From Psychiatry to Neurology: Psychedelics as Prospective Therapeutics for Neurodegenerative Disorders

This review (2021) finds that psychedelics may act as modulators of the immune system by reducing levels of pro-inflammatory biomarkers. The early evidence points towards psychedelics also being effective in treating or preventing brain injury and neurodegenerative diseases (e.g. Alzheimer’s Disease).

Abstract

“The studies of psychedelics, especially psychedelic tryptamines like psilocybin, are rapidly gaining interest in neuroscience research. Much of this interest stems from recent clinical studies demonstrating that they have a unique ability to improve the debilitating symptoms of major depressive disorder (MDD) long-term after only a single treatment. Indeed, the Food and Drug Administration (FDA) has recently designated two Phase III clinical trials studying the ability of psilocybin to treat forms of MDD with “Breakthrough Therapy” status. If successful, the use of psychedelics to treat psychiatric diseases like depression would be revolutionary. As more evidence appears in the scientific literature to support their use in psychiatry to treat MDD on and substance use disorders (SUD), recent studies with rodents revealed that their therapeutic effects might extend beyond treating MDD and SUD. For example, psychedelics may have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases such as Alzheimer Disease. Preclinical work has highlighted psychedelics’ ability to induce neuroplasticity and synaptogenesis, and neural progenitor cell proliferation. Psychedelics may also act as immunomodulators by reducing levels of proinflammatory biomarkers, including IL-1β, IL-6, Tumor Necrosis Factor-α (TNF-α). Their exact molecular mechanisms, and induction of cellular interactions, especially between neural and glial cells, leading to therapeutic efficacy, remain to be determined. In this review, we discuss recent findings and information on how psychedelics may act therapeutically on cells within the Central Nervous System (CNS) during brain injuries and neurodegenerative diseases.“

Authors: Urszula Kozlowska, Charles D. Nichols, Kalina Wiatr & Maciej Figiel

Notes

As we are progressing through the so-called Psychedelic Renaissance it would appear that the potential of psychedelics knows no limits. What if the therapeutic effects of psychedelics may extend beyond mental disorders and additionally, help those with brain injuries and neurodegenerative disorders like Alzheimer’s disease? Neuroimaging studies have shown that psychedelics decrease modularity in the brain. New evidence argues it may also be possible that psychedelics decrease levels of inflammation-inducing biomarkers in the brain. Although such a statement remains speculative at best, for people living with a disease like Alzheimer’s and Parkinson’s, for which there is currently no cure, the potential role of psychedelics as immunomodulators offer hope for the future.

The present study offers food for thought regarding the role of psychedelics as modulators of the brains innate immune system. Based on previous research, the authors of the paper at hand discuss the influence psychedelics may have on neural tissue homeostasis. That is, the ability of cells within the central nervous system to self-regulate and maintain normal functioning.

What the review proposes:

• Psychedelics can induce neurogenesis and neuroplasticity while simultaneously reducing inflammation and oxidative stress, two significant issues in neurodegenerative disorders.
• Cytokines are a broad category of small proteins that play a vital role in cell signaling. Studies in cells (in vitro) have shown that DMT and 5-MeO-DMT reduce levels of the proinflammatory cytokines IL-1ẞ, IL-6 and TNF-α while promoting the expression of the anti-inflammatory cytokine IL-10.
• Psychedelics may interact with serotonin receptor subtypes that are involved in mediating the central nervous systems immune response, leading to downregulation of proinflammatory cytokines.
• In patients with neurodegenerative disorders, the psychotropic effects of psychedelics may be a limiting factor when treating patients with these disorders. The authors suggest that novel psychedelic compounds devoid of hallucinogenic properties may be of benefit.

This review gives a comprehensive overview regarding how psychedelics could be used to treat neurodegenerative disorders. The evidence discussed leads one to believe that this potential role of psychedelics cannot go unnoticed. Nevertheless, as is the case with the majority of psychedelic research, further research is needed to realize these speculations.

Summary

From psychiatry to neurology: psychedelics as prospective therapeutics for neurodegenerative disorders Urszula Kozlowska1,2, Charles Nichols3, Kalina Wiatr2, Maciej Figiel2 1. Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Sciences

Psychedelics, especially psilocybin, are rapidly gaining interest in neuroscience research due to their ability to improve the symptoms of major depressive disorder and substance use disorders. However, recent studies have revealed that they may also have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases.

Abbreviations

A number of proteins and genes are involved in the development of the central nervous system, including the apoptosis protease activating factor 1, the Bcl-2-associated X protein, the c-Fos proto-oncogene, the ERK1/2 kinase, the NFKB inhibitor alpha, the IgE, the LIMK1 and the mTOR pathways.

Subfamily 4 group A member 1, NQO1, OPC, PECAM, PERK, PKC, PLCbeta, PLD1, PTSD, rsFC, SCA3, SHH, TAAR, TBG, TCAs, TRXPs, TLR 4, TRD, QUIN, VCAM1, ZO are involved in the development of post-traumatic stress disorder. Psychedelics are a class of drugs that primarily produce their effects through serotonin 5-HT 2 A receptor activation. They were made illegal to use or possess around the world in the late 1960’s, but are now making a comeback as a possible clinical therapy for psychiatric conditions.

Newer derivatives of psychedelic compounds include DOx and 2C compounds such as ( R )-DOI and 2C-B. These drugs can produce similar perceptual alterations but are not considered psychedelics. In the late 1960’s and early 1970’s, research using psychedelics was essentially banned worldwide. However, in recent years, interest in this field has gained momentum, and clinical trials have shown promise for these drugs as potential new therapeutics. We hypothesize that psychedelics can be used as therapeutics in the treatment of neurodegenerative diseases and brain injuries.

Psychedelics have been used in the treatment of major depressive disorder and schizophrenia, but most studies were not up to current standards. Nevertheless, 264 million people suffer from depression globally, and 800 000 people commit suicide every year. Several drugs are used to treat MDD, but one-third of patients do not respond to these conventional treatments. S-ketamine, a nonmonoaminergic antagonist of NMDA receptors, is a new medicine for TRD, but the cost is relatively high.

In clinical trials, psilocybin improves wellbeing of cancer patients when used together with psychotherapy. The positive behavioral effects lasting through the studies’ 6 month duration, and the long-term follow-up study suggests positive outcomes lasting at least 4.5 years. Imaging studies using fMRI have mapped functional changes in neural network connectivity in depressed individuals, and this may be relevant to the therapeutic effects of psilocybin.

Psilocybin increases network connectivity, which then gives way to more normal connections, similar to a defibrillator re-synchronizing electrophysiological signals within the heart. MDD affects several aspects of neurobiology, from network connectivity to cellular function. Psychedelics may affect these aspects via activation of 5-HT 2A , Sigma-1, and TAAR receptors, which may reduce neuroinflammation and prevent relapse into a depressed state. Reducing inflammation is a recently proposed antidepressant strategy, and psychedelics have been shown to lower inflammation and promote hippocampal neurogenesis. It remains to be investigated if this anti-inflammatory mechanism is also involved in the antidepressant effects of psychedelics to treat MDD.

Tryptophan is metabolized to kynurenine by indoleamine 2,3-dioxygenase (IDO), which is produced by immune cells in response to proinflammatory cytokines. The anti-inflammatory properties of psychedelics may therefore involve prevention of immune cells to synthetize IDO, and disruption of IDO/kynurenine pathways. In a recent clinical study, psilocybin appeared to have similar therapeutic effects to an SSRI (escitalopram) to treat major depressive disorder. However, more studies are needed to determine the broad applicability of psychedelics to treat neuropsychiatric disorders. Although psychedelics are generally accepted to have little to no addictive potential, there is a slight risk for certain patients to experience sporadically occurring adverse psychological effects, including symptoms of psychosis or schizophrenia.

Psychedelics induce neuroplasticity and neurogenesis, which are processes involving neurons, astrocytes, microglia, and oligodendrocytes. This process is still poorly understood, but may be associated with increased neural plasticity mechanisms at the cellular level. Psychedelics and 5-HT 2 A receptor activation induce changes in synaptic architecture, which can be explained by direct signaling downstream of 5-HT 2 A receptor stimulation by psychedelics or indirect modulation of synaptic architecture by elevated glutamate levels.

Several genes involved in synaptic plasticity and neurogenesis are changed in response to psychedelics, and microglia may be a factor in the mechanism of action for therapeutic effect. Microglia are tissue-specific, self-renewable CNS macrophage-like cells that are different from other cell types. Psychedelics may stimulate neural plasticity through microglia regulation, since many receptors targeted by psychedelics are also present on microglia. Microglia are involved in the process of synaptic pruning, which is also involved in the progression of certain mental illnesses. The activation of NMDA receptors on a single neuron’s dendrites can stimulate the growth of microglial extensions. Psilocin increases the expression of TREM2 on microglia and reduces the expression of p65, TLR4 and CD80 pro-inflammatory markers, suggesting that psilocin may prevent neuronal damage in microglia-neuron co-culture. Neurodegeneration is a very fragile and hardly accessible organ, and there are only limited therapeutic approaches. One recently proposed solution is the application of traditional psychedelics.

Psychedelics have been shown to prevent neural loss and stimulate neurogenesis, and may be able to treat MDD by reducing the effects of oxidative stress and promoting neurogenesis.

Oxidative cell damage occurs due to an imbalance between free radicals, reactive oxygen species, and reactive nitrogen species, and the presence of antioxidants and antioxidative proteins. This imbalance is observed in many psychiatric conditions and in the pathology of ALS, PD, AD, and DNA repeat expansion disorders.

Psychedelics such as ayahuasca and psilocybin may induce gliogenesis and neural progenitor cell migration, and may also reduce oxidative stress damage in retinal pigment epithelium/choroid in Sod2 knockout mice.

Psychedelics target the Sigma-1 receptor, which may protect cells from Endoplasmatic Reticulum Stress (ERS). ERS damage is reported in MDD and several neurodegenerative disorders, and targeting Sigma-1 receptors may be a novel therapeutic strategy.

The blood-brain barrier (BBB) is composed of astrocytes, perivascular macrophages, and pericytes, and separates the intracereberall circulatory system (CSF) from peripheral vascular system (blood). Breakdown of the BBB can originate from prolonged exposure to oxidative stress and/or immune cell activity. Chronic social stress causes BBB disruption via claudin-5 downregulation, which leads to the infiltration of proinflammatory factors and depression-like behaviors. Psychedelics have been shown to have potent anti-inflammatory effects of suppressing many of the same proinflammatory biomarkers in peripheral tissues.

Oligodendrocytes protect and support neurons and their axons by providing myelin that improves electric signal transmission. Psychedelics can target Sigma-1 receptors, which are essential in stimulating OPC differentiation, and may play a protective role in myelin and oligodendrocyte cell survival.

Psychedelics can modulate both adaptive and innate immune responses via several 5-HT receptor subtypes, Sigma-1R, and TAAR, which are mediators of immunological response. These modulations involve intracellular Ca2+ mobilization via 5-HT and Sigma-1R, and regulation of inflammatory response via NF b/IRF signal transduction pathways.

Serotonin receptors are present on most types of cells in the central nervous system (CNS), and their activation can influence cellular membrane polarization states through multiple mechanisms. Serotonin plays significant roles in regulating whole-body homeostasis, including heart rate, intestinal motility, and the immune response.

Although 5-HT 2A receptors are primarily described as activators of proinflammatory pathways, they surprisingly have anti-inflammatory properties when activated by certain, but not all, psychedelics. This is likely due to functional selectivity, in which different ligands induce slightly different conformations of the receptor to recruit different sets of effector pathways. Nasal administration of ( R )-DOI at a very low dose completely prevents symptoms of allergic asthma in rodent models. Further examination of the lung tissue revealed prevention of eosinophilia and a reduction in Th2 cell recruitment.

Psychedelics have been shown to have anti-inflammatory properties against neuroinflammation. Furthermore, activation of 5-HT2B receptors in CD1+ monocyte-derived dendritic cells regulates immune responses by downregulating proinflammatory cytokine protein expression and prevents T-cell activation to inflammatory Th1 and Th-17 phenotypes. Sigma-1 receptors are located in mitochondria and the endoplasmatic reticulum and mediate a neuroprotective effect via modulation of Ca 2 + homeostasis, mitigation of oxidative stress, regulation of gliosis, neuroplasticity, and glutamate activity.

Targeting of Sigma-1R may be a promising therapeutic strategy for psychiatric and neurodegenerative conditions, as it is involved in the transition between M1-like proinflammatory and M2-like pro-regenerative and tolerogenic microglia phenotypes. DMT, an agonist of Sigma-1Rs, was found to protect cells from hypoxia-induced apoptosis via Sigma-1 receptor stimulation. It was later found to reduce the size and number of lesions in a rat model of stroke and increase levels of anti-inflammatory cytokines. Sigma-1R mediated changes in microglia phenotypes may be responsible for the elevated anti-inflammatory cytokine levels after DMT administration in these stroke models.

Trace amine-associated receptors (TAARs) are G-protein coupled receptors abundantly present in the CNS. They are also expressed in non-CNS tissues such as the thyroid, stomach, pancreas, and intestine, where they may regulate body functions in an endocrine manner. TAARs are found in immune cells and can elicit immunomodulatory effects. However, our knowledge about TAARs and immune responses is limited.

Silencing of TAAR1 and TAAR2 reduces IgE secretion in B-cells and PMN chemotactic migration. DMT, ( R )-DOI, d-LSD, and 5-MeO-DMT are TAAR1 agonists.

Psychedelic treatment for MDD can be beneficial due to the induction of neurogenesis and neuroplasticity.

Psychedelics may be beneficial in treating depression, stroke, and neurodegenerative diseases. The development of effective therapeutics lags behind other fields such as cardiovascular diseases and cancer, so it is a top priority to search for novel candidates for therapeutic approaches. Psychedelics are a novel approach for treating psychiatric disorders and have been used safely by indigenous populations for centuries. They promote structural plasticity via BDNF signaling and are thus proposed as potential therapeutics for MDD and related disorders.

In polyQ disorders such as spinocerebellar ataxia type 3 (SCA3), the expression of BDNF is downregulated, and several essential proteins belonging to the BDNF signaling pathway are also downregulated. BDNF is an immediate upstream regulator of the MAPK cascade, which is involved in longterm synaptic plasticity. Psychedelics may affect the levels of several proteins, including Rac1, Rhoa, Mapk1, Map2k1, Pea15, and BDNF, which are necessary for BDNF signal transduction to the nucleus and may promote synaptic plasticity. Psychedelics have been shown to reduce oxidative stress, which is a significant issue in models of neurodegenerative disorders.

Studies have shown that psychedelics can reduce stress by breaking down ROS, and that Txn downregulation in SCA3 mice might increase the vulnerability of neurons to ROS. Therefore, activation of serotonergic signaling in SCA3 patients with psychedelic agents is a promising therapeutic strategy. Non-hallucinogenic psychedelics approach is an alternative to psychedelic-assisted psychotherapeutical approach. Ibogaine is not classified as a psychedelic, but it is a type of hallucinogen that may have therapeutic efficacy to treat substance use disorder.

A new class of molecules that lack hallucinogenic properties has been found to be effective in multiple animal models of disease. These new molecules may represent potential non-hallucinogenic derivatives of hallucinogenic parent molecules with therapeutic effect.

The immunomodulatory properties of psychedelics may be relevant to regenerative medicine, as the immune response to NSC/NPC transplantation is poor. However, the downregulation of CD80 co-stimulatory molecule expression on the surface of microglial cells is an attractive immunosuppressive strategy.

Microdoses of psychedelics are believed to improve creative thinking, cognitive function and overal psychological well-being, but there have been few rigorous controlled studies of microdoses. Further, repeated administration of LSD (5-20 g) in health individuals produced no significant changes in several cognitive outcome measures. There have been several reports of people taking low doses of psychedelics to treat depression, but no rigorous and controlled studies have been conducted in patients with diagnosed depressive disorder.

Psychedelics are promising candidates for future therapeutics for psychiatric, neurodegenerative, and movement disorders, and have even been designated with “Breakthrough Therapy” status by the FDA in the United States for two different Phase III clinical trials.

Funding information

Psychedelics activate 5-HT2A and Sig -1 receptors, which lead to transcription of brain-derived neurotrophic factor (BDNF), which in turn leads to increased neural plasticity. BDNF also activates several other signaling cascades, including RAC1/PAK1/LIMK1 and MKP-1, which promote axon branching.

Psychedelics may act via stimulation of 5-HT1A, 5HT2A and Sigma-1, which results in the upregulation of antioxidant genes and proteins expression. Sigma-1, a protein complex consisting of receptors, ion transporters, and anchoring proteins, protects cells against ER stress via down-regulation of CHOP2, ATF4, ATF6, and the creation of bax (apoptotic) vs. bcl2 equilibrium. Psychedelics may target the mechanisms of neurodegeneration, neural tissue damage, and inflammation via 5-HTRs, Sigma-1, and TAAR1 receptor stimulation, and upregulate the expression of neurogenic and anti-inflammatory factors (BDNF, GDNF, IL-10), thereby eliciting neuroprotective activity.