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

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.

Keywords: DMT; PTSD; Psychedelic; anxiety; depression; microdosing; neural plasticity; subhallucinogenic.

Figure 1

Experimental design for testing the effects of chronic, intermittent, low doses of DMT on rats. Blue boxes indicate the days when drug was administered. Behavioral testing was performed on the days between doses. Gray boxes indicate days the animals spent in their home cages with no testing being performed. CLAMS = Comprehensive Lab Animal Monitoring System.

Figure 2

Chronic, intermittent, low doses of DMT do not produce anxiogenic-like effects in rats. (a) DMT-treated and vehicle-treated groups display similar phenotypes in the NIL (a) and EPM (b) paradigms. Error bars represent SEM, ns = not significant. See Supplementary Table 1 for details of all statistical tests.

Figure 3

Chronic, intermittent, low doses of DMT enhance fear extinction in rats. (a) Experimental design for the fear conditioning and extinction experiments. (b, c) DMT- and vehicle-treated groups displayed comparable levels of freezing in the 2 min period before (b) and after (c) receiving foot shocks. (d, e) Neither contextual fear memory (d) nor cued fear memory (e) were impaired by chronic, intermittent treatment with low doses of DMT. (f) DMT-treated animals exhibited enhanced cued extinction memory as compared to vehicle-treated controls. n = 11 DMT-treated animals (5 male and 6 female), n = 12 vehicle-treated animals (6 male and 6 female); error bars represent SEM, ns = not significant, *p < 0.05. See Supplementary Table 1 for details of all statistical tests.

Figure 4

Chronic, intermittent, low doses of DMT produce antidepressant-like effects in rats. Such effects include reduced immobility (a), increased climbing (b), and increased swimming (c) in the FST. Error bars represent SEM, ns = not significant, *p < 0.05. See Supplementary Table 1 for details of all statistical tests.

Figure 5

Chronic, intermittent, low doses of DMT decrease dendritic spine density in the PFC of female, but not male, rats. (a) Dendritic spine density on layer V pyramidal neurons is reduced following psychedelic microdosing in females (DMT n = 20 cells from 2 animals; VEH n = 20 cells from 2 animals), but not males (DMT n = 12 cells from 2 animals; VEH n = 21 cells from 2 animals) as measured via Golgi–Cox staining. (b) Representative images of Golgi–Cox stained layer V pyramidal neurons in the PFC of rats. M = males, F = females, Error bars represent SEM, ns = not significant, *p < 0.05. See Supplementary Table 1 for details of all statistical tests.

Figure 6

Chronic, intermittent, low doses of DMT produce minimal effects on gene expression in the PFC of rats. Gene expression studies (ddPCR) from rat PFC tissue indicate that psychedelic microdosing produces minimal effects on gene expression (n = 5 females and 3–5 males per group). To account for multiple hypothesis testing, a Bonferroni correction was made such that the α = 0.05/6 comparisons = 0.0083 for this family of experiments. Error bars represent SEM, ns = not significant. See Supplementary Table 1 for details of all statistical tests.