Effects of N, N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression

Mood and anxiety disorders cause large amounts of disability worldwide and current antidepressant medications often take weeks to become effective, with about 30% of patients failing to respond. This therapeutic gap has prompted interest in fast-acting alternatives such as ketamine and classical serotonergic psychedelics. Ayahuasca, a traditional Amazonian tisane that combines DMT-containing Psychotria viridis with MAO-inhibiting Banisteriopsis caapi, has shown antidepressant and anxiolytic effects in humans and in some animal paradigms, but the contribution of individual constituents—particularly N,N-dimethyltryptamine (DMT), the principal hallucinogenic component—remains unclear. Cameron and colleagues set out to characterise the behavioural effects of a hallucinogenic dose of DMT in adult male Sprague-Dawley rats using standard assays relevant to anxiety, post-traumatic stress disorder (PTSD), and depression. The study aimed to determine both acute and longer-lasting behavioural consequences of DMT administration in paradigms including novelty-induced locomotion (NIL), the elevated plus maze (EPM), fear conditioning and extinction (cued and contextual), and the forced swim test (FST). This work seeks to clarify whether DMT alone can account for the anxiogenic, anxiolytic, or antidepressant effects attributed to ayahuasca and whether its profile resembles that of other fast-acting agents such as ketamine.

Adult male Sprague-Dawley rats (8–14 weeks old) were used. Animals were housed two per cage with ad libitum food and water, maintained on a 12:12 light cycle, and experiments were performed during the light phase. The extracted text does not clearly report group sample sizes for each experiment; the paper indicates further details are provided in a Table that was not included in the extraction. All procedures were approved by the UC Davis IACUC. DMT was synthesised as the fumarate salt (2:1 DMT:fumaric acid), characterised by NMR and LC-MS, stored at −20ºC, and freshly prepared in 0.9% sterile saline for each experiment. DMT•fumarate was administered intraperitoneally at 10 mg/kg with an injection volume of 1 mL/kg. Ketamine•HCl (10 mg/kg, i.p.) served as a positive control in the FST; vehicle controls received 0.9% saline. The authors chose 10 mg/kg as a hallucinogenic dose in rats based on allometric scaling and prior drug discrimination literature. DMT’s half-life in rats following i.p. injection is reported as 5–15 min and it is cleared from tissues within 1 h; behavioural testing was therefore generally initiated 1 h after dosing to avoid confounding acute somatic effects. Behavioural assays comprised: novelty-induced locomotion (NIL) in an open-field chamber for 45 min with automated tracking of horizontal motion, rotations, rearings and stereotypies; the elevated plus maze (EPM) for 5 min to measure open-arm time and entries; auditory-cued and contextual fear conditioning followed by tests of memory and extinction using standard shock/tone protocols and automated Video Freeze scoring; and the forced swim test (FST) with a pre-test (15 min) followed 24 h later by a 5-min test. For the FST, rats received a subchronic dosing schedule of three administrations (23.5, 6, and 1 h before the test), a regimen noted to be effective for a range of antidepressants. Freezing and FST behaviours (immobility, swimming, climbing) were scored as specified. Statistical analyses used GraphPad Prism. Time-dependent data were analysed via two-way repeated measures ANOVA where appropriate. Comparisons between DMT and vehicle used two-tailed Student’s t-tests or two-way ANOVAs with Sidak post-hoc tests; the contextual extinction data, which showed a bimodal distribution, were analysed with a Mann–Whitney test. FST data involving multiple comparisons were analysed by one-way ANOVA with Tukey’s post hoc test. Data are reported as means ± SEM, with significance thresholds noted in the text.

Immediately after a 10 mg/kg intraperitoneal dose, DMT produced acute somatic signs in the home cage—flat body posture and hind limb abduction—consistent with serotonin syndrome; head-twitches and wet-dog shakes were not observed. Somatic signs subsided within 30 min and by 1 h animals were qualitatively similar to vehicle-treated controls, so subsequent behavioural testing was conducted at 1 h when the compound is reported to be cleared from brain and plasma. In the novelty-induced locomotion test, DMT-treated rats showed reduced exploratory behaviour: total distance travelled was significantly shorter than in vehicle-treated animals, and both the number of rearings and time spent rearing were reduced. DMT decreased the time spent in stereotypies but did not alter the total number of stereotypic events, and it did not affect thigmotaxis. These results indicate an anxiogenic/neophobic effect in a novel open-field environment. Elevated plus maze results corroborated anxiogenic effects: DMT-treated animals spent a smaller percentage of time in open arms and made fewer open-arm entries compared with controls. Total distance travelled in the maze and average velocity were not statistically different between groups, and the number of closed-arm entries did not differ (Mean ± SEM; VEH = 9.375 ± 1.179; DMT = 8.556 ± 1.642; P = 0.6977), indicating no gross locomotor impairment at 1 h. In fear conditioning experiments, acute DMT given 1 h prior to conditioning did not alter baseline freezing before shocks but produced increased immediate freezing following training shocks, consistent with an anxiogenic effect during conditioning. When contextual and cued fear memory were assessed in the days after conditioning, no significant differences were found between DMT- and vehicle-treated groups, suggesting DMT did not alter consolidation of the original fear memories under the acute dosing regimen used. When the investigators administered DMT 1 h prior to cued-extinction training (animals conditioned drug-free), DMT-treated rats exhibited enhanced extinction: on a drug-free test the following day tone presentations produced significantly less freezing in the DMT group compared with controls, indicating stronger cued extinction memory. For contextual extinction using a stronger shock protocol to raise baseline freezing to approximately 60%, DMT was given 1 h prior to repeated extinction sessions on days 3–5; contextual extinction measured on day 6 (no drug) did not differ significantly between groups. The authors note the contextual extinction data had a bimodal distribution, suggesting presence of responders and non-responders. In the forced swim test, DMT significantly reduced immobility time and increased swimming counts relative to vehicle-treated animals, with no significant effect on climbing behaviour. The magnitude of the effects of DMT in the FST was indistinguishable from that of ketamine at the same dose, with no statistical differences between DMT- and ketamine-treated animals for immobility, swimming, or climbing. Across assays, the authors report that DMT produces an initial anxiogenic/neophobic profile in novel environments but later facilitates fear extinction (cued) and produces antidepressant-like effects in the FST. Quantitative details such as group sample sizes and exact p-values for many comparisons are not provided in the extracted text and appear to be listed in a Table not included here.

Cameron and colleagues interpret their findings as indicating that a single, hallucinogenic dose of DMT produces an early anxiogenic response in novel or threatening contexts but also yields longer-lasting behavioural effects consistent with antidepressant and anxiolytic actions. Specifically, DMT reduced exploratory behaviour and promoted anxiety-like responses in the open field and elevated plus maze, yet it facilitated cued fear extinction and reduced immobility in the forced swim test—effects the authors equate with potential therapeutic benefits relevant to PTSD and depression. The authors position their results relative to prior work on ayahuasca and its constituents. They note that DMT reproduces several behavioural features previously ascribed to ayahuasca (reduced exploration and increased anxiety in some paradigms, reduced immobility in the FST), suggesting DMT may be the ayahuasca component responsible for decreased exploration and acute anxiety in rats. At the same time, other ayahuasca components (β-carbolines such as harmine) have distinct effects and may contribute to or modulate antidepressant outcomes; the authors highlight that harmine alone has antidepressant-like effects in the FST and that combined or interactive effects between DMT and β-carbolines warrant investigation. Mechanistically, the investigators caution that simple serotonin transporter inhibition is an unlikely sole explanation for the antidepressant-like effects because DMT’s reported Ki at SERT is much weaker than that of typical SSRIs. Instead, they raise the possibility that DMT and ketamine—although acting primarily at different receptor systems (5-HT receptors versus NMDA receptors)—might converge on downstream mechanisms that promote neural plasticity. Supportive observations include the rapid metabolism and clearance of DMT despite persistent behavioural effects, and external reports (cited by the authors) that 5-MeO-DMT can induce proteins associated with dendritic spine formation in human organoids. They therefore suggest future studies should test whether DMT promotes structural and functional plasticity in prefrontal cortical neurons, similar to proposed mechanisms for ketamine. The authors acknowledge several uncertainties and limitations within the extracted text. Differences between acute and chronic dosing paradigms may account for discrepancies with prior studies of ayahuasca; acute DMT did not alter fear memory consolidation in their hands but did enhance extinction when given before extinction training. The contextual extinction data displayed a bimodal distribution indicating heterogeneous responsiveness, and the extracted text does not provide sample sizes or full statistical detail for every comparison (these appear to be in tables not included here). Safety considerations are noted: transient serotonin syndrome-like signs were observed immediately after dosing. Finally, the authors call for additional work to determine persistence of antidepressant effects, potential synergistic actions with β-carbolines, and whether endogenous DMT has a physiological role in mood regulation. In sum, the paper concludes that DMT alone can produce a behavioural profile in rats that includes acute anxiogenesis in novel contexts together with facilitation of fear extinction and antidepressant-like effects in the FST, and the authors argue these findings strengthen the rationale for further mechanistic and translational research into classical serotonergic psychedelics as fast-acting therapeutics.