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D. Olson

The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects

March 14, 2022 / Papers / Leave a Comment / By /

Abstract

Psychedelics represent one of the most promising classes of experimental medicines for the treatment of neuropsychiatric disorders due to their ability to promote neural plasticity and produce both rapid and sustained therapeutic effects following a single administration. Conventional wisdom holds that peak mystical experiences induced by psychedelics are a critical component of their therapeutic mechanisms of action, though evidence supporting that claim is largely correlational. Here, I present data suggesting that the subjective effects induced by psychedelics may not be necessary to produce long-lasting changes in mood and behavior. Understanding the role of subjective effects in the therapeutic mechanisms of psychedelics will have important implications for both basic neuroscience and for increasing patient access to the next generation of medicines developed as a result of psychedelic research.

Olson D. E. (2020). The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects. ACS pharmacology & translational science, 4(2), 563–567. https://doi.org/10.1021/acsptsci.0c00192

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A non-hallucinogenic psychedelic analogue with therapeutic potential

January 21, 2022 / Iboga / Ibogaine, Neuroscience, Papers, Pharmacology & Chemistry, Substance Use Disorder / Leave a Comment / By / , , , , , , , , , , , , , , , , , , , ,

Abstract

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Cameron, L. P., Tombari, R. J., Lu, J., Pell, A. J., Hurley, Z. Q., Ehinger, Y., Vargas, M. V., McCarroll, M. N., Taylor, J. C., Myers-Turnbull, D., Liu, T., Yaghoobi, B., Laskowski, L. J., Anderson, E. I., Zhang, G., Viswanathan, J., Brown, B. M., Tjia, M., Dunlap, L. E., Rabow, Z. T., … Olson, D. E. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842), 474–479. https://doi.org/10.1038/s41586-020-3008-z

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Chronic, Intermittent Microdoses of the Psychedelic N,N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents

March 4, 2019 / Anxiety Disorders / PTSD, Depressive Disorders, DMT, Papers, Psychology, Publications / By / , , , ,

Abstract

Drugs capable of ameliorating symptoms of depression and anxiety while also improving cognitive function and sociability are highly desirable. Anecdotal reports have suggested that serotonergic psychedelics administered in low doses on a chronic, intermittent schedule, so-called “microdosing”, might produce beneficial effects on mood, anxiety, cognition, and social interaction. Here, we test this hypothesis by subjecting male and female Sprague Dawley rats to behavioral testing following the chronic, intermittent administration of low doses of the psychedelic N,N-dimethyltryptamine (DMT). The behavioral and cellular effects of this dosing regimen were distinct from those induced following a single high dose of the drug. We found that chronic, intermittent, low doses of DMT produced an antidepressant-like phenotype and enhanced fear extinction learning without impacting working memory or social interaction. Additionally, male rats treated with DMT on this schedule gained a significant amount of body weight during the course of the study. Taken together, our results suggest that psychedelic microdosing may alleviate symptoms of mood and anxiety disorders, though the potential hazards of this practice warrant further investigation.
Cameron, L. P., Benson, C. J., DeFelice, B. C., Fiehn, O., & Olson, D. E. (2019). Chronic, Intermittent Microdoses of the Psychedelic N, N-Dimethyltryptamine (DMT) Produce Positive Effects on Mood and Anxiety in Rodents. ACS chemical neuroscience., 10.1021/acschemneuro.8b00692
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Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics

September 19, 2018 / Neuroscience, Papers, Psychology, Publications / By /

Abstract

Neural plasticity-the ability to change and adapt in response to stimuli-is an essential aspect of healthy brain function and, in principle, can be harnessed to promote recovery from a wide variety of brain disorders. Many neuropsychiatric diseases including mood, anxiety, and substance use disorders arise from an inability to weaken and/or strengthen pathologic and beneficial circuits, respectively, ultimately leading to maladaptive behavioral responses. Thus, compounds capable of facilitating the structural and functional reorganization of neural circuits to produce positive behavioral effects have broad therapeutic potential. Several known drugs and experimental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow-acting. Here, I describe psychoplastogens-a relatively new class of fast-acting therapeutics, capable of rapidly promoting structural and functional neural plasticity. Psychoplastogenic compounds include psychedelics, ketamine, and several other recently discovered fast-acting antidepressants. Their use in psychiatry represents a paradigm shift in our approach to treating brain disorders as we focus less on rectifying “chemical imbalances” and place more emphasis on achieving selective modulation of neural circuits.
Olson, D. E. (2018). Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics. Journal of experimental neuroscience, 12, 1179069518800508., 10.1177/1179069518800508
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Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT).

July 23, 2018 / DMT, Papers, Psychology, Publications / By / ,

Abstract

Though relatively obscure, N, N-dimethyltryptamine (DMT) is an important molecule in psychopharmacology as it is the archetype for all indole-containing serotonergic psychedelics. Its structure can be found embedded within those of better-known molecules such as lysergic acid diethylamide (LSD) and psilocybin. Unlike the latter two compounds, DMT is ubiquitous, being produced by a wide variety of plant and animal species. It is one of the principal psychoactive components of ayahuasca, a tisane made from various plant sources that has been used for centuries. Furthermore, DMT is one of the few psychedelic compounds produced endogenously by mammals, and its biological function in human physiology remains a mystery. In this review, we cover the synthesis of DMT as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss the history of DMT in chemical neuroscience and why this underappreciated molecule is so important to the field of psychedelic science.
Cameron, L. P., & Olson, D. E. (2018). Dark classics in chemical neuroscience: N, N-Dimethyltryptamine (DMT). ACS chemical neuroscience, 9(10), 2344-2357., 10.1021/acschemneuro.8b00101
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Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine

July 12, 2018 / Humanities & Art, MDMA, Neuroscience, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Psychology, Publications / By / , ,

Abstract

Better known as “ecstasy”, 3,4-methylenedioxymethamphetamine (MDMA) is a small molecule that has played a prominent role in defining the ethos of today’s teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compounds like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compounds capable of reliably producing prosocial behavioral states. As a result, MDMA has captured the attention of recreational users, the media, artists, psychiatrists, and neuropharmacologists alike. Here, we detail the synthesis of MDMA as well as its pharmacology, metabolism, adverse effects, and potential use in medicine. Finally, we discuss its history and why it is perhaps the most important compound for the future of psychedelic science-having the potential to either facilitate new psychedelic research initiatives, or to usher in a second Dark Age for the field.

Dunlap, L. E., Andrews, A. M., & Olson, D. E. (2018). Dark classics in chemical neuroscience: 3, 4-Methylenedioxymethamphetamine. ACS chemical neuroscience, 9(10), 2408-2427., 10.1021/acschemneuro.8b00155
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Effects of N, N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression

April 24, 2018 / Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, DMT, Papers, Psychology, Publications / By / , , ,

Abstract

Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to positively affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N, N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague-Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.
Cameron, L. P., Benson, C. J., Dunlap, L. E., & Olson, D. E. (2018). Effects of N, N-dimethyltryptamine on rat behaviors relevant to anxiety and depression. ACS chemical neuroscience. 10.1021/acschemneuro.8b00134
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