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Psychoplastogen

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Psychoplastogens 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.[1][2] 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.[3]

Etymology and nomenclature

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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.[3]

The term neuroplastogen is sometimes used as a synonym for psychoplastogen, especially when speaking to the biological substrate rather than the therapeutic.

Chemistry

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Psychoplastogens come in a variety of chemotypes and chemical families, but, by definition, are small-molecule drugs.[1] Ketamine has been described as, "the prototypical psychoplastogen".[3]

Pharmacology

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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.[3][4] Convergence at TrkB and mTOR parallels that of traditional antidepressants with known efficacies, but with more rapid onset.[5]

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.[6]

Psychedelics show complex effects on neuroplasticity and can both promote and inhibit neuroplasticity depending on the circumstances.[7] Single doses of DMT, 5-MeO-DMT, psilocybin, and DOI have been found to produce robust and long-lasting increases in neuroplasticity in animals.[7] Likewise, repeated doses of LSD for 7 days increased neuroplasticity.[7] However, chronic intermittent administration of DMT for several weeks resulted in dendritic spine retraction, suggesting physiological homeostatic compensation in response to overstimulation.[7] In addition, DOI has been found to decrease brain-derived neurotrophic factor (BDNF) levels in the hippocampus.[7] 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.[7] 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.[7]

In terms of neurogenesis, DOI and LSD showed no impact on hippocampal neurogenesis, while psilocybin and 25I-NBOMe decreased hippocampal neurogenesis.[7] 5-MeO-DMT however has been found to increase hippocampal neurogenesis, and this could be blocked by sigma σ1 receptor antagonists.[7]

Approved medical uses

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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.[6]

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.[8] As of 2022, it is the only psychoplastogen approved in the US for the treatment of a neuropsychiatric disorder.[6] Esketamine is the S(+) enantiomer of ketamine and functions as an NMDA receptor antagonist.[9]

Clinical development

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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.[10] MDMA-assisted psychotherapy is also currently in Phase 2 trials for eating disorders,[11] anxiety associated with life-threatening illness,[12] and social anxiety in autistic adults.[13]
  • 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,[14][15] smoking addiction,[16][17] and anxiety and depression in people with cancer diagnoses.[18]
  • LSD is being tested in phase 2 trials for cluster headaches and anxiety.[19]
  • DMT is being studied for depression.[20]
  • 5-MeO-DMT is being studied for depression and eating disorders.[21]
  • Ibogaine and Noribogaine are being studied for addiction.[22][23][24]

List of known psychoplastogens

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See also

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Notes

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  1. ^ [1][2][3][6]
  2. ^ [1][2][3][6]
  3. ^ [1][2][3][6]
  4. ^ [1][2][3][6]

References

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  1. ^ a b c d e f g h 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.
  2. ^ a b c d e f Benko J, Vranková S (March 2020). "Natural Psychoplastogens As Antidepressant Agents". Molecules. 25 (5): 1172. doi:10.3390/molecules25051172. PMC 7179157. PMID 32150976.
  3. ^ a b c d e f g h i j k l m 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ a b c d e f g h i j 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.
  7. ^ a b c d e f g h i Hatzipantelis CJ, Olson DE (February 2024). "The Effects of Psychedelics on Neuronal Physiology". Annu Rev Physiol. 86: 27–47. doi:10.1146/annurev-physiol-042022-020923. PMC 10922499. PMID 37931171.
  8. ^ 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 Adminitartion. Retrieved 2021-08-26.
  9. ^ Olympic Behavioral Health
  10. ^ 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.
  11. ^ 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
  12. ^ 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
  13. ^ 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
  14. ^ Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall MB, et al. (October 2017). "Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms". Scientific Reports. 7 (1): 13187. Bibcode:2017NatSR...713187C. doi:10.1038/s41598-017-13282-7. PMC 5640601. PMID 29030624.
  15. ^ 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
  16. ^ 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.
  17. ^ Clinical trial number NCT01943994 for "Psilocybin-facilitated Smoking Cessation Treatment: A Pilot Study" at ClinicalTrials.gov
  18. ^ Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, et al. (December 2016). "Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial". Journal of Psychopharmacology. 30 (12): 1181–1197. doi:10.1177/0269881116675513. PMC 5367557. PMID 27909165.
  19. ^ 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
  20. ^ Steven AB (June 2022). "Administration of N,N-dimethyltryptamine (DMT) in psychedelic therapeutics and research and the study of endogenous DMT". Psychopharmacology. 239 (6): 1749–1763. doi:10.1007/s00213-022-06065-0. PMC 8782705. PMID 35064294.
  21. ^ Davis AK, So S, Lancelotta R, Barsuglia JP, Griffiths RR (2019-03-04). "5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety". The American Journal of Drug and Alcohol Abuse. 45 (2): 161–169. doi:10.1080/00952990.2018.1545024. PMC 6430661. PMID 30822141.
  22. ^ Parkins K (10 March 2021). "DemeRx and Atai get MHRA nod to start trial of ibogaine for opioid use disorder". Clinical Trials Arena. Retrieved 2022-05-11.
  23. ^ Davis AK, Barsuglia JP, Windham-Herman AM, Lynch M, Polanco M (November 2017). "Subjective effectiveness of ibogaine treatment for problematic opioid consumption: Short- and long-term outcomes and current psychological functioning". Journal of Psychedelic Studies. 1 (2): 65–73. doi:10.1556/2054.01.2017.009. PMC 6157925. PMID 30272050.
  24. ^ "Ibogaine Use in Addiction Treatment: An Overview". INN. 2022-02-23. Retrieved 2022-05-11.
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