsNeuroplastogen
UseMedical, microdosing
Mechanism of actionVarious
Biological targetVarious
Chemical classVarious
Legal status
Legal status
In Wikidata

Psychoplastogens, also known as plastogens (categorically) or neuroplastogens (nonhallucinogenic plastogens), are a group of small-molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single administration.

Existing psychoplastogens with demonstrated therapeutic effects include ketamine, MDMA, scopolamine, and the serotonergic psychedelics, including LSD, psilocin (the active metabolite of psilocybin), DMT, and 5-MeO-DMT.

Such compounds are under development for brain disorders, including depression, addiction, and PTSD. The ability to rapidly promote neuronal changes via mechanisms of neuroplasticity was recently discovered as the common therapeutic activity and mechanism of action.

Etymology

The term psychoplastogen comes from the Greek roots psych- (mind), -plast (molded), and -gen (producing), and covers a variety of chemotypes and receptor targets. It was coined by David E. Olson in collaboration with Valentina Popescu, both at the University of California, Davis in their 2018 publication.

The term neuroplastogen is used as a synonym for certain types of plastogens, especially when speaking to the biological effects. This term is used to describe nonhallucinogenic plastogens, and delineates those compounds that promote rapid, sustained, structural plasticity without the mind-altering effects of the psychoplastogens.

Chemistry

Plastogens come in a variety of chemotypes and chemical families, but, by definition, are small-molecule drugs. Ketamine has been described as, "the prototypical psychoplastogen".

Pharmacology

Psychoplastogens exert their effects by promoting structural and functional neural plasticity through diverse targets including, but not limited to, 5-HT2A, NMDA, and muscarinic receptors. Some are biased agonists. [citation needed] While each compound may have a different receptor binding profile, signaling appears to converge at the tyrosine kinase B (TrkB) and mammalian target of rapamycin (mTOR) pathways. Convergence at TrkB and mTOR parallels that of traditional antidepressants with known efficacies, but with more rapid onset. Although many serotonin 5-HT2A receptor agonists are known to produce psychoplastogenic effects, serotonin itself is not psychoplastogenic owing to poor lipophilicity and inability to activate intracellular serotonin 5-HT2A receptors.

Due to their rapid and sustained effects, psychoplastogens could potentially be dosed intermittently. In addition to the neuroplasticity effects, these compounds can have other epiphenomena including sedation, dissociation, and hallucinations.

Psychedelics show complex effects on neuroplasticity and can both promote and inhibit neuroplasticity depending on the circumstances. Single doses of DMT, 5-MeO-DMT, psilocybin, and DOI have been found to produce robust and long-lasting increases in neuroplasticity in animals. Likewise, repeated doses of LSD for 7 days increased neuroplasticity. However, chronic intermittent administration of DMT for several weeks resulted in dendritic spine retraction, suggesting physiological homeostatic compensation in response to overstimulation. In addition, DOI has been found to decrease brain-derived neurotrophic factor (BDNF) levels in the hippocampus. The effects of psychedelics on neuroplasticity appear to be dependent on serotonin 5-HT2A receptor activation, as they are abolished in 5-HT2A receptor knockout mice. Nonhallucinogenic serotonin 5-HT2A receptor agonists, like tabernanthalog and lisuride, have also been found to increase neuroplasticity, and to a magnitude comparable to psychedelics.

In terms of neurogenesis, DOI and LSD showed no impact on hippocampal neurogenesis, while psilocybin and 25I-NBOMe decreased hippocampal neurogenesis. 5-MeO-DMT however has been found to increase hippocampal neurogenesis, and this could be blocked by sigma σ1 receptor antagonists.

Certain psychedelics such as LSD and psilocin have been reported to act as highly potent positive allosteric modulators of the tropomyosin receptor kinase B (TrkB), one of the receptors of brain-derived neurotrophic factor (BDNF). In addition to serotonin 5-HT2A receptor agonism, this action has been implicated as a possible contributor to the psychoplastogenic effects of these psychedelics. However, subsequent studies did not reproduce these findings and instead reported no interaction of LSD or psilocin with TrkB.

NMDA receptor modulators have also been explored in this vein. Zelquistinel, an NMDA receptor modulator, has shown rapid onset and sustained duration of action after just one administration in animal studies.

Psychoplastogens describe what some call "event-driven pharmacology" a term originally used to describe targeted protein degraders.

Clinical development

Several psychoplastogens have either been approved (ketamine, spravato) or are in development for the treatment of a variety of brain disorders associated with neuronal atrophy where neuroplasticity can elicit beneficial effects (psilocybin, DMT, zalsupindole, etc.).

Esketamine, sold under the brand name Spravato and produced by Janssen Pharmaceuticals, was approved by the FDA in March 2019 for the treatment of Treatment-Resistant Depression (TRD) and suicidal ideation. As of 2022, it is the only psychoplastogen approved in the US for the treatment of a neuropsychiatric disorder. Esketamine is the S(+) enantiomer of ketamine and functions as an NMDA receptor antagonist.

Other psychoplastogens that are being investigated in the clinic include:

List of psychoplastogens

Hallucinogenic

Nonhallucinogenic

See also

References

Footnotes

  1. ↑ Nonhallucinogenic psychoplastogens are also referred to as neuroplastogens.

Citations

  1. ↑ Cooper T, Seigler MD, Stahl S. Rapid onset brain plasticity at novel pharmacologic targets hypothetically drives innovations for rapid onset antidepressant actions. J Psychopharmacol. 2023 Mar;37(3):242-247.
  2. ↑ Jarow O (25 July 2023). "Psychedelics might revolutionize therapy. What happens if you remove the trip?". Vox. Retrieved 19 May 2025.
  3. 1 2 3 4 5 6 7 Olson DE (January 2018). "Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics". Journal of Experimental Neuroscience. 12 1179069518800508. doi:10.1177/1179069518800508. PMC 6149016. PMID 30262987.
  4. 1 2 3 4 5 6 Benko J, Vranková S (March 2020). "Natural Psychoplastogens As Antidepressant Agents". Molecules. 25 (5): 1172. doi:10.3390/molecules25051172. PMC 7179157. PMID 32150976.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, et al. (June 2018). "Psychedelics Promote Structural and Functional Neural Plasticity". Cell Reports. 23 (11): 3170–3182. doi:10.1016/j.celrep.2018.05.022. PMC 6082376. PMID 29898390.
  6. ↑ Cooper T, Seigler MD, Stahl S. Rapid onset brain plasticity at novel pharmacologic targets hypothetically drives innovations for rapid onset antidepressant actions. J Psychopharmacol. 2023 Mar;37(3):242-247.
  7. ↑ Voleti B, Navarria A, Liu RJ, Banasr M, Li N, Terwilliger R, et al. (November 2013). "Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses". Biological Psychiatry. 74 (10): 742–749. doi:10.1016/j.biopsych.2013.04.025. PMC 3773272. PMID 23751205.
  8. ↑ Chakrapani S, Eskander N, De Los Santos LA, Omisore BA, Mostafa JA (November 2020). "Neuroplasticity and the Biological Role of Brain Derived Neurotrophic Factor in the Pathophysiology and Management of Depression". Cureus. 12 (11) e11396. doi:10.7759/cureus.11396. PMC 7725195. PMID 33312794.
  9. ↑ Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chemical Reviews. 124 (1): 124–163. doi:10.1021/acs.chemrev.3c00375. PMID 38033123. In contrast, serotonin fails to promote neuroplasticity as it cannot effectively reach the intracellular 5- HT2ARs due to low lipophilicity and poor membrane permeability.284 However, it was observed that serotonin can induce the growth of cortical neurons when they are treated with electroporation or transfected with postsynaptic SERT to facilitate serotonin import. In a mouse model of depression, serotonin exhibited antidepressant effects when postsynaptic SERT was expressed.284 These findings suggest that psychedelics such as DMT may induce antidepressant effects by activating intracellular 5-HT2ARs, distinguishing them from the endogenous neurotransmitter serotonin.
  10. ↑ Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, et al. (February 2023). "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors". Science. 379 (6633): 700–706. Bibcode:2023Sci...379..700V. doi:10.1126/science.adf0435. PMC 10108900. PMID 36795823.
  11. 1 2 3 4 5 6 7 8 9 10 Vargas MV, Meyer R, Avanes AA, Rus M, Olson DE (2021). "Psychedelics and Other Psychoplastogens for Treating Mental Illness". Frontiers in Psychiatry. 12 727117. doi:10.3389/fpsyt.2021.727117. PMC 8520991. PMID 34671279.
  12. 1 2 3 4 5 6 7 8 9 10 Hatzipantelis CJ, Olson DE (February 2024). "The Effects of Psychedelics on Neuronal Physiology". Annual Review of Physiology. 86: 27–47. doi:10.1146/annurev-physiol-042022-020923. PMC 10922499. PMID 37931171.
  13. ↑ Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, et al. (June 2023). "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nature Neuroscience. 26 (6): 1032–1041. doi:10.1038/s41593-023-01316-5. PMC 10244169. PMID 37280397.
  14. 1 2 Jain MK, Gumpper RH, Slocum ST, Schmitz GP, Madsen JS, Tummino TA, et al. (October 2025). "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics". Neuron. 113 (19): 3129–3142.e9. doi:10.1016/j.neuron.2025.06.012. PMC 13632693. PMID 40683247. Recent studies have suggested that psychedelics such as LSD directly interact with TrkB with high affinity, promoting BDNF-mediated neuroplasticity and antidepressant-like effects via allosteric potentiation of BDNF signaling in active synapses.8 To investigate this, we screened LSD across 450 human kinases, including TrkB, but found no significant interactions between LSD and any tested human kinases. Further experiments in transfected cells revealed no effect of LSD or psilocin on BDNF-mediated activation of a TrkB reporter. We note that similar negative preliminary results, which have not yet been published in a peer-reviewed journal, were recently reported by Boltaev et al.63
  15. ↑ Donello JE, McIntyre RS, Pickel DB, Stahl SM (January 2025). "Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor". Pharmaceuticals. 18 (2): 157. doi:10.3390/ph18020157. PMC 11858332. PMID 40005971.
  16. ↑ Buntz B (14 September 2023). "GATE Neurosciences: event-driven pharmacology in depression". Drug Discovery Trends. Retrieved 5 October 2025.
  17. ↑ Lai AC, Crews CM (February 2017). "Induced protein degradation: an emerging drug discovery paradigm". Nature Reviews. Drug Discovery. 16 (2): 101–114. Bibcode:2017NRvDD..16..101L. doi:10.1038/nrd.2016.211. PMC 5684876. PMID 27885283.
  18. ↑ Office of the Commissioner (2020-03-24). "FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic". U.S. Food and Drug Administration. Archived from the original on May 1, 2019. Retrieved 2021-08-26.
  19. ↑ Olympic Behavioral Health
  20. ↑ Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, Parker-Guilbert K, et al. (June 2021). "MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study". Nature Medicine. 27 (6): 1025–1033. doi:10.1038/s41591-021-01336-3. PMC 8205851. PMID 33972795.
  21. ↑ Clinical trial number NCT04454684 for "An Open-Label, Multi-Site Phase 2 Study of the Safety and Feasibility of MDMA-Assisted Psychotherapy for Eating Disorders" at ClinicalTrials.gov
  22. ↑ Clinical trial number NCT02427568 for "A Randomized, Double-Blind, Placebo-Controlled Phase 2 Pilot Study of MDMA-Assisted Psychotherapy for Anxiety Associated With a Life-Threatening Illnes" at ClinicalTrials.gov
  23. ↑ Clinical trial number NCT02008396 for "A Placebo-controlled, Randomized, Blinded, Dose Finding Phase 2 Pilot Safety Study of MDMA-assisted Therapy for Social Anxiety in Autistic Adults" at ClinicalTrials.gov
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  25. ↑ Clinical trial number NCT05029466 for "The Efficacy and Tolerability of Psilocybin in Participants With Treatment-Resistant Depression: a Phase 2, Randomized Feasibility Study" at ClinicalTrials.gov
  26. ↑ Johnson MW, Garcia-Romeu A, Griffiths RR (January 2017). "Long-term follow-up of psilocybin-facilitated smoking cessation". The American Journal of Drug and Alcohol Abuse. 43 (1): 55–60. doi:10.3109/00952990.2016.1170135. PMC 5641975. PMID 27441452.
  27. ↑ Clinical trial number NCT01943994 for "Psilocybin-facilitated Smoking Cessation Treatment: A Pilot Study" at ClinicalTrials.gov
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  29. ↑ Clinical trial number NCT03781128 for "Safety and Efficacy of Lysergic Acid Diethylamide (LSD) as Treatment for Cluster Headache: a Randomized, Double-blind, Placebo-controlled Phase II Study" at ClinicalTrials.gov
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  37. 1 2 Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chemical Reviews. 124 (1): 124–163. doi:10.1021/acs.chemrev.3c00375. PMID 38033123.
  38. ↑ Olson DE (April 2021). "The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects". ACS Pharmacology & Translational Science. 4 (2): 563–567. doi:10.1021/acsptsci.0c00192. PMC 8033607. PMID 33861218. [6-MeO-isoDMT] exhibits significantly reduced hallucinogenic potential, as measured by the mouse head-twitch response (HTR) assay, while retaining psychoplastogenic potency comparable to its hallucinogenic congener (Figure 1).31 Because 6-MeO-isoDMT is at least equipotent to 5-MeO-DMT with respect to its ability to promote neural plasticity, it cannot simply be viewed as a less potent hallucinogen. In fact, many of the nonhallucinogenic analogues of psychedelics that our group has developed will not produce hallucinogenic behavioral responses in rodents even at extremely high doses. [...] Figure 1. Hallucinogenic and psychoplastogenic effects can be decoupled through careful chemical design. [...]
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