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 Rapastinel () (former developmental code name GLYX-13) is a novel antidepressant that was under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant depression. It is a centrally active ...

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 desire ...

, Scopolamine, 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 of ...

s, including

LSD Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, vi ...

psilocin Psilocin (also known as 4-HO-DMT, 4-hydroxy DMT, psilocine, psilocyn, or psilotsin) is a substituted tryptamine alkaloid and a serotonergic psychedelic substance. It is present in most psychedelic mushrooms together with its phosphorylated cou ...

– 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.&nbs ...

, 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 A neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Examples of symptoms include paralysis, muscle weak ...

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 o ...

, 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 ...

. 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 p ...

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 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 chemotypes 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 sh ...

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-rec ...

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 The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...

(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 Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the ''S''(+) enantiomer of ketamine, is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand n ...

, sold under the brand name Spravato and produced by

Janssen Pharmaceuticals Janssen Pharmaceuticals is a pharmaceutical company headquartered in Beerse, Belgium, and wholly-owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen. In 1961, Janssen Pharmaceuticals was purchased by New Jersey-based American c ...

, was approved by the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

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. 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.

Clinical development

Other psychoplastogens that are being investigated in the clinic include: *

, a compound that enhances

NMDAR 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 and ...

-mediated

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

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.&nbs ...

, 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'', ''Pa ...

that serves as a prodrug for

, 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. *

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. Pre ...

and

Noribogaine Noribogaine (actually O-desmethylibogaine), or 12-hydroxyibogamine, is the principal psychoactive metabolite of the oneirogen ibogaine. It is thought to be involved in the antiaddictive effects of ibogaine-containing plant extracts, such as '' ...

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 (NH2) group via an ethy ...

Psilocin Psilocin (also known as 4-HO-DMT, 4-hydroxy DMT, psilocine, psilocyn, or psilotsin) is a substituted tryptamine alkaloid and a serotonergic psychedelic substance. It is present in most psychedelic mushrooms together with its phosphorylated cou ...

, DMT,

Lysergamides Amides of lysergic acid are collectively known as lysergamides, and include a number of compounds with potent agonist and/or antagonist activity at various serotonin and dopamine Receptor (biochemistry), receptors. See also * Ergoline * Brom ...

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 sub ...

: DOI,

* Iboga:

* Tabernanthalog * AAZ-A-154 *

* Scopolamine *

References

{{Reflist Neuropharmacology