Psychoplastogens, also known as neuroplastogens, 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 cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

scopolamine Scopolamine, also known as hyoscine, or Devil's Breath, is a medication used to treat motion sickness and postoperative nausea and vomiting. It is also sometimes used before surgery to decrease saliva. When used by injection, effects begin a ...

, and the

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

s, including

LSD Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a semisynthetic, hallucinogenic compound derived from ergot, known for its powerful psychological effects and serotonergic activity. I ...

psilocin Psilocin, also known as 4-hydroxy-''N'',''N''-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocy ...

(the active metabolite of

psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...

DMT Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a serotonergic hallucinogen and investigational drug of the tryptamine family that occurs naturally in many plants and animals, including humans. D ...

, and

5-MeO-DMT 5-MeO-DMT (5-methoxy-''N'',''N''-dimethyltryptamine), also known as ''O''-methylbufotenin or mebufotenin (), is a naturally occurring psychedelic of the tryptamine family. It is found in a wide variety of plant species, and is also secreted by ...

. Compounds of this sort are being explored as therapeutics for a variety of

brain disorders Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...

including depression,

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

, and

PTSD Post-traumatic stress disorder (PTSD) is a mental disorder that develops from experiencing a traumatic event, such as sexual assault, domestic violence, child abuse, warfare and its associated traumas, natural disaster, traffic collision, ...

. The ability to rapidly promote neuronal changes via mechanisms of

neuroplasticity Neuroplasticity, also known as neural plasticity or just plasticity, is the ability of neural networks in the brain to change through neurogenesis, growth and reorganization. Neuroplasticity refers to the brain's ability to reorganize and rewir ...

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. 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

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 and chemical families, but, by definition, are small-molecule drugs. Ketamine has been described as, "the prototypical psychoplastogen".

Pharmacology

Psychoplastogens exert their effects by promoting structural and functional

neural plasticity Neuroplasticity, also known as neural plasticity or just plasticity, is the ability of neural networks in the brain to change through growth and reorganization. Neuroplasticity refers to the brain's ability to reorganize and rewire its neural ...

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 functions as a G protein-coupled receptor (GPCR). It is a cell surface receptor that activates multiple intracellular signalling cascade ...

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. Unl ...

, and

muscarinic receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

s. Some are

biased agonist Functional selectivity (or agonist trafficking, biased agonism, biased signaling, ligand bias, and differential engagement) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the end ...

s. 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 sirolimus, 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 ''M ...

(mTOR) pathways. Convergence at TrkB and mTOR parallels that of traditional antidepressants with known efficacies, but with more rapid onset. 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.

Psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

s show complex effects on neuroplasticity and can both promote and inhibit neuroplasticity depending on the circumstances. Single doses of

, and DOI have been found to produce robust and long-lasting increases in neuroplasticity in animals. Likewise, repeated doses of

for 7days increased neuroplasticity. However, chronic intermittent administration of DMT for several weeks resulted in dendritic spine retraction, suggesting physiological homeostatic compensation in response to overstimulation. In addition, DOI has been found to decrease

brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the can ...

(BDNF) levels in the

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

. The effects of psychedelics on neuroplasticity appear to be dependent on

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_2A receptor activation, as they are abolished in 5-HT_2A receptor

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

. Non-hallucinogenic serotonin 5-HT_2A receptor agonists, like

tabernanthalog Tabernanthalog (TBG, DLX-007) is a novel water-soluble, non-toxic ibogalog or simplified analogue of the psychoactive drug tabernanthine first synthesized by David E. Olson at UC Davis. Tabernanthalog is a non-hallucinogenic serotonin 5-HT2A ...

and

lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline family which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of l ...

, have also been found to increase neuroplasticity, and to a magnitude comparable to psychedelics. In terms of

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...

, DOI and LSD showed no impact on hippocampal neurogenesis, while psilocybin and

25I-NBOMe 25I-NBOMe, also known as 2C-I-NBOMe, Cimbi-5, and shortened to "25I", is a psychedelic drug of the phenethylamine, 2C, and NBOMe (25-NB) families. Since 2010, it has circulated in the recreational drug scene, often misrepresented as LSD. It is ...

decreased hippocampal neurogenesis. 5-MeO-DMT however has been found to increase hippocampal neurogenesis, and this could be blocked by

sigma Sigma ( ; uppercase Σ, lowercase σ, lowercase in word-final position ς; ) is the eighteenth letter of the Greek alphabet. In the system of Greek numerals, it has a value of 200. In general mathematics, uppercase Σ is used as an operator ...

σ₁ receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.

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, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...

, sold under the brand name Spravato and produced by

Janssen Pharmaceuticals Johnson & Johnson Innovative Medicine (formerly Janssen Pharmaceuticals) is a Belgian pharmaceutical company headquartered in Beerse, Belgium, and wholly owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen. In 1961, Janssen Ph ...

, 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 (TRD) is often defined as major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Inad ...

(TRD) and

suicidal ideation Suicidal ideation, or suicidal thoughts, is the thought process of having ideas or ruminations about the possibility of dying by suicide.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal i ...

. 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 (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

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 predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

antagonist.

Clinical development

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

-assisted

psychotherapy Psychotherapy (also psychological therapy, talk therapy, or talking therapy) is the use of Psychology, psychological methods, particularly when based on regular Conversation, personal interaction, to help a person change behavior, increase hap ...

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, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...

, a compound in

psilocybin mushrooms Psilocybin mushrooms, or psilocybin-containing mushrooms, commonly known as magic mushrooms or as shrooms, are a type of hallucinogenic mushroom and a polyphyletic informal group of fungi that contain the prodrug psilocybin, which turns into t ...

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. *

is being studied for depression. *

is being studied for depression and eating disorders. *

Ibogaine Ibogaine is a psychoactive indole alkaloid derived from plants such as '' Tabernanthe iboga'', characterized by hallucinogenic and oneirogenic effects. Traditionally used by Central African foragers, it has undergone controversial research ...

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

* Substituted tryptamines:

(including

and 4-AcO-DMT/psilacetin),

, and

Ergolines Ergoline is a core structure in many alkaloids and their synthetic derivatives. Ergoline alkaloids were first characterized in ergot. Some of these are implicated in the condition of ergotism, which can take a convulsive form or a gangrenous for ...

and

Substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

s: DOI,

methylone Methylone, also known as 3,4-methylenedioxy-''N''-methylcathinone (MDMC), is an entactogen and stimulant drug of the amphetamine, cathinone, and benzodioxole families related to 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"). It is th ...

, and

mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...

Dissociatives Dissociatives, colloquially dissos, are a subclass of hallucinogens that distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

(including

esketamine Esketamine, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...

and

arketamine Arketamine (developmental code names PCN-101, HR-071603), also known as (''R'')-ketamine or (''R'')-(−)-ketamine, is the (''R'')-(−) enantiomer of ketamine. Similarly to racemic ketamine and esketamine, the ''S''(+) enantiomer of ke ...

) * Iboga-derivatives:

ibogaine Ibogaine is a psychoactive indole alkaloid derived from plants such as '' Tabernanthe iboga'', characterized by hallucinogenic and oneirogenic effects. Traditionally used by Central African foragers, it has undergone controversial research ...

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 ...

tabernanthine Tabernanthine is an alkaloid found in ''Tabernanthe iboga''. It has been used in laboratory experiments to study how addiction affects the brain. Tabernanthine persistently reduced the self-administration of cocaine and morphine in rats. Phar ...

, and

(DLX-007) *

Tropomyosin receptor kinase Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signaling cascades. However, the activatio ...

positive allosteric modulators In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a Receptor (biochemistry), receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol (drug), alcohol, functi ...

: ACD855 (Ponazuril),

ACD856 ACD856, or ACD-856, is a tropomyosin receptor kinase TrkA, TrkB, and TrkC positive allosteric modulator which is under development for the treatment of Alzheimer's disease, depressive disorders, sleep disorders, and traumatic brain injuries. I ...

. *

Zalsupindole Zalsupindole,https://iris.who.int/bitstream/handle/10665/380497/9789240107038-eng.pdf "zalsupindolum zalsupindole (2R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine antidepressant" also known by its developmental code names DLX-001 and ...

(DLX-001; AAZ-A-154), DLX-159,

DLX-2270 DLX-2270 is an experimental serotonin receptor modulator which is under investigation for the potential treatment of schizophrenia. It acts as a serotonin 5-HT2A receptor antagonist and serotonin 5-HT2C receptor agonist. In contrast to conven ...

, and JRT *

Scopolamine Scopolamine, also known as hyoscine, or Devil's Breath, is a medication used to treat motion sickness and postoperative nausea and vomiting. It is also sometimes used before surgery to decrease saliva. When used by injection, effects begin a ...

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, ...

* Tropoflavin (7,8-DHF) (including R7 and R13) *

LY-341495 LY-341495 is a research drug developed by the pharmaceutical company Eli Lilly, which acts as a potent and selective orthosteric antagonist for the group II metabotropic glutamate receptors ( mGluR2/3). It is used in scientific research in sever ...

Isoflurane Isoflurane, sold under the brand name Forane among others, is a halogenated ether used as a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritat ...

Notes

References

{{Reflist Neuropharmacology

Etymology and nomenclature

Chemistry

Pharmacology

Approved medical uses

Clinical development

List of known psychoplastogens

See also

Notes

References