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]

Contents

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. [3]

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. [1] Ketamine has been described as, "the prototypical psychoplastogen". [3]

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. [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

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

Other psychoplastogens that are being investigated in the clinic include:

List of known psychoplastogens

See also

Notes

Related Research Articles

<span class="mw-page-title-main">Psilocybin</span> Chemical compound found in some species of mushrooms

Psilocybin, also known as 4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT), and formerly sold under the brand name Indocybin, is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. Psilocybin is itself biologically inactive but is quickly converted by the body to psilocin, which has mind-altering effects similar, in some aspects, to those of other classical psychedelics. Effects include euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and perceived spiritual experiences. It can also cause adverse reactions such as nausea and panic attacks.

<span class="mw-page-title-main">Psychedelic drug</span> Hallucinogenic class of psychoactive drug

Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states and a perceived "expansion of consciousness". Also referred to as classic hallucinogens or serotonergic hallucinogens, the term psychedelic is sometimes used more broadly to include various types of hallucinogens, such as those which are atypical or adjacent to psychedelia like salvia and MDMA, respectively.

<span class="mw-page-title-main">5-MeO-DMT</span> Chemical compound

5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), also known as O-methylbufotenin or mebufotenin, is a psychedelic of the tryptamine family. It is found in a wide variety of plant species, and also is secreted by the glands of at least one toad species, the Colorado River toad. Like its close relatives dimethyltryptamine (DMT) and bufotenin (5-HO-DMT), it has been used as an entheogen in South America. Slang terms include Five-methoxy, the power, bufo, and toad venom.

Psychedelic therapy refers to the proposed use of psychedelic drugs, such as psilocybin, ayahuasca, LSD, psilocin, mescaline (peyote), DMT, 5-MeO-DMT,Ibogaine,MDMA, to treat mental disorders. As of 2021, psychedelic drugs are controlled substances in most countries and psychedelic therapy is not legally available outside clinical trials, with some exceptions.

<span class="mw-page-title-main">Psilocin</span> Chemical compound

Psilocin, also known as 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin. Psilocin is a Schedule I drug under the Convention on Psychotropic Substances. Acting on the serotonin 5-HT2A receptors, psilocin's psychedelic effects are directly correlated with the drug's occupancy at these receptor sites. The subjective mind-altering effects of psilocin are highly variable and are said to resemble those of lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT).

<span class="mw-page-title-main">Hallucinogen persisting perception disorder</span> Medical condition

Hallucinogen persisting perception disorder (HPPD) is a non-psychotic disorder in which a person experiences apparent lasting or persistent visual hallucinations or perceptual distortions after using drugs, including but not limited to psychedelics, dissociatives, entactogens, tetrahydrocannabinol (THC), and SSRIs. Despite being designated as a hallucinogen-specific disorder, the specific contributory role of psychedelic drugs is unknown.

The Beckley Foundation is a UK-based think tank and UN-accredited NGO, dedicated to activating global drug policy reform and initiating scientific research into psychoactive substances. The foundation is a charitable trust which collaborates with leading scientific and political institutions worldwide to design and develop research and global policy initiatives. It also investigates consciousness and its modulation from a multidisciplinary perspective, working in collaboration with scientists. The foundation is based at Beckley Park near Oxford, United Kingdom. It was founded in 1998, and is directed by Amanda Feilding, Countess of Wemyss.

<span class="mw-page-title-main">ALTO-100</span> BDNF-modulating drug for depression and PTSD

ALTO-100, previously known as NSI-189, is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor (BDNF) modulator which is under development for the treatment of major depressive disorder (MDD), bipolar depression, and post-traumatic stress disorder (PTSD). There has also been interest in ALTO-100 for possible treatment of cognitive impairment and neurodegeneration. It is taken by mouth.

<span class="mw-page-title-main">1-Methylpsilocin</span> Chemical compound

1-Methylpsilocin (developmental code names CMY, CMY-16) is a tryptamine derivative developed by Sandoz which acts as a selective agonist of the serotonin 5-HT2C receptor (IC50Tooltip half-maximal inhibitory concentration of 12 nM, vs. 633 nM at 5-HT2A), and an inverse agonist at 5-HT2B (Ki of 38 nM). While 1-methylpsilocin does have higher affinity for 5-HT2C than 5-HT2A, it does produce a head-twitch response in mice that is dependent on 5-HT2A, so it is not entirely free of effects on 5-HT2Ain vivo. In contrast to psilocin, 1-methylpsilocin did not activate 5-HT1A receptors in mice.

<span class="mw-page-title-main">Psilocybin therapy</span> Experimental use of psilocybin to treat anxiety & depression

Psilocybin therapy is the use of psilocybin in treating a range of mental health conditions, such as depression, anxiety, addictions, obsessive compulsive disorder, and psychosis. It is one of several forms of psychedelic therapy under study. Psilocybin was popularized as a psychedelic recreational drug in the 1970s and was classified as a Schedule I drug by the DEA. Research on psilocybin as a medical treatment was restricted until the 1990s because of the sociocultural fear of dependence on this drug. As of 2022, psilocybin is the most commonly researched psychedelic due to its safety and low potential for abuse and dependence. Clinical trials are being conducted at universities and there is evidence confirming the use of psilocybin in the treatment of depression, PTSD and end of life anxiety.

MDMA-assisted psychotherapy is the use of prescribed doses of MDMA as an adjunct to psychotherapy sessions. Research suggests that MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), including Complex PTSD, might improve treatment effectiveness. In 2017, a Phase II clinical trial led to "breakthrough therapy" designation by the US Food and Drug Administration (FDA) for potential use as a treatment for PTSD.

<span class="mw-page-title-main">MindMed Inc.</span> Psychedelic medicine biotech company

Mind Medicine (MindMed) Inc., doing business as MindMed, is a New York-based biotechnology company that is currently developing clinical and therapeutic applications for psychedelic and, more broadly, psychoplastogenic drugs.

<span class="mw-page-title-main">Delix Therapeutics</span> American biotech company

Delix Therapeutics is an American biotech company based in Boston, Massachusetts. The company develops novel neuroplasticity-promoting therapeutics for central nervous system (CNS) diseases such as depression and post-traumatic stress disorder (PTSD). It was co-founded in 2019 by David E. Olson and Nick Haft.

Psychedelic treatments for trauma-related disorders are the use of psychedelic substances, either alone or used in conjunction with psychotherapy, to treat trauma-related disorders. Trauma-related disorders, such as post-traumatic stress disorder (PTSD), have a lifetime prevalence of around 8% in the US population. However, even though trauma-related disorders can hinder the everyday life of individuals with them, less than 50% of patients who meet criteria for PTSD diagnosis receive proper treatment. Psychotherapy is an effective treatment for trauma-related disorders. A meta-analysis of treatment outcomes has shown that 67% of patients who completed treatment for PTSD no longer met diagnostic criteria for PTSD. For those seeking evidence-based psychotherapy treatment, it is estimated that 22-24% will drop out of their treatment. In addition to psychotherapy, pharmacotherapy (medication) is an option for treating PTSD; however, research has found that pharmacotherapy is only effective for about 59% of patients. Although both forms of treatment are effective for many patients, high dropout rates of psychotherapy and treatment-resistant forms of PTSD have led to increased research in other possible forms of treatment. One such form is the use of psychedelics.

Ketamine-assisted psychotherapy(KAP) is the use of prescribed doses of ketamine as an adjunct to psychotherapy sessions. KAP shows significant potential in treating mental disorders such as treatment-resistant depression (TRD), anxiety, obsessive–compulsive disorders (OCD), post-traumatic stress disorders (PTSD), and other conditions. It can also be used for those experiencing substance abuse and physical pain. While it is primarily used as a veterinary anaesthetic, ketamine has also been found to have rapid analgesic and hallucinogenic effects, which has sparked interest in its use as an antidepressant. Despite initial trials of its use in the treatment of mental disorders focussing primarily on its antidepressant effects, newer studies are attempting to harness its psychedelic effects to bring about altered states of consciousness, which will augment the adjunct psychotherapy. Ketamine's neuroplasticity-promoting effects strengthen the cognitive restructuring that takes place through traditional psychotherapy, thereby leading to long-lasting behavioural change. KAP offers promising directions for research on new antidepressant alternatives, but is still not sufficiently defined or evaluated as a treatment combination.

A trip killer, or hallucinogen antidote, is a drug that aborts or reduces the effects of a hallucinogenic drug experience. As there are different types of hallucinogens that work in different ways, there are different types of trip killers. They can completely block or reduce the effects of hallucinogens or they can simply provide anxiety relief and sedation. Examples of trip killers, in the case of serotonergic psychedelics, include serotonin receptor antagonists, like antipsychotics and certain antidepressants, and benzodiazepines. Trip killers are sometimes used by recreational psychedelic users as a form of harm reduction to manage so-called bad trips, for instance difficult experiences with prominent anxiety. They can also be used clinically to manage effects of hallucinogens, like anxiety and psychomotor agitation, for instance in the emergency department.

(<i>R</i>)-MDMA Psychoactive drug taken by mouth

(R)-3,4-Methylenedioxy-N-methylamphetamine ((R)-MDMA), also known as (R)-midomafetamine or as levo-MDMA, is the (R)- or levorotatory (l-) enantiomer of 3,4-methylenedioxy-N-methylamphetamine (MDMA; midomafetamine; "ecstasy"), a racemic mixture of (R)-MDMA and (S)-MDMA. Like MDMA, (R)-MDMA is an entactogen or empathogen. It is taken by mouth.

BMB-202 is a serotonin 5-HT2A receptor agonist and psychedelic hallucinogen which is under development for the treatment of depressive disorders and post-traumatic stress disorder (PTSD). It is taken by mouth. However, BMB-202 has also been evaluated by injection in preclinical studies.

References

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  2. 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.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 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.
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  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.
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  24. ↑ "Ibogaine Use in Addiction Treatment: An Overview". INN. 2022-02-23. Retrieved 2022-05-11.
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