Sex- and frequency-dependent acute pharmacokinetic and pharmacodynamic effects of smoked cannabis: a randomized controlled trial
Stephanie Lake, Elisa Pabon, Samantha L Baglot, Alisha Eversole, Conor H. Murray, Katherine E. Hampilos, Timothy W. Fong, Holly R. Middlekauff, Margaret Haney, Suzette M. Evans, Adren Tran, Alexa Torrens, Daniele Piomelli, Ziva D. Cooper
Neuropsychopharmacology October 29, 2026 DOI: 10.1038/s41386-026-02571-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blind, placebo-controlled crossover study Peer reviewed |
|---|---|
| Sample size | 44 |
| Population | Adults who smoke cannabis, 22 female, balanced by use frequency (more than 4 vs. 4 or fewer days/week) |
| Interventions | 0% 4% |
| Dose | 0% (~0 mg) THC, 4% (~20 mg) THC, 10% (~60 mg) THC |
| Topics | Cannabis |
| Key points | Active cannabis increased subjective effects and plasma THC/metabolites versus placebo. Exploratory analyses indicated frequent users showed greater misuse-related ratings and self-administered more cannabis than occasional users, without modification by sex, while occasional-use males reported higher 'High', sedation/impairment, dysphoric arousal, and 'Bad effect' at active strengths. The authors state these results contrast with prior evidence of greater female sensitivity and point to sex-dependent exposure thresholds for tolerance. |
Abstract
Cannabis use is rising among women. Studies suggest females are more sensitive to the intoxicating and misuse-related effects of delta-9-tetrahydrocannabinol (THC). While preclinical studies point to sex-specific development of tolerance, this has not been translated to humans. In this randomized, double-blind, placebo-controlled crossover study, 44 participants (22 F) smoked three cannabis strengths (0% [~0 mg] THC, 4% [~20 mg] THC, 10% [~60 mg] THC), provided blood for plasma analysis, and completed subjective mood and drug effects assessments and a self-administration task. Outcomes were analyzed by cannabis strength, sex, and use frequency ( > 4 vs. ≤4 days/week; balanced across sex). Relative to placebo, active cannabis strengths increased subjective effects and plasma THC and metabolites (ps < 0.05). Exploratory follow-up of interactions (cannabis strength*frequency p < 0.10) showed the frequent-use group exhibiting significant increases from placebo in misuse-related ratings ("Like", "Take again") and self-administering more cannabis than the occasional-use group (ps < 0.05), and this was not modified by sex. Ratings of "High", Sedation/impairment, Dysphoric arousal, and "Bad effect" were higher at active strengths for occasional-use males relative to sex- and/or frequency-matched counterparts (ps < 0.05; via exploratory follow-up for "High" and Sedation/impairment). THC and metabolites tended to be highest in frequent-use males. These findings contrast with previous evidence of greater cannabis sensitivity among females and point toward future investigation into sex-dependent exposure thresholds for tolerance development/escalation. Sex and frequency of use are both implicated in cannabis use disorder risk, and consideration of their interaction is critical in characterizing the acute effects of, and tolerance to, cannabis.
Comparable studies
Other randomized controlled trials on cannabis, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment Healthy participants | 2012 | Randomized controlled trial | n = 48 |
| Distinct Effects of Δ9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing Healthy, English-native, right-handed men who had used cannabis 15 times or less in... | 2009 | Double-blind, randomized, placebo-controlled crossover trial | n = 15 |
| Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers Healthy male subjects | 2012 | Randomized controlled trial | n = 16 |
| Modulation of Mediotemporal and Ventrostriatal Function in Humans by Δ9-Tetrahydrocannabinol Healthy, native English-speaking, right-handed men of white race/ethnicity who had used... | 2009 | Randomized controlled trial | n = 15 |
| Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition Healthy volunteers with a history of light cannabis use | 2019 | Randomized, double-blind, within-subjects crossover | n = 14 |
Citations in the library
Cites 15
- Sex differences in acute cannabis effects revisited: Results from two randomized, controlled trials Addiction Biology December 22, 2021
- Sex differences in the acute effects of oral THC: a randomized, placebo-controlled, crossover human laboratory study. Psychopharmacology October 1, 2024
- Sex Differences in the Safety and Subjective Effects of Two Oral Δ9-Tetrahydrocannabinol-Containing Cannabis Products over Multiple Doses Among Healthy Adults. Cannabis and Cannabinoid Research August 2024
- Sex differences in the acute effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC). Psychopharmacology May 2022
- Pharmacokinetic and pharmacodynamic properties of aerosolized ("vaped") THC in adolescent male and female rats. Psychopharmacology December 2021
and 10 more in the library