Psychoplastogen

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, Rapastinel, MDMA, Scopolamine, and the serotonergic psychedelics, including LSD, psilocin – the active metabolite of psilocybin, DMT, and 5-MeO-DMT.[3] Compounds of this sort are being explored as therapeutics for a variety of brain disorders including depression, addiction, and PTSD.[4] The ability to rapidly promote neuronal changes via mechanisms of neuroplasticity was recently discovered as the common therapeutic activity and mechanism of action.[5]

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.[6] It was coined by David E. Olson in collaboration with Valentina Popescu, both at the University of California, Davis.[5]

Chemistry

Psychoplastogens come in a variety of chemotypes but, by definition, are small molecules.[1]

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.[5][7]

Due to their rapid and sustained effects, psychoplastogens could potentially be dosed intermittently.[8]

In addition to the neuroplasticity effects, these compounds can have other epiphenomena including sedation, dissociation, and hallucinations.[8]

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.[8][9]

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

Clinical development

Other psychoplastogens that are being investigated in the clinic include:

  • Rapastinel, a compound that enhances NMDAR-mediated neural plasticity, has been investigated for treatment of depression. As of 2015, the drug has achieved phase II proof of concept as a rapid-acting antidepressant without eliciting ketamine-like psychotomimetic or other significant side effects.[11]
  • 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.[12] MDMA-assisted psychotherapy is also currently in Phase 2 trials for eating disorders,[13] anxiety associated with life-threatening illness,[14] and social anxiety in autistic adults.[15]
  • 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,[16][17] smoking addiction,[18][19] and anxiety and depression in people with cancer diagnoses.[20]
  • LSD is being tested in phase 2 trials for cluster headaches and anxiety.[21]
  • DMT is being studied for depression and stroke.[22][23]
  • 5-MeO-DMT is being studied for depression and eating disorders.[24]
  • Ibogaine and Noribogaine are being studied for addiction.[25][26][27]

List of known psychoplastogens

See also

References
  1. 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. Benko J, Vranková S (March 2020). "Natural Psychoplastogens As Antidepressant Agents". Molecules. 25 (5): 1172. doi:10.3390/molecules25051172. PMC 7179157. PMID 32150976.
  3. Mackenzie RJ (2022). "An Introduction to Five Psychedelics: Psilocybin, DMT, LSD, MDMA and Ketamine". Neuroscience from Technology Networks. Retrieved 2022-05-10.
  4. Olson DE, MacDonald A. "Non-Hallucinogenic Psychedelic Analogs Could Be Game Changers for Neuropsychiatry". Neuroscience from Technology Networks. Retrieved 2022-05-10.
  5. 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. Rubin E (11 July 2018). "A Possible New Category of Medications: Psychoplastogens". Psychology Today. Retrieved 2022-05-10.
  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. 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.
  9. Sumner N (22 April 2022). "The Trials and Tribulations of Psychedelic Research". Microdose. Retrieved 2022-05-11.
  10. 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.
  11. Preskorn, Sheldon; Macaluso, Matthew; Mehra, Do Vishaal; Zammit, Gary; Moskal, Joseph R.; Burch, Ronald M.; Group, the GLYX-13 Clinical Study (March 2015). "Randomized Proof of Concept Trial of GLYX-13, an N-Methyl-D-Aspartate Receptor Glycine Site Partial Agonist, in Major Depressive Disorder Nonresponsive to a Previous Antidepressant Agent". Journal of Psychiatric Practice. 21 (2): 140–149. doi:10.1097/01.pra.0000462606.17725.93.
  12. 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.
  13. 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
  14. 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
  15. 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
  16. 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.
  17. 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
  18. 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.
  19. Clinical trial number NCT01943994 for "Psilocybin-facilitated Smoking Cessation Treatment: A Pilot Study" at ClinicalTrials.gov
  20. 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.
  21. 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
  22. Walker-Journey JW (11 March 2021). "Algernon to Investigate DMT Microdose for Stroke Treatment". Psychedelic Spotlight. Retrieved 2022-05-11.
  23. Hockaday J (2021-02-04). "Stroke victims to be given psychedelic drug DMT in groundbreaking study". Metro. Retrieved 2022-05-11.
  24. 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.
  25. 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.
  26. 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.
  27. "Ibogaine Use in Addiction Treatment: An Overview". INN. 2022-02-23. Retrieved 2022-05-11.
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