Psychedelic-Assisted Neuroplasticity for the Treatment of Mental Health Disorders

Abstract

The renaissance of research into psychedelics class of drugs has renewed interest for a possible psychedelic clinical therapy for treating psychiatric conditions such as treatment-resistant depression, major depressive-disorder, post-traumatic stress disorder, and other neuropsychiatric diseases. Psychedelics are known to stimulate neurogenesis and gliogenesis, reduce inflammation, and ameliorate oxidative stress, which makes them promising candidates for therapeutics in psychiatric, neurodegenerative, and movement disorders. The patent highlight showcase methods for treating mental health disorders and promoting neural plasticity.

Important Compound Classes

Titles

Pharmaceutical Compositions and Methods for Treating Mental Health Disorders and Promoting Neural Plasticity; Dosing Regimens of Pharmaceutical and Nutraceutical Mushroom and Cannabis Compositions and Their Use to Treat CNS Disorders and Improve Mental Health; Improved Methods for the Use of Psychedelics; and Method of Titrating Dose of Psychedelics

Patent Publication Numbers

US 2022/0323378 A1 (URL: https://patents.google.com/patent/US20220323378A1/en?oq=US+2022%2f0323378+A1); WO 2022/187973 A1 (URL: https://patents.google.com/patent/WO2022187973A1/en?oq=WO+2022%2f187973+A1); WO 2022/195489 A2 (URL: https://patents.google.com/patent/WO2022195489A2/en?oq=WO+2022%2f195489+A2); and WO 2022/235529 A1 (URL: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022235529&_cid=P11-LAXHL9-73687-1)

Publication Dates

October 13, 2022; September 15, 2022; September 22, 2022; and November 10, 2022.

Priority Applications

US63/277,998; US63/160,235; US63/161,070; and US63/183,579

Priority Dates

November 10, 2021; March 12, 2021; March 15, 2021; and May 3, 2021

Inventors

Shawn, J. (US 2022/0323378 A1); Milanova, R.; Smeeding, J.; Hughes, C. (WO 2022/187973 A1); Gilligan, J.; Norder, L. (WO 2022/195489 A2); and Barrow, R.; Karlin, D. R. (WO 2022/235529 A1).

Assignee Companies

Allied Corp. [CA/CA], 1405 St. Paul Street, #201, Kelowna, British Columbia VIY 2E4, Canada (WO 2022/187973 A1); TRYP Therapeutics Inc. [CA/CA], 301-1665 Ellis Street, Kelowna, British Columbia VIY 2B3, Canada (WO 2022/195489 A2); and Mind Medicine, Inc. [US/US], One World Trade Center, Suite 8500, New York, New York 10007, United States (WO 2022/235529 A1)

Disease Area

Mental health disorders

Biological Target

Serotonin receptor

Summary

Mental health conditions are the leading cause of disability worldwide. Two of the most common mental health conditions, depression and anxiety, cost the global economy US $1 trillion each year (https://www.who.int/health-topics/mental-health#tab=tab_1, accessed 11/20/2022), in spite of the fact that many mental conditions can be effectively treated at relatively low cost. However, some mental health conditions and psychiatric disorders, such as post-traumatic stress disorder (PTSD), are highly debilitating and notoriously difficult to treat. Unfortunately, although selective serotonin reuptake inhibitors (SSRIs) are the recommended first-line treatment, up to 40% of SSRI-treated patients do not respond to pharmacotherapy and >70% never achieve full remission. The urgent need exists for novel treatment options for patients who cannot access or do not respond to current interventions.

The renaissance of research into the psychedelics class of drugs has renewed interest for a possible psychedelic clinical therapy for treating psychiatric conditions such as treatment-resistant depression (TRD), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and other neuropsychiatric diseases. Psychedelics are known to stimulate neurogenesis and gliogenesis, reduce inflammation, and ameliorate oxidative stress, which makes them promising candidates for therapeutics in psychiatric, neurodegenerative, and movement disorders. In addition, they not only provide symptomatic relief but also hold the promise of being disease-modifying therapeutics. However, it remains unknown how just a single administration of a psychedelic drug can produce a long-term therapeutic effect.

Psychedelics likely work by dysregulating internal activity in systems and circuits that encode habits of thought and behavior, which possibly allows recalibration of the brain as the acute effects of the drugs subside. Classic psychedelics like LSD, DMT, 5-MeO-DMT, and psilocin are known to have the potential of interacting with several 5-HT receptor subtypes, sigma-1R, and TAAR, which are present in the central nervous system (CNS) and other tissues, including cells of innate and adaptive immunity like macrophages, dendritic cells, monocytes, and T cells. The action of these classic serotonergic psychedelics is mediated primarily through agonism of the 5-hydroxytryptamine 2A (5-HT2A) receptor, which is maximally expressed in the cerebral cortex. This is exemplified by positron emission tomography research that shows the effects of psilocybin in humans are predicted by the degree of occupancy of the 5-HT2A receptor, revealed by displacement of the agonist tracer [11C]Cimbi-36. Moreover, ketanserin, a known 5-HT2A receptor antagonist, has been shown to block the psychedelic effects. There are several serotonin receptor subtypes that are expressed in mammalian peripheral tissues and cells outside the CNS, including adaptive and innate immune cells.

Serotonin is one of the most critical factors during fetal brain development and neurogenesis, being responsible for the formation of axons and dendrites and for adult axonal regeneration. In neurons, activation of serotonin can influence cellular membrane polarization states through multiple mechanisms. Serotonin also plays significant roles aside from being a neurotransmitter. There are several proposed theories on the effects of psychedelics, such as the induction of anti-inflammatory responses, which could involve activation of 5-HT2A, sigma-1, and TAA receptors present in multiple cell types involved in the immunomodulation of the CNS. A large percentage of depressed individuals have shown elevated inflammatory biomarkers and also show reduction in pro-inflammatory biomarker expression in several models, including in vitro, animal, and human studies. Another proposed antidepressant mechanism of psychedelics involves stimulation of 5-HT2A receptors and subsequent effects on resting-state functional connectivity (rsFC), disintegrating the default mode network (DMN) and producing a net hyperconnectivity. Imaging studies using fMRI that scan the brains of depressed individuals have mapped functional changes in neural network connectivity and shown that, for a subset of patients, MDD is associated with rigid, predictable reality processing through fixed neural connections that make it difficult to escape negative thought patterns. It is apparent that psychedelics activate ensembles of excitatory neurons, inhibitory interneurons, and non-neuronal cells like astrocytes and glia as well as increase synaptic density and connections between neurons. These complex heterogeneous effects at the cellular and molecular levels may be responsible for the observed normalization in network connectivity and the therapeutic outcomes.

Furthermore, psychedelics may act as immunomodulators, in which there is cross-talk between pattern recognition receptors (PRR), such as Toll-like receptor 4 (TLR4), 5-HTRs, and sigma-1R, and regulation of inflammatory response via NFκB/IRF signal transduction pathways. These modulations result in changes in IFN-α, IL-8, IL-6, IL-1β, and TNF-α gene expression and involve regulation of intracellular Ca²⁺ mobilization via 5-HT and sigma-1R. Neural plasticity is still poorly understood, as these cellular interactions are characterized by complicated homeostatic processes employing both paracrine and direct cell-to-cell communication. Loss of neurons or connections can have profound effects, given the thousands of synaptic connections each neuron makes. Similarly, gain or return of neuronal activity can provide exponential connections.

The patent application US 2022/0323378 A1 relates to methods and compositions for the treatment of one or more health conditions, including mental health, pain, aging conditions, and PTSD. The composition comprises a serotonergic psychedelic and ketamine, and derivatives, which induces increasing neural plasticity of neuronal cells for treating a brain condition or disorder. Ketamine and serotonergic psychedelics influence mTOR via different mechanisms, the former via NMDA receptor interactions and the latter via 5-HT2A and/or TrkB receptor interactions, which enable a cooperative, concerted, and amplified effect on mTOR. This circumvents or lowers the probability of addiction to ketamine.

The disclosure in patent WO 2022/187973 A1 comprises compositions from mushrooms and cannabis, including with synergistic and entourage-enhanced combinations of tryptamines, cannabinoids, and other active agents, which can be useful in treating CNS and mental health disorders such as PTSD, obsessive compulsive disorder (OCD), attention deficit/hyperactivity disorder, personality disorders, attachment disorder, anxiety disorder, addiction, eating disorders, and depressive disorders.

The disclosure in patent WO 2022/195489 A2 describes the intravenous administration (circumventing the hepatic first-pass effect) of a psychedelic such psilocybin or psilocin to a subject to treat or prevent a psychological disorder. The amount of the psychedelic is sufficient to induce a dissociative state in the subject less than or about 30 min after administration, with a non-invasive measurement of brain activity obtained to determine when the subject enters the dissociative state.

Finally, the disclosure in patent WO 2022/235529 A1 provides a method for dosing a psychedelic that avoids side effects of hallucinations and perceptual disturbances by administering the psychedelic to an individual in a titrating dosing regimen to reduce the side effects and other immediately detectable effects of the psychedelic while preserving the therapeutic benefits. The methods described are for treating conditions or diseases that include anxiety disorder, headache disorder, depression, OCD, drug disorders, opioid dependence, pain, dementia, Alzheimer’s disease, movement disorders, and so forth.

Key Structures

Biological Assay

Molecular docking/binding affinity model

Biological Data

The table below show exemplary administration of a psychedelic mushroom composition comprising psilocybin or a psilocybin extract, denoted by M+; functional mushroom comprising no psilocybin or psilocybin extract, M–; cannabis comprising THC, C+; and cannabis comprising no THC, C–.

Recent Review Articles

See refs (1−6).

The author declares no competing financial interest.