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. Several existing psychoplastogens have been identified and their therapeutic effects demonstrated; several are presently at various stages of development as medications including

Ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...

, Rapastinel,

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desired ...

Scopolamine Scopolamine, also known as hyoscine, or Devil's Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion sickness and postoperative nausea and vomit ...

, and the

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science ...

s, including LSD, psilocin – the active metabolite of

psilocybin Psilocybin ( , ) is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. The most potent are members of the genus ''Psilocybe'', such as '' P. azurescens'', '' P. semilanceata'', and '' P.&n ...

, DMT, and

5-MeO-DMT 5-MeO-DMT (5-methoxy-''N'',''N''-dimethyltryptamine) or O-methyl-bufotenin is a psychedelic of the tryptamine class. 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 R ...

. Compounds of this sort are being explored as therapeutics for a variety of brain disorders including depression,

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...

, and

PTSD Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on a ...

. The ability to rapidly promote neuronal changes via mechanisms of

neuroplasticity Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it ...

was recently discovered as the common therapeutic activity and mechanism of action.

Etymology and nomenclature

The term psychoplastogen comes from the Greek roots - (mind), - (molded), and - (producing) and covers a variety of chemotypes and receptor targets. It was coined by

David E. Olson David E. Olson is an American chemist and neuroscientist. He is an associate professor of chemistry, biochemistry and molecular medicine at the University of California, Davis. Olson is best known for his work investigating neuroplasticity promot ...

in collaboration with Valentina Popescu, both at the University of California, Davis. There are many subtypes of psychoplastogens. One being neuroplastogen, which is used as a synonym for psychoplastogen, especially when speaking to the biological substrate rather than the therapeutic.

Chemistry

Psychoplastogens come in a variety of

chemotype A chemotype (sometimes chemovar) is a chemically distinct entity in a plant or microorganism, with differences in the composition of the secondary metabolites. Minor genetic and epigenetic changes with little or no effect on morphology or anatomy ...

s but, by definition, are small molecules.

Pharmacology

Psychoplastogens exert their effects by promoting structural and functional

neural plasticity Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it p ...

through diverse targets including, but not limited to,

5-HT2A The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations. 5-HT is s ...

NMDA ''N''-methyl--aspartic acid or ''N''-methyl--aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike ...

, and

muscarinic Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-re ...

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. Due to their rapid and sustained effects, psychoplastogens could potentially be dosed intermittently. In addition to the

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 Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment- ...

(TRD) and

suicidal ideation Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...

. As of 2022, it is the only psychoplastogen approved in the US for the treatment of a neuropsychiatric disorder. Esketamine is the S(+)

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

of ketamine and functions as an

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...

antagonist.

Clinical development

Other psychoplastogens that are being investigated in the clinic include: * Rapastinel, a compound that enhances NMDAR-mediated

, has been investigated for treatment of depression. As of 2015, the drug has achieved

phase II Phase II, Phase 2 or Phase Two may refer to: Media * Marvel Cinematic Universe: Phase Two, six American superhero films from 2013–2015 * ''Star Trek: Phase II'', an unrealized television series based on the characters of Gene Roddenberry's ''S ...

proof of concept Proof of concept (POC or PoC), also known as proof of principle, is a realization of a certain method or idea in order to demonstrate its feasibility, or a demonstration in principle with the aim of verifying that some concept or theory has prac ...

as a rapid-acting antidepressant without eliciting ketamine-like psychotomimetic or other significant side effects. *

-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. 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 Psilocybin ( , ) is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. The most potent are members of the genus ''Psilocybe'', such as '' P. azurescens'', '' P. semilanceata'', and '' P.&n ...

, a compound in

psilocybin mushrooms Psilocybin mushrooms, commonly known as magic mushrooms, are a polyphyletic informal group of fungi that contain psilocybin which turns into psilocin upon ingestion. Biological genera containing psilocybin mushrooms include ''Psilocybe'', '' P ...

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, smoking addiction, and anxiety and depression in people with cancer diagnoses. * LSD is being tested in phase 2 trials for cluster headaches and anxiety. * DMT is being studied for depression and stroke. *

is being studied for depression and eating disorders. *

Ibogaine Ibogaine is a naturally occurring psychoactive substance found in plants in the family Apocynaceae such as '' Tabernanthe iboga'', '' Voacanga africana'', and '' Tabernaemontana undulata''. It is a psychedelic with dissociative properties. Pr ...

and Noribogaine are being studied for addiction.

List of known psychoplastogens

Tryptamines Substituted tryptamines, or serotonin analogues, are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino group, amino (NH2) group ...

: Psilocin, DMT,

* Lysergamides: LSD *

Amphetamines Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with su ...

: DOI,

Iboga ''Tabernanthe iboga'' (iboga) is an evergreen rainforest shrub native to Central Africa. A member of the Apocynaceae family indigenous to Gabon, the Democratic Republic of Congo, and the Republic of Congo, it is cultivated across Central Africa ...

, Noribogaine *

Tabernanthalog Tabernanthalog is a novel water-soluble, non-toxic azepinoindole analog of the psychoactive drug ibogaine first synthesized by Professor David E. Olson at UC Davis. * In rodents, it was found to promote structural neural plasticity, reduce dru ...

AAZ-A-154 AAZ-A-154 is a novel isotryptamine derivative which acts as a 5-HT2A receptor agonist discovered and synthesized by the lab of Professor David E. Olson at UCDavis. Animal studies suggest that it produces antidepressant effects without the psy ...

* Rapastinel

References

{{Reflist Neuropharmacology