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

Lindsay P. Cameron, Charlie J. Benson, Brian C. DeFelice, Oliver Fiehn, and David E. Olson

ACS Chemical Neurosciences, 2019

DOI: 10.1021/acschemneuro.8b00692

 

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,Ndimethyltryptamine (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.

KEYWORDS : Psychedelic, microdosing, DMT, depression, PTSD, anxiety, subhallucinogenic, neural plasticity

 

■ INTRODUCTION

Mood and anxiety disorders are among the leading causes of disability worldwide,1,2 and anti-depressants remain one of the most highly prescribed medications in the United States.3 Current therapeutic strategies for treating these disorders are slow-acting and prove to be ineffective for many patients.4 Thus, there is a critical need to develop new treatment strategies for these disorders.

Serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and N,N dimethyl-tryptamine (DMT), have a long history of use as experimental therapeutics in the clinic for treating depression, anxiety, and substance use disorder. 5−10 However, it is unclear whether hallucinogenic doses of these drugs are required for them to produce therapeutic effects. Psychedelic microdosingthe practice of administering subhallucinogenic doses of psychedelic compounds on a chronic, intermittent scheduleis rapidly gaining popularity due to its alleged antidepressant and anxiolytic effects.11−13
Despite the prevalence of psychedelic microdosing, there are essentially no peer-reviewed studies that have investigated the potential benefits and risks of this practice.14,15

Psychedelics are potent psychoplastogens,16 and their effects on neural plasticity have been invoked to explain their longlasting behavioral effects related to mood and anxiety.17 Previously, we observed that even a low dose of DMT caused changes in the frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs) in the prefrontal cortex (PFC) of rats that lasted long after the drug had been cleared from the body.16 Therefore, we hypothesized that administration of this low dose on a chronic, intermittent schedule might impact behaviors relevant to mood and anxiety that involve the PFC.18−23 Here, we demonstrate that chronic (∼2 months), intermittent (every third day), low (1 mg/kg) doses of DMT facilitate fear extinction learning and reduce immobility in the forced swim test without producing the anxiogenic-like effects characteristic of a high dose (10 mg/kg).24 However, the
former dosing regimen also significantly increases bodyweight in male rats. Taken together, the data presented here suggest that subhallucinogenic doses of psychedelic compounds might possess value for treating and/or preventing mood and anxiety disorders. Despite the therapeutic potential of psychedelic
microdosing, this practice is not without risks, and future studies need to better define the potential for negative neurobiological or metabolic repercussions.

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Cameron-ChronicIntermittentMicrodosesofthePsychedelicNNDimethyltryptamineDMTProducePositiveEffectsonMoodandAnxietyinRodentsACSCHEMNEURO2019