Psychoplastogens, also known as neuroplastogens,[1] 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.[2][3]
Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including ketamine, MDMA, scopolamine, and the serotonergic psychedelics, including LSD, psilocin (the active metabolite of psilocybin), DMT, and 5-MeO-DMT.
Compounds of this sort are being explored as therapeutics for a variety of 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.[4]
Etymology and nomenclature
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.[4]
The term neuroplastogen is sometimes used as a synonym for psychoplastogen, especially when speaking to the biological substrate rather than the therapeutic.
Chemistry
Psychoplastogens come in a variety of chemotypes and chemical families, but, by definition, are small-molecule drugs.[2] Ketamine has been described as, "the prototypical psychoplastogen".[4]
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. 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.[4][5] Convergence at TrkB and mTOR parallels that of traditional antidepressants with known efficacies, but with more rapid onset.[6] 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.[7][8]
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.[9]
Psychedelics show complex effects on neuroplasticity and can both promote and inhibit neuroplasticity depending on the circumstances.[10] Single doses of DMT, 5-MeO-DMT, psilocybin, and DOI have been found to produce robust and long-lasting increases in neuroplasticity in animals.[10] Likewise, repeated doses of LSD for 7days increased neuroplasticity.[10] However, chronic intermittent administration of DMT for several weeks resulted in dendritic spine retraction, suggesting physiological homeostatic compensation in response to overstimulation.[10] In addition, DOI has been found to decrease brain-derived neurotrophic factor (BDNF) levels in the hippocampus.[10] The effects of psychedelics on neuroplasticity appear to be dependent on serotonin5-HT2A receptor activation, as they are abolished in 5-HT2A receptor knockout mice.[10] Non-hallucinogenic serotonin 5-HT2A receptor agonists, like tabernanthalog and lisuride, have also been found to increase neuroplasticity, and to a magnitude comparable to psychedelics.[10]
In terms of neurogenesis, DOI and LSD showed no impact on hippocampal neurogenesis, while psilocybin and 25I-NBOMe decreased hippocampal neurogenesis.[10] 5-MeO-DMT however has been found to increase hippocampal neurogenesis, and this could be blocked by sigmaσ1 receptorantagonists.[10]
Certain psychedelics such as LSD and psilocin have been reported to act as highly potentpositive allosteric modulators of the tropomyosin receptor kinase B (TrkB), one of the receptors of brain-derived neurotrophic factor (BDNF).[10][11] In addition to serotonin 5-HT2A receptor agonism, this action has been implicated as a possible contributor to the psychoplastogenic effects of these psychedelics.[12] However, subsequent studies failed to reproduce these findings and instead found no interaction of LSD or psilocin with TrkB.[12]
Approved medical uses
Several psychoplastogens have either been approved or are in development for the treatment of a variety of brain disorders associated with neuronal atrophy where neuroplasticity can elicit beneficial effects.[9]
Other psychoplastogens that are being investigated in the clinic include:
MDMA-assisted psychotherapy is being investigated for treatment of PTSD. A recent placebo controlled Phase 3 trial found that 67% of participants in the MDMA+therapy group no longer met the diagnostic criteria for PTSD whereas 32% of those in the placebo+therapy group no longer met PTSD threshold.[15] MDMA-assisted psychotherapy is also currently in Phase 2 trials for eating disorders,[16] anxiety associated with life-threatening illness,[17] and social anxiety in autistic adults.[18]
Psilocybin, a compound in psilocybin mushrooms that serves as a prodrug for psilocin, is currently being investigated in clinical trials of Hallucinogen-Assisted Therapy for a variety of neuropsychiatric disorders. To date studies have explored the utility of psilocybin in a variety of diseases, including TRD,[19][20] smoking addiction,[21][22] and anxiety and depression in people with cancer diagnoses.[23]
LSD is being tested in phase 2 trials for cluster headaches and anxiety.[24]
^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. PMID38033123. 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.
^Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, Antenucci L, Kot EF, Goncharuk SA, Kaurinkoski K, Kuutti M, Fred SM, Elsilä LV, Sakson S, Cannarozzo C, Diniz CR, Seiffert N, Rubiolo A, Haapaniemi H, Meshi E, Nagaeva E, Öhman T, Róg T, Kankuri E, Vilar M, Varjosalo M, Korpi ER, Permi P, Mineev KS, Saarma M, Vattulainen I, Casarotto PC, Castrén E (June 2023). "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nat Neurosci. 26 (6): 1032–1041. doi:10.1038/s41593-023-01316-5. PMC10244169. PMID37280397.
^ abJain MK, Gumpper RH, Slocum ST, Schmitz GP, Madsen JS, Tummino TA, Suomivuori CM, Huang XP, Shub L, DiBerto JF, Kim K, DeLeon C, Krumm BE, Fay JF, Keiser M, Hauser AS, Dror RO, Shoichet B, Gloriam DE, Nichols DE, Roth BL (July 2025). "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics"(PDF). Neuron. doi:10.1016/j.neuron.2025.06.012. PMID40683247. 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
^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
^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
^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
^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
^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
^Tuck JR, Dunlap LE, Khatib YA, Hatzipantelis CJ, Weiser Novak S, Rahn RM, Davis AR, Mosswood A, Vernier AM, Fenton EM, Aarrestad IK, Tombari RJ, Carter SJ, Deane Z, Wang Y, Sheridan A, Gonzalez MA, Avanes AA, Powell NA, Chytil M, Engel S, Fettinger JC, Jenkins AR, Carlezon WA, Nord AS, Kangas BD, Rasmussen K, Liston C, Manor U, Olson DE (April 2025). "Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential". Proc Natl Acad Sci U S A. 122 (16): e2416106122. doi:10.1073/pnas.2416106122. PMC12037037. PMID40228113.
