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C. Nichols

Microdosing psychedelics: More questions than answers? An overview and suggestions for future research.

July 14, 2019 / LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , ,

Abstract

BACKGROUND:
In the past few years, the issue of ‘microdosing’ psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is.
AIM:
This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies.
APPROACH:
Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned.
CONCLUSION:
It is concluded that while most anecdotal reports focus on the positive experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clinical studies including biological (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential negative consequences microdosing could have.
Kuypers, K. P., Ng, L., Erritzoe, D., Knudsen, G. M., Nichols, C. D., Nichols, D. E., … & Nutt, D. (2019). Microdosing psychedelics: More questions than answers? An overview and suggestions for future research. Journal of Psychopharmacology, 0269881119857204., https://doi.org/10.1177/0269881119857204
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Psychedelics as anti-inflammatory agents

August 13, 2018 / Mushrooms / Psilocybin, Papers, Psychiatry & Medicine, Publications / By / ,

Abstract

Serotonin (5-hydroxytryptamine, 5-HT)2A receptor agonists have recently emerged as promising new treatment options for a variety of disorders. The recent success of these agonists, also known as psychedelics, like psilocybin for the treatment of anxiety, depression, obsessive-compulsive disorder (OCD), and addiction, has ushered in a renaissance in the way these compounds are perceived in the medical community and populace at large. One emerging therapeutic area that holds significant promise is their use as anti-inflammatory agents. Activation of 5-HT2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioural levels. This review discusses the role of the 5-HT2A receptor in the inflammatory response, as well as highlight studies using the 5-HT2A agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] to treat inflammation in cellular and animal models. It also examines potential mechanisms by which 5-HT2A agonists produce their therapeutic effects. Overall, psychedelics regulate inflammatory pathways via novel mechanisms, and may represent a new and exciting treatment strategy for several inflammatory disorders.

Flanagan, T. W., & Nichols, C. D. (2018). Psychedelics as anti-inflammatory agents. International Review of Psychiatry, 30(4), 363-375., 10.1080/09540261.2018.1481827

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Psychedelic Drugs in Biomedicine

September 22, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Substance Use Disorder / By / , , , ,

Abstract

Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R., Nichols, D. E., & Kalueff, A. V. (2017). Psychedelic Drugs in Biomedicine. Trends in Pharmacological Sciences. 10.1016/j.tips.2017.08.003
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The Effects of Hallucinogens on Gene Expression

July 5, 2017 / LSD, Neuroscience, Papers / By / ,

Abstract

The classic serotonergic hallucinogens, or psychedelics, have the ability to profoundly alter perception and behavior. These can include visual distortions, hallucinations, detachment from reality, and mystical experiences. Some psychedelics, like LSD, are able to produce these effects with remarkably low doses of drug. Others, like psilocybin, have recently been demonstrated to have significant clinical efficacy in the treatment of depression, anxiety, and addiction that persist for at least several months after only a single therapeutic session. How does this occur? Much work has recently been published from imaging studies showing that psychedelics alter brain network connectivity. They facilitate a disintegration of the default mode network, producing a hyperconnectivity between brain regions that allow centers that do not normally communicate with each other to do so. The immediate and acute effects on both behaviors and network connectivity are likely mediated by effector pathways downstream of serotonin 5-HT2A receptor activation. These acute molecular processes also influence gene expression changes, which likely influence synaptic plasticity and facilitate more long-term changes in brain neurochemistry ultimately underlying the therapeutic efficacy of a single administration to achieve long-lasting effects. In this review, we summarize what is currently known about the molecular genetic responses to psychedelics within the brain and discuss how gene expression changes may contribute to altered cellular physiology and behaviors.
Martin, D. A., & Nichols, C. D. (2017). The Effects of Hallucinogens on Gene Expression. 10.1007/7854_2017_479
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Psychedelics As A New Anti-Inflammatory Therapeutic For Atherosclerosis

April 1, 2017 / Neuroscience, Papers, Psychiatry & Medicine / By / , ,

Abstract

Background and Objective We previously discovered that serotonin 5-HT2A receptor activation with psychedelics has potent anti-inflammatory activity in both cell culture and whole animals, which indicated potent anti-inflammatory effects in vascular tissues among others. More recently we found that the psychedelic (R)-DOI potently prevents the development of allergic asthma in a mouse model. The effects of (R)-DOI were found to not result from a generalized anti-inflammatory process, but due to specific inflammatory pathways inhibition in both innate and Th2 cells. In this work, we have examined the therapeutic effects of the psychedelic (R)-DOI in the ApoE −/− high-fat model of atherosclerosis.

Methods Osmotic minipumps were used to deliver very low doses of (R)-DOI to male ApoE −/− mice that were divided into four treatment groups [Saline, normal chow; (R)-DOI, normal chow; Saline, hi-fat diet; (R)-DOI, hi-fat diet]. After 16 weeks, mice were euthanized and tissues collected for analysis

Results Calculated steady state levels of ~0.0013 mg/kg (R)-DOI resulted in a significant reduction of mRNA expression for inflammatory markers like Il6 in vascular tissue, reduced levels of glucose, and a reduction in circulating cholesterol in the high fat fed animals. Additional ongoing studies are examining arterial plaque size and heart pathology.

Summary Extremely low levels of the psychedelic (R)-DOI were sufficient to significantly block the development of vascular inflammation, normalize glucose homeostasis, and prevent the increase in cholesterol associated with a hi-fat ‘western’ high diet. Activation of serotonin 5-HT2A receptor therefore represents a powerful new strategy to treat inflammatory-related vascular disease.

Nichols, C. D., Sebastian, M., & Flanagan, T. (2017). Psychedelics As A New Anti-Inflammatory Therapeutic For Atherosclerosis. The FASEB Journal, 31(1 Supplement), 825-3.
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Anti-inflammatory effects of serotonin 5-HT2A receptor activation in ovalbumin-induced allergic asthma models

April 1, 2017 / Neuroscience, Papers, Psychiatry & Medicine / By / , ,

Abstract

Only recently has the full therapeutic value of serotonin [5-hydroxytryptophan (5-HT)] receptor activation begun to be explored. Currently there are two 5-HT2A receptor agonists in human clinical trials for the treatment of depression and obesity. An exciting new therapeutic avenue in which 5-HT2A agonists might be employed is the modulation of inflammation in allergic airways disease. Our lab has previously used an ovalbumin (OVA)-induced asthma model to demonstrate that administration of (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] prior to allergen challenge prevents many of the symptoms of allergic asthma. Here we have utilized a modified protocol to test the effectiveness of (R)-DOI in treating persistent allergic asthma. We demonstrate that administration of (R)-DOI in a chronic model attenuates the elevated airway hyperresponsiveness (AHR) typically observed in an asthmatic response. We also have probed for the expression of inflammatory markers in the lung and BALF. We concurrently are testing for the impact psilocybin and other tryptamines have on AHR in rodents using our OVA model. Overall our strategy is to develop 5-HT2A receptor agonism as a viable treatment modality against asthma and other inflammatory disorders.
Flanagan, T. W., Sebastian, M. N., & Nichols, C. D. (2017). Anti-inflammatory effects of serotonin 5-HT2A receptor activation in ovalbumin-induced allergic asthma models. The FASEB Journal, 31(1 Supplement), 820-4.
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Psychedelics as Medicines: An emerging new paradigm

November 4, 2016 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2Areceptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing anti-inflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network “resetting” after acute effects have resolved. Anti-inflammatory effects may hold promise for efficacy in treatment of inflammation-related non-psychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched.

Nichols, D. E., Johnson, M. W., & Nichols, C. D. (2016). Psychedelics as Medicines: An emerging new paradigm. Clinical Pharmacology & Therapeutics. 10.1002/cpt.557
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Serotonin 5-HT₂ receptor activation prevents allergic asthma in a mouse model.

January 1, 2015 / Neuroscience, Papers, Psychiatry & Medicine, Publications / By / , , , , ,

Abstract

Asthma is an inflammatory disease of the lung characterized by airways hyper-responsiveness (AHR), inflammation, and mucus hyperproduction. Current mainstream therapies include bronchodilators that relieve bronchoconstriction and inhaled glucocorticoids to reduce inflammation. The small molecule hormone and neurotransmitter serotonin has long been known to be involved in inflammatory processes; however, its precise role in asthma is unknown. We have previously established that activation of serotonin 5-hydroxytryptamine (5-HT)(2A) receptors has potent anti-inflammatory activity in primary cultures of vascular tissues and in the whole animal in vasculature and gut tissues. The 5-HT(2A) receptor agonist, (R)-2,5-dimethoxy-4-iodoamphetamine [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][(R)-DOI] is especially potent. In this work, we have examined the effect of (R)-DOI in an established mouse model of allergic asthma. In the ovalbumin mouse model of allergic inflammation, we demonstrate that inhalation of (R)-DOI prevents the development of many key features of allergic asthma, including AHR, mucus hyperproduction, airways inflammation, and pulmonary eosinophil recruitment. Our results highlight a likely role of the 5-HT2 receptors in allergic airways disease and suggest that 5-HT2 receptor agonists may represent an effective and novel small molecule-based therapy for asthma.

Nau, F., Miller, J., Saravia, J., Ahlert, T., Yu, B., Happel, K. I., … & Nichols, C. D. (2015). Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model. American Journal of Physiology-Lung Cellular and Molecular Physiology, 308(2), L191-L198.
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