Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects

Classic serotonergic psychedelics such as lysergic acid diethylamide (LSD) and psilocybin are under investigation as adjuncts to psychotherapy. Both produce their acute subjective effects primarily via activation of the serotonin 5-HT2A receptor, but LSD has a substantially longer acute duration (typically ~8.5–11 h at common doses) than psilocybin. Ketanserin, a 5-HT2A antagonist with additional affinity for adrenergic α1A and histamine H1 receptors, reliably prevents the subjective effects of psychedelics when given before dosing, but it is unknown whether ketanserin can attenuate or shorten an LSD experience once the psychedelic effects are already established. The question is clinically relevant because a safe, effective antagonist could shorten long sessions or serve as an emergency rescue medication for intolerable acute effects. Becker and colleagues therefore tested the predefined hypothesis that oral ketanserin (40 mg) administered 1 hour after oral LSD (100 µg) would shorten the subjective response to LSD. The primary outcome was the duration of the subjective effect as measured by a visual analogue scale (VAS) for “any drug effect.” Secondary measures included other subjective scales, autonomic measures, plasma biomarkers (BDNF), and pharmacokinetic assessments to examine whether ketanserin’s effects occur despite continued systemic presence of LSD.

The investigators used a randomized, double-blind, placebo-controlled, crossover design with two 14-hour experimental sessions per participant. In each session subjects received oral LSD (nominally 100 µg; analytically confirmed mean content ~92.5 µg) at 09:00 and, one hour later (10:00), either oral ketanserin 40 mg or matching placebo. Treatment order was randomised and counterbalanced; sessions were separated by at least 10 days (mean 23 days). Participants and investigators were blinded and a double-dummy method was used; participants were asked to guess treatment assignment at the end of sessions. Twenty-four healthy participants completed the study (12 women, 12 men; mean age 34 ± 12 years, range 25–64). Exclusion criteria included pregnancy, major personal psychiatric disorders or a first-degree family history of psychosis, current use of interfering medications (e.g., antidepressants, antipsychotics, sedatives), significant physical illness, heavy smoking (>10 cigarettes/day), lifetime hallucinogen use > 20 times, and recent illicit drug use. Participants were instructed to limit alcohol and were monitored by urine drug tests; eleven had prior hallucinogen experience and three had previously used LSD 1–2 times. Subjective effects were assessed repeatedly by VAS (including an “any drug effect” item) at baseline and multiple post-dose timepoints (0.5, 1, 1.5, 2, 2.5 h and additional times), with onset, tmax (time to maximal effect), offset and effect duration defined on individual effect–time plots using a 10% of individual maximum threshold. Additional instruments included the Adjective Mood Rating Scale (AMRS) at 3, 6, 9, 12 h, the 5D-ASC (12 h) with its 3D-OAV total, and the States of Consciousness Questionnaire including MEQ30 (12 h) for mystical-type experiences. Autonomic measures (blood pressure, heart rate, tympanic temperature, pupil size) were recorded repeatedly; adverse effects were documented using the List of Complaints. Plasma brain-derived neurotrophic factor (BDNF) was measured at baseline and 6, 9, and 12 h. Plasma concentrations of LSD and its metabolite O‑H‑LSD, and ketanserin, were measured up to 12 h and non-compartmental pharmacokinetic parameters were estimated. The primary endpoint was the duration of the subjective response on the VAS “any drug effect.” Peak effects (Emax), peak change from baseline (ΔEmax) and area under the effect curve (AUEC) were computed for repeated measures and compared between LSD+ketanserin and LSD+placebo using paired two-sided t-tests. Analyses were conducted in RStudio, significance set at p < 0.05, and no correction for multiple testing was applied because outcomes were predefined. A priori power calculations indicated >16 subjects were required for the primary endpoint; the sample of 24 aimed to provide additional power for secondary, more exploratory analyses.

Primary outcome: ketanserin markedly shortened the duration of the subjective LSD response. Mean duration of “any drug effect” was reduced from 8.5 h in the LSD+placebo condition to 3.5 h in the LSD+ketanserin condition, a reduction of approximately 60%, and this difference was statistically significant. The peak magnitude (Emax) of LSD’s effect was not significantly reduced by ketanserin, but reductions in mean VAS ratings were apparent from 2 h after LSD administration and thereafter. Subjective secondary outcomes: ketanserin substantially reduced AUEC values (60–70% reductions) for multiple LSD-typical subjective effects, including “good drug effects,” stimulation, auditory and visual alterations, synesthesia, alterations in time perception, ego-dissolution and nausea. On the AMRS, ketanserin reversed LSD-induced changes in introversion, emotional excitation and concentration. On the 5D-ASC, ketanserin reduced the 3D-OAV and the 5D-ASC total scores relative to placebo. By contrast, ketanserin did not significantly alter the MEQ30 total score (mystical-type experiences) produced by LSD in this study. Autonomic and adverse effects: ketanserin reduced the overall (AUEC) LSD-induced elevations in blood pressure and rate–pressure product but did not significantly change peak autonomic responses. Ketanserin reversed LSD-induced mydriasis (pupil dilation). On the List of Complaints there was no significant difference in acute adverse effects between conditions; the most commonly reported complaints within 12 h were fatigue, lack of concentration and lack of energy, with similar counts across conditions. Notably, VAS ratings of tiredness were significantly lower in the ketanserin condition. BDNF: LSD increased peak plasma BDNF levels compared with baseline in both conditions, and ketanserin given after LSD did not attenuate this LSD-associated increase in BDNF. Pharmacokinetics: ketanserin did not alter the pharmacokinetics of LSD or O‑H‑LSD. Mean time to maximal plasma concentration of LSD was approximately 2 h in both conditions. Plasma ketanserin concentrations typically reached a maximum at a median of 2 h (range 1–5 h) and declined with an apparent half-life of about 3.5 h. Reported pharmacokinetic parameters and concentration–time curves are provided in the paper’s tables and figures.

Becker and colleagues interpret the findings as evidence that the acute subjective and some autonomic effects of LSD in humans are predominantly mediated by the 5-HT2A receptor and can be reversed even after effects are established. Administering ketanserin 40 mg orally 1 h after LSD 100 µg produced a rapid and substantial reduction in effect duration (from ~8.5 h to ~3.5 h) and lowered overall exposure to subjective effects as indexed by AUEC, while not substantially lowering the peak effect. The authors note that reversal occurred within about 2.5 h after ketanserin dosing and that intravenous administration would likely produce faster antagonism. The differing impact of ketanserin on questionnaire measures is discussed: the 5D-ASC and VAS AUEC (measures of overall response over time) were reduced, whereas the MEQ30 (which the authors suggest primarily reflects peak response) was not significantly changed. This pattern is offered as a possible explanation for why ketanserin diminished integrated measures of LSD response but left some peak-related mystic-type scores intact. Clinical and mechanistic implications are considered. The investigators suggest ketanserin could be used to shorten planned LSD sessions or serve as a rescue medication in cases of acute intolerance, potentially enabling LSD regimens of adjustable duration; timing of antagonist administration could modulate total experience length. The observation that ketanserin did not prevent LSD-induced increases in plasma BDNF leads the authors to propose that neuroplasticity-related effects may be mediated by mechanisms at least partly independent of 5-HT2A receptor activation, raising the question whether blocking the acute subjective experience would preclude longer-term therapeutic effects. Preclinical data are cited to indicate some synaptic/antidepressant-like effects can persist despite 5-HT2A antagonism, but the authors emphasise that whether therapeutic effects are retained in humans when the psychedelic response is blocked remains unknown and requires investigation. Safety and tolerability: known ketanserin adverse effects include sedation and hypotension, but in this study adverse reports were limited (only two participants reported nasal congestion attributable to ketanserin) and measures of tiredness and concentration improved under ketanserin, consistent with its antagonism of LSD effects. Blood-pressure lowering observed could reflect both ketanserin’s direct effects and reversal of LSD-induced elevations; the authors state they cannot fully disentangle these contributions. Strengths and limitations noted by the investigators include the randomised, double-blind, placebo-controlled crossover design, GMP-manufactured LSD, and within-subject comparisons as strengths. Limitations are the absence of a true LSD-placebo (i.e., non-LSD) control arm, the enrolment of healthy volunteers only, testing a single LSD dose (100 µg), and the fixed timing of ketanserin administration at 1 h post-LSD, which may not generalise to later antagonist use. The authors conclude that ketanserin can shorten or reverse the acute LSD response and may be useful as a planned adjunct or emergency rescue treatment in psychedelic-assisted therapy, while recognising open questions about the relationship between the subjective experience and any longer-term therapeutic effects.