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Psychoplastogen

From EverybodyWiki Bios & Wiki



Psychoplastogens are a class of small molecule drugs that produce rapid and sustained effects on neuronal structure and function after a single administration.[1] The term was first introduced in a 2018 publication by David E. Olson, and comes from the Greek roots psych- (mind), -plast (molded), and -gen (producing). Unlike neuropsychiatric pharmacotherapies such as SSRIs and SNRIs which modulate levels of the neurotransmitters serotonin and norepinephrine, psychoplastogens act as direct modulators of neural circuitry.  Thus, they are being explored as rapid-acting therapeutics for a variety of brain disorders including depression, addiction, and PTSD, among many others. Psychoplastogens include dissociatives such as ketamine and psychedelics such as N,N-dimethyltryptamine . While these compounds have a long history of use for treating brain disorders, their ability to rapidly promote plasticity was only recently discovered.[2] [3] Psychoplastogens also include recently discovered compounds such as tabernanthalog (TBG)[4] and AAZ-A-154 (AAZ)[5], which are non-hallucinogenic in preclinical species unlike their psychedelic and dissociative counterparts.

Mechanism of Action

Psychoplastogens exert their effects by promoting structural and functional neural plasticity through a variety of diverse targets including, but not limited to, 5-HT2A, NMDA, and muscarinic receptors.

Stimulation of theses receptors can lead to phenotypes that include increased neuritogenesis, spinogenesis, and/or synaptogenesis. While psychoplastogens such as ketamine, scopolamine, and serotonergic psychedelics have different receptor binding profiles, they both appear to induce these structural changes through downstream stimulation of the tyrosine kinase B (TrkB) and mammalian target of rapamycin (mTOR) signaling pathways.[6][3][2]

These effects on structure produce functional changes in vivo. For instance, both ketamine and the psychedelic N,N-Dimethyltryptamine were found to increase both the frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs) in rat cortical pyramidal neurons.[2][3] More recently, psilocybin was shown to elevate excitatory neurotransmission in the medial frontal cortex and produce long-lasting increases in dendritic spine density.[7]

Importantly, these changes in neuronal function translate to behavioral effects in rodent models of depression. In 2019, Liston and colleagues conducted longitudinal imaging of medial PFC microcircuits and found that prefrontal spinogenesis plays a critical role in ketamine’s sustained antidepressant-like effects.[8] They provided the first evidence that ketamine’s plasticity-promoting properties are not simply correlated with antidepressive efficacy, but are in fact causally related. 

Unlike ketamine, which acts primarily as an NMDA receptor antagonist, the downstream activation of TrkB and mTOR signaling pathways by serotonergic psychoplastogens is thought to involve activation of 5HT2 receptors. In-vitro, the 5HT2 receptor antagonist ketanserin blocks the ability of DMT, LSD, and DOI to promote neuritogenesis and spinogenesis.[2] In rodents, pretreatment with ketanserin (1mg/kg) also reduces the spinogenesis induced by psilocybin in the frontal cortex.[7] While ketanserin does not completely block psilocybin-induced structural plasticity, this dose of ketanserin was previously reported to only block roughly 30% of 5HT2A receptors in the rat neocortex.[9] In 2021, de la Fuente reported that a single dose of the psychedelic 5HT2A/2C agonist DOI increases dendritic spine density in wild type, but not 5-HT2A receptor knockout mice.[10]

While psychoplastogens act rapidly, there is some evidence that their long-lasting effects might be the result of changes in gene expression. In 2021, The group of Javier Gonzalez-Maeso reported that a single dose of DOI leads to long lasting epigenomic and transcriptomic alterations in the mouse frontal cortex.[10] In particular, they found that DOI promotes the expression of genes involved in synaptic plasticity.

Plasticity in Depression

Researchers have proposed that changes in neural plasticity are a common substrate to all effective antidepressants.[11][12] For instance, SSRIs and electroconvulsive therapy (ECT) both modulate levels of BDNF and TrkB mRNA, which are key mediators of plasticity.[13] Moreover, the timing of these changes to the PFC observed following chronic SSRI administration correlate with the 3-6 week onset to efficacy observed in human patients.[14]

Psychoplastogens promote plasticity in the PFC more rapidly and robustly than traditional antidepressants.[8][15] The PFC is a region involved in critical circuits relating to cognitive and affective behaviors. [16] Moreover, atrophy and reduced neuronal complexity in the PFC is associated with many neuropsychiatric disorders, including depression, PTSD, and substance use disorders.[17][18][19] Therefore, the ability of psychoplastogens to rapidly promote plasticity in this region makes them attractive candidates as novel therapeutics.[1]

Existing and proposed medical use

Several psychoplastogens have either been approved or are in development for the treatment of mood and anxiety disorders.

Approved medical uses of psychoplastogens

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.[20] It is the first psychoplastogen approved for the treatment of a neuropsychiatric disorder. Esketamine is the S(+) enantiomer of ketamine.

Other psychoplastogens in ongoing clinical development

MDMA-assisted psychotherapy for PTSD recently showed robust efficacy in a Phase 3 trial.[21] At 18 weeks after the start of the trial, 67% of participants in the MDMA group no longer met the diagnostic criteria for PTSD, compared to just 32% of those in the placebo group. Moreover, MDMA-assisted psychotherapy was equally effective in patient with comorbidities such as dissociation, depression, and addiction. 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.[22]

Psilocybin, a compound in “magic mushrooms” that serves as a prodrug for psilocin, is currently being investigated in clinical trials for a variety of neuropsychiatric disorders. Similar to MDMA, it is also typically delivered in conjunction with supporting therapy. It has shown efficacy for a variety of diseases, including TRD,[23] smoking addiction,[24] and anxiety and depression in people with cancer diagnoses.[25]

LSD is being tested in phase 2 trials for cluster headaches and anxiety.[26]

Non-hallucinogenic psychoplastogens

Ketamine and psychedelics both produce hallucinations at therapeutic doses, which could limit their clinical application. As a result, several companies are seeking to develop non-hallucinogenic psychoplastogens.

Tabernanthalog[4] and AAZ-A-154[5] are two psychoplastogens that are non-hallucinogenic in rodents and were recently discovered by the Olson Lab at UC Davis. Both show efficacy in rodent models of neuropsychiatric diseases.

Partial list of published psychoplastogens

Tryptamines: psilocin, DMT, 5-MeO-DMT

Lysergamides: LSD

Amphetamines: DOI, MDMA

Iboga: ibogaine, noribogaine

Tabernanthalog

AAZ-A-154

Ketamine

Scopolamine

References

  1. ↑ 1.0 1.1 Olson, David E (January 2018). "Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics". Journal of Experimental Neuroscience. 12: 117906951880050. doi:10.1177/1179069518800508. ISSN 1179-0695. PMC 6149016. PMID 30262987.
  2. ↑ 2.0 2.1 2.2 2.3 Ly, Calvin; Greb, Alexandra C.; Cameron, Lindsay P.; Wong, Jonathan M.; Barragan, Eden V.; Wilson, Paige C.; Burbach, Kyle F.; Soltanzadeh Zarandi, Sina; Sood, Alexander; Paddy, Michael R.; Duim, Whitney C. (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.
  3. ↑ 3.0 3.1 3.2 Li, N.; Lee, B.; Liu, R.-J.; Banasr, M.; Dwyer, J. M.; Iwata, M.; Li, X.-Y.; Aghajanian, G.; Duman, R. S. (2010-08-20). "mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists". Science. 329 (5994): 959–964. Bibcode:2010Sci...329..959L. doi:10.1126/science.1190287. ISSN 0036-8075. PMC 3116441. PMID 20724638.
  4. ↑ 4.0 4.1 Cameron, Lindsay P.; Tombari, Robert J.; Lu, Ju; Pell, Alexander J.; Hurley, Zefan Q.; Ehinger, Yann; Vargas, Maxemiliano V.; McCarroll, Matthew N.; Taylor, Jack C.; Myers-Turnbull, Douglas; Liu, Taohui (2021-01-21). "A non-hallucinogenic psychedelic analogue with therapeutic potential". Nature. 589 (7842): 474–479. Bibcode:2021Natur.589..474C. doi:10.1038/s41586-020-3008-z. ISSN 0028-0836. PMC 7874389 Check |pmc= value (help). PMID 33299186 Check |pmid= value (help).
  5. ↑ 5.0 5.1 Dong, Chunyang; Ly, Calvin; Dunlap, Lee E.; Vargas, Maxemiliano V.; Sun, Junqing; Hwang, In-Wook; Azinfar, Arya; Oh, Won Chan; Wetsel, William C.; Olson, David E.; Tian, Lin (May 2021). "Psychedelic-inspired drug discovery using an engineered biosensor". Cell. 184 (10): 2779–2792.e18. doi:10.1016/j.cell.2021.03.043. PMC 8122087 Check |pmc= value (help). PMID 33915107 Check |pmid= value (help). Unknown parameter |pmc-embargo-date= ignored (help)
  6. ↑ Voleti, Bhavya; Navarria, Andrea; Liu, Rong-Jian; Banasr, Mounira; Li, Nanxin; Terwilliger, Rose; Sanacora, Gerard; Eid, Tore; Aghajanian, George; Duman, Ronald S. (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.
  7. ↑ 7.0 7.1 Shao, Ling-Xiao; Liao, Clara; Gregg, Ian; Davoudian, Pasha A.; Savalia, Neil K.; Delagarza, Kristina; Kwan, Alex C. (August 2021). "Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo". Neuron. 109 (16): 2535–2544.e4. doi:10.1016/j.neuron.2021.06.008. PMC 8376772 Check |pmc= value (help). PMID 34228959 Check |pmid= value (help). Unknown parameter |pmc-embargo-date= ignored (help)
  8. ↑ 8.0 8.1 Moda-Sava, R. N.; Murdock, M. H.; Parekh, P. K.; Fetcho, R. N.; Huang, B. S.; Huynh, T. N.; Witztum, J.; Shaver, D. C.; Rosenthal, D. L.; Alway, E. J.; Lopez, K. (2019-04-12). "Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation". Science. 364 (6436). doi:10.1126/science.aat8078. ISSN 1095-9203. PMC 6785189 Check |pmc= value (help). PMID 30975859.
  9. ↑ Smith, R. L.; Barrett, R. J.; Sanders-Bush, E. (November 1995). "Neurochemical and behavioral evidence that quipazine-ketanserin discrimination is mediated by serotonin2A receptor". The Journal of Pharmacology and Experimental Therapeutics. 275 (2): 1050–1057. ISSN 0022-3565. PMID 7473132.
  10. ↑ 10.0 10.1 de la Fuente Revenga, Mario; Zhu, Bohan; Guevara, Christopher A.; Naler, Lynette B.; Saunders, Justin M.; Zhou, Zirui; Toneatti, Rudy; Sierra, Salvador; Wolstenholme, Jennifer T.; Beardsley, Patrick M.; Huntley, George W. (2021-02-25). "Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice". doi:10.1101/2021.02.24.432725. Unknown parameter |s2cid= ignored (help)
  11. ↑ Casarotto, Plinio C.; Girych, Mykhailo; Fred, Senem M.; Kovaleva, Vera; Moliner, Rafael; Enkavi, Giray; Biojone, Caroline; Cannarozzo, Cecilia; Sahu, Madhusmita Pryiadrashini; Kaurinkoski, Katja; Brunello, Cecilia A. (March 2021). "Antidepressant drugs act by directly binding to TRKB neurotrophin receptors". Cell. 184 (5): 1299–1313.e19. doi:10.1016/j.cell.2021.01.034. PMC 7938888 Check |pmc= value (help). PMID 33606976 Check |pmid= value (help).
  12. ↑ Rantamäki, Tomi; Hendolin, Panu; Kankaanpää, Aino; Mijatovic, Jelena; Piepponen, Petteri; Domenici, Enrico; Chao, Moses V; Männistö, Pekka T; Castrén, Eero (October 2007). "Pharmacologically Diverse Antidepressants Rapidly Activate Brain-Derived Neurotrophic Factor Receptor TrkB and Induce Phospholipase-Cγ Signaling Pathways in Mouse Brain". Neuropsychopharmacology. 32 (10): 2152–2162. doi:10.1038/sj.npp.1301345. ISSN 0893-133X. PMID 17314919. Unknown parameter |s2cid= ignored (help)
  13. ↑ Nibuya, M; Morinobu, S; Duman, Rs (1995-11-01). "Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments". The Journal of Neuroscience. 15 (11): 7539–7547. doi:10.1523/JNEUROSCI.15-11-07539.1995. ISSN 0270-6474. PMC 6578063 Check |pmc= value (help). PMID 7472505.
  14. ↑ Duman, Ronald S.; Deyama, Satoshi; Fogaça, Manoela Viar (January 2021). "Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants". European Journal of Neuroscience. 53 (1): 126–139. doi:10.1111/ejn.14630. ISSN 0953-816X. PMC 7274898 Check |pmc= value (help). PMID 31811669. Unknown parameter |pmc-embargo-date= ignored (help)
  15. ↑ Lu, Ju; Tjia, Michelle; Mullen, Brian; Cao, Bing; Lukasiewicz, Kacper; Shah-Morales, Sajita; Weiser, Sydney; Cameron, Lindsay P.; Olson, David E.; Chen, Lu; Zuo, Yi (2021-05-25). "An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress". Molecular Psychiatry: 1–16. doi:10.1038/s41380-021-01159-1. ISSN 1359-4184. PMC 8613316 Check |pmc= value (help). PMID 34035476 Check |pmid= value (help). Unknown parameter |pmc-embargo-date= ignored (help); Unknown parameter |s2cid= ignored (help)
  16. ↑ Hare, Brendan D.; Duman, Ronald S. (November 2020). "Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions". Molecular Psychiatry. 25 (11): 2742–2758. doi:10.1038/s41380-020-0685-9. ISSN 1359-4184. PMC 7442605 Check |pmc= value (help). PMID 32086434 Check |pmid= value (help).
  17. ↑ Holmes, Sophie E.; Scheinost, Dustin; Finnema, Sjoerd J.; Naganawa, Mika; Davis, Margaret T.; DellaGioia, Nicole; Nabulsi, Nabeel; Matuskey, David; Angarita, Gustavo A.; Pietrzak, Robert H.; Duman, Ronald S. (December 2019). "Lower synaptic density is associated with depression severity and network alterations". Nature Communications. 10 (1): 1529. Bibcode:2019NatCo..10.1529H. doi:10.1038/s41467-019-09562-7. ISSN 2041-1723. PMC 6449365. PMID 30948709.
  18. ↑ Cardenas, Valerie A.; Samuelson, Kristin; Lenoci, Maryann; Studholme, Colin; Neylan, Thomas C.; Marmar, Charles R.; Schuff, Norbert; Weiner, Michael W. (August 2011). "Changes in brain anatomy during the course of posttraumatic stress disorder". Psychiatry Research: Neuroimaging. 193 (2): 93–100. doi:10.1016/j.pscychresns.2011.01.013. PMC 3175765. PMID 21683556.
  19. ↑ Mechtcheriakov, S.; Brenneis, C.; Egger, K.; Koppelstaetter, F.; Schocke, M.; Marksteiner, J. (2007-06-01). "A widespread distinct pattern of cerebral atrophy in patients with alcohol addiction revealed by voxel-based morphometry". Journal of Neurology, Neurosurgery & Psychiatry. 78 (6): 610–614. doi:10.1136/jnnp.2006.095869. ISSN 0022-3050. PMC 2077939. PMID 17088334.
  20. ↑ Commissioner, Office of the (2020-03-24). "FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic". FDA. Retrieved 2021-08-26.
  21. ↑ Mitchell, Jennifer M.; Bogenschutz, Michael; Lilienstein, Alia; Harrison, Charlotte; Kleiman, Sarah; Parker-Guilbert, Kelly; Ot’alora G., Marcela; Garas, Wael; Paleos, Casey; Gorman, Ingmar; Nicholas, Christopher (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. ISSN 1078-8956. PMC 8205851 Check |pmc= value (help). PMID 33972795 Check |pmid= value (help).
  22. ↑ "MDMA-Assisted Psychotherapy". MAPS. Retrieved 2021-08-26.
  23. ↑ Carhart-Harris, Robin L; Roseman, Leor; Bolstridge, Mark; Demetriou, Lysia; Pannekoek, J Nienke; Wall, Matthew B; Tanner, Mark; Kaelen, Mendel; McGonigle, John; Murphy, Kevin; Leech, Robert (December 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. ISSN 2045-2322. PMC 5640601. PMID 29030624.
  24. ↑ Johnson, Matthew W.; Garcia-Romeu, Albert; Griffiths, Roland R. (2017-01-02). "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. ISSN 0095-2990. PMC 5641975. PMID 27441452.
  25. ↑ Griffiths, Roland R; Johnson, Matthew W; Carducci, Michael A; Umbricht, Annie; Richards, William A; Richards, Brian D; Cosimano, Mary P; Klinedinst, Margaret A (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. ISSN 0269-8811. PMC 5367557. PMID 27909165.
  26. ↑ "Psychedelics Drug Development Tracker". Psilocybin Alpha. Retrieved 2021-08-26.


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