Psychoplastogen Explained

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

The term psychoplastogen comes from the Greek roots Greek, Ancient (to 1453);: psych- (mind), -Greek, Ancient (to 1453);: plast (molded), and -Greek, Ancient (to 1453);: 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.

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 but, by definition, are small molecules.

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] 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.^[6]

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

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.

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.^[7] 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.^[8]

Clinical development

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.^[9] MDMA-assisted psychotherapy is also currently in Phase 2 trials for eating disorders, anxiety associated with life-threatening illness, and social anxiety in autistic adults.
• 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,^[10] smoking addiction,^[11] and anxiety and depression in people with cancer diagnoses.^[12]
• LSD is being tested in phase 2 trials for cluster headaches and anxiety.
• DMT is being studied for depression.^[13]
• 5-MeO-DMT is being studied for depression and eating disorders.^[14]
• Ibogaine and Noribogaine are being studied for addiction.^{[15] [16] [17]}

List of known psychoplastogens

• Tryptamines: Psilocin, DMT, 5-MeO-DMT
• Lysergamides: LSD
• Amphetamines: DOI, MDMA
• Iboga: ibogaine, noribogaine
• Tabernanthalog
• AAZ-A-154
• Ketamine, esketamine
• Scopolamine
• Rapastinel

See also

• • • Neuroplasticity
• Ketamine
• Psilocybin
• LSD
• DMT
• TBG
• AAZ
• 4C-D

Notes and References

1. Olson DE . Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics . Journal of Experimental Neuroscience . 12 . 1179069518800508 . January 2018 . 30262987 . 6149016 . 10.1177/1179069518800508 .
2. Benko J, Vranková S . Natural Psychoplastogens As Antidepressant Agents . Molecules . 25 . 5 . 1172 . March 2020 . 32150976 . 7179157 . 10.3390/molecules25051172 . free .
3. Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, Burbach KF, Soltanzadeh Zarandi S, Sood A, Paddy MR, Duim WC, Dennis MY, McAllister AK, Ori-McKenney KM, Gray JA, Olson DE . 6 . Psychedelics Promote Structural and Functional Neural Plasticity . English . Cell Reports . 23 . 11 . 3170–3182 . June 2018 . 29898390 . 6082376 . 10.1016/j.celrep.2018.05.022 .
4. Voleti B, Navarria A, Liu RJ, Banasr M, Li N, Terwilliger R, Sanacora G, Eid T, Aghajanian G, Duman RS . 6 . Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses . Biological Psychiatry . 74 . 10 . 742–749 . November 2013 . 23751205 . 3773272 . 10.1016/j.biopsych.2013.04.025 .
5. Chakrapani S, Eskander N, De Los Santos LA, Omisore BA, Mostafa JA . Neuroplasticity and the Biological Role of Brain Derived Neurotrophic Factor in the Pathophysiology and Management of Depression . Cureus . 12 . 11 . e11396 . November 2020 . 33312794 . 7725195 . 10.7759/cureus.11396 . free .
6. Vargas MV, Meyer R, Avanes AA, Rus M, Olson DE . Psychedelics and Other Psychoplastogens for Treating Mental Illness . Frontiers in Psychiatry . 12 . 727117 . 2021 . 34671279 . 8520991 . 10.3389/fpsyt.2021.727117 . free .
7. Web site: 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 . 2021-08-26 . U.S, Food and Drug Adminitartion . en.
8. https://olympicbehavioralhealth.com/ Olympic Behavioral Health
9. Mitchell JM, Bogenschutz M, Lilienstein A, Harrison C, Kleiman S, Parker-Guilbert K, Ot'alora GM, Garas W, Paleos C, Gorman I, Nicholas C, Mithoefer M, Carlin S, Poulter B, Mithoefer A, Quevedo S, Wells G, Klaire SS, van der Kolk B, Tzarfaty K, Amiaz R, Worthy R, Shannon S, Woolley JD, Marta C, Gelfand Y, Hapke E, Amar S, Wallach Y, Brown R, Hamilton S, Wang JB, Coker A, Matthews R, de Boer A, Yazar-Klosinski B, Emerson A, Doblin R . 6 . MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study . Nature Medicine . 27 . 6 . 1025–1033 . June 2021 . 33972795 . 8205851 . 10.1038/s41591-021-01336-3 .
10. Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall MB, Tanner M, Kaelen M, McGonigle J, Murphy K, Leech R, Curran HV, Nutt DJ . 6 . Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms . Scientific Reports . 7 . 1 . 13187 . October 2017 . 29030624 . 5640601 . 10.1038/s41598-017-13282-7 . 2017NatSR...713187C .
11. Johnson MW, Garcia-Romeu A, Griffiths RR . Long-term follow-up of psilocybin-facilitated smoking cessation . The American Journal of Drug and Alcohol Abuse . 43 . 1 . 55–60 . January 2017 . 27441452 . 5641975 . 10.3109/00952990.2016.1170135 .
12. Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA . 6 . 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 . December 2016 . 27909165 . 5367557 . 10.1177/0269881116675513 .
13. Psychopharmacology . Steven AB . Administration of N,N-dimethyltryptamine (DMT) in psychedelic therapeutics and research and the study of endogenous DMT . 35064294 . 10.1007/s00213-022-06065-0 . 8782705 . June 2022 . 239 . 6 . 1749–1763 .
14. Davis AK, So S, Lancelotta R, Barsuglia JP, Griffiths RR . 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 . 2019-03-04 . 30822141 . 6430661 . 10.1080/00952990.2018.1545024 .
15. Web site: Parkins K . 10 March 2021 . DemeRx and Atai get MHRA nod to start trial of ibogaine for opioid use disorder . 2022-05-11 . Clinical Trials Arena . en-US.
16. Davis AK, Barsuglia JP, Windham-Herman AM, Lynch M, Polanco M . 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 . November 2017 . 30272050 . 6157925 . 10.1556/2054.01.2017.009 .
17. Web site: 2022-02-23 . Ibogaine Use in Addiction Treatment: An Overview . 2022-05-11 . INN . en.