5-HT1A receptor blockade potentiates the subjective effects of DMT

Serotonergic psychedelics are being investigated as potential treatments for a range of disorders and as tools for improving well-being, partly because the acute subjective experience may influence longer-term outcomes. Most work has focused on 5-HT2A receptor agonism as the main mechanism behind psychedelic effects, but the role of the 5-HT1A receptor remains uncertain. Previous animal and human studies suggested that 5-HT1A agonism or blockade can alter psychedelic phenomenology, yet the direction and scope of these effects have not been clearly established in humans. The authors set out to quantify the effects of 5-HT1A receptor blockade, using pindolol pre-treatment, on the subjective effects of intravenous N,N-dimethyltryptamine (DMT). They revisited data from an earlier clinical trial that had not reported quantitative subjective outcomes, with the aim of determining whether blocking 5-HT1A receptors changes the intensity or profile of the DMT experience. This paper is therefore a re-analysis of an earlier randomised crossover study, and it is presented as the first quantitative examination of 5-HT1A receptor blockade on psychedelic-induced subjective effects in humans.

The researchers analysed data from a double-blind, randomised, placebo-controlled, within-subjects trial conducted in an inpatient setting at the University of New Mexico Hospital General Clinical Research Centre. Twelve experienced hallucinogen users took part, including 10 men and 2 women, with a mean age of 44.8 years; participants were medically and psychiatrically screened to exclude current medical or psychiatric disorders and any history of psychosis. Treatments were separated by at least 1 week for men and at least 1 month for women, and female participants were studied during the early follicular phase of the menstrual cycle. The trial compared four conditions: DMT 0.1 mg/kg intravenously after oral placebo pre-treatment, DMT 0.1 mg/kg intravenously after 30 mg oral racemic pindolol pre-treatment, pindolol alone, and placebo alone. The DMT was infused over 30 seconds through an indwelling forearm catheter and followed by saline flush. The main comparison for this paper was DMT plus placebo pre-treatment versus DMT plus pindolol pre-treatment, to isolate the effects of 5-HT1A blockade on the DMT experience. Subjective effects were assessed after the acute experience had resolved, around 30–45 minutes after injection, using the Hallucinogen Rating Scale (HRS), a 125-item self-administered instrument with six subscales: Somaesthesia, Affect, Perception, Cognition, Volition, and a global intensity measure. Cardiovascular data, including heart rate and blood pressure, were collected at multiple time points from baseline to 60 minutes after DMT. The cardiovascular analysis was described as descriptive rather than inferential. For the subjective outcomes, the authors used a Bayesian hierarchical linear model implemented in R with Stan/Hamiltonian Monte Carlo. HRS subscale scores were z-score standardised, and the model estimated subscale-specific treatment effects while accounting for between-subject variability and baseline differences across subscales. The authors reported posterior means, 89% credible intervals, probability of direction, back-transformed raw score estimates, and Cohen's d effect sizes. Four chains were run for 4000 iterations each, including warm-up.

Pindolol pre-treatment increased the subjective effects of DMT on the Hallucinogen Rating Scale. The global standardised effect size was 0.514 with an 89% credible interval of 0.331 to 0.694, and the mean raw score difference was 0.297 with an 89% credible interval of 0.190 to 0.403. All six HRS subscales showed positive effects, although the strength of evidence varied somewhat by domain. The largest estimated effect was for global intensity, with a mean standardised effect size of 0.654 (89% CrI 0.219 to 1.082; probability of direction 0.99). Other subscales were also increased: Somaesthesia 0.523 (0.092 to 0.956; 0.97), Affect 0.456 (0.019 to 0.882; 0.95), Perception 0.549 (0.114 to 0.984; 0.98), Cognition 0.497 (0.070 to 0.938; 0.96), and Volition 0.404 (-0.019 to 0.828; 0.94). The Volition estimate was positive but its credible interval slightly crossed zero, so it was the least certain of the six domains. The authors also note that participants anecdotally reported less anxiety with pindolol than with earlier higher-dose DMT sessions. Cardiovascularly, pindolol pre-treatment was associated with a larger blood pressure response to DMT. Mean heart rate increased by 13 bpm at 2 minutes in the DMT-plus-placebo condition but by only 1 bpm in the DMT-plus-pindolol condition. By contrast, peak blood pressure changes at 2 minutes were larger with pindolol: systolic/diastolic increases of 36/15 mmHg versus 19/7 mmHg without pindolol, and mean arterial pressure rose by 22 mmHg versus 11 mmHg. The authors note that blood pressure in the pindolol condition ranged as high as 194/109 mmHg at 2 minutes in one participant before falling quickly thereafter.

The authors interpret these findings as quantitative evidence that 5-HT1A receptor blockade amplifies the subjective effects of DMT, with a moderate effect size. They argue that the results, together with earlier human work showing that 5-HT1A agonism with buspirone reduces psilocybin effects, are consistent with a functional antagonism between 5-HT1A and 5-HT2A receptor-mediated contributions to psychedelic experience. They also suggest that the enhanced blood pressure response may reflect inhibition of a normally dampening 5-HT1A influence on cardiovascular function, although they acknowledge that it could also simply follow from stronger subjective effects and consequent sympathetic activation. In mechanistic terms, the authors discuss the opposing actions of 5-HT1A and 5-HT2A receptors on cortical circuitry and excitation/inhibition balance. They suggest that changing the balance between these receptors may shift the brain into a more globally excited state and thereby alter perception during the acute psychedelic experience. They argue that future human work should test excitation/inhibition balance during psychedelic states, for example using EEG analyses, and should combine these with PET imaging to measure receptor occupancy across psychedelics. The authors also note that previous buspirone-psilocybin data suggest 5-HT1A agonism may especially dampen visual effects, raising the possibility that 5-HT1A blockade might selectively modify certain phenomenological features rather than merely intensifying all subjective domains equally. They speculate that the distinct phenomenology of 5-MeO-DMT may relate to its stronger affinity for 5-HT1A receptors, and they anticipate that pindolol might alter its effects as well. They further suggest that pindolol could potentially intensify psilocybin experiences, and they mention anecdotal reports of reduced anxiety, which they relate to known anxiolytic properties of beta-blockade. The main limitations they acknowledge are the reliance on a single subjective outcome measure, the Hallucinogen Rating Scale, and the use of only one dose of DMT and one dose of pindolol.