For years, the working assumption in cannabis science has been simple: women are more sensitive to THC. A new controlled trial on cannabis smoking, sex differences and pharmacokinetics turns that assumption on its head. When researchers at UCLA matched men and women by how often they use cannabis, the group that reacted most strongly to a joint was not women at all, but men who smoke only occasionally. They felt higher, more sedated, more anxious and had faster heart rates, even though their blood THC levels were no higher than anyone else’s.
The study, by Stephanie Lake, Ziva Cooper and colleagues, was published online at the end of October 2026 in Neuropsychopharmacology under the title Sex- and frequency-dependent acute pharmacokinetic and pharmacodynamic effects of smoked cannabis: a randomized controlled trial. It is open access, and the trial is registered as NCT04385082 on ClinicalTrials.gov. Pharmacokinetics describes what the body does to a drug: how fast THC reaches the blood, how high it peaks and how it is broken down. Pharmacodynamics is the other side: what the drug does to you, from the “high” to a racing pulse. This trial measured both at once.
Key Takeaways
In a randomized, double-blind, placebo-controlled crossover trial, 44 healthy adults (22 women and 22 men) smoked cannabis containing 0%, 4% or 10% THC on three separate days, and were split by sex and by how often they use cannabis: more than four days a week or four days or fewer. Among occasional users, men reported stronger intoxication at 4% THC, more sedation and impairment, more anxious and unpleasant feelings and a larger rise in heart rate than occasional-use women, even though their peak blood levels of THC and its active metabolite 11-hydroxy-THC were similar. Frequent users, regardless of sex, liked the cannabis more, wanted it again more and chose to smoke extra puffs more often, which the authors read as a sign of higher misuse liability tied to frequency rather than to sex. The highest blood THC levels were seen in frequent-use men. Many of these findings came from exploratory follow-up tests in a small sample, so they are signals that need replication, not settled facts.
Cannabis Smoking and Sex Differences in THC Pharmacokinetics: How the Trial Worked
The research was carried out at the Cannabis and Cannabinoid Research Laboratory at the University of California, Los Angeles. Participants were community-recruited healthy adults aged 21 to 55 who had used cannabis at least twice in the month before screening. Each sex group included 12 frequent users (more than four days a week) and 10 occasional users (four days a week or fewer). The authors note that the four-day cut-point matches how major US surveys define daily or near-daily use.
Every volunteer came in for three six-hour sessions, at least 48 hours apart, and smoked a different strength each time in random order. Neither the participants nor the staff running the sessions knew which cigarette was which. The cannabis came from the National Institute on Drug Abuse. In each session participants smoked about 560 mg of a cigarette weighing roughly 800 mg in total, which at 0%, 4% and 10% THC works out to approximately 0, 20 and 60 mg of THC.
To stop people from simply smoking harder or faster, the researchers used a paced puffing routine: inhale for 5 seconds, hold for 10, exhale for 5, then rest for 40 seconds, and repeat until the set amount had burned. Volunteers were asked to avoid cannabis for 21 hours before each session and arrived without breakfast, which was then provided in a standardized form.
Two design choices set this trial apart from earlier work. First, it recruited men and women in equal numbers and balanced them by use frequency from the start, instead of pooling leftover data from older studies. Second, it controlled for hormones. Female participants were regularly cycling, did not use hormonal birth control, and were tested only during the mid-to-late follicular phase of the menstrual cycle, a window of high estradiol and low progesterone that blood tests confirmed. Animal research had suggested that estradiol is when females would be most sensitive to THC, so this was deliberately the toughest test of the “women are more sensitive” idea.
What Was Measured: From “Feeling High” to Blood THC and 11-Hydroxy-THC
Before and repeatedly after smoking, participants rated 44 mood and body sensations on a 100 mm visual scale, from “not at all” to “extremely”. The researchers grouped these into clusters such as relaxed positive feelings, energetic positive feelings, dysphoric arousal (anxious, miserable) and sedation or impairment (sedated, difficulty concentrating). A separate form asked how strong the effect felt, whether it felt good or bad, whether they liked it and whether they wanted to take it again.
At 165 minutes after smoking, volunteers could spend their own study earnings on one to three extra puffs of the same cannabis, at $1 per puff. This self-administration task is a standard laboratory way to gauge how rewarding a drug is.
Blood was drawn at baseline and six times after smoking, and plasma was analyzed for THC and its two main breakdown products. The first, 11-hydroxy-THC (11-OH-THC), is itself psychoactive. The second, THC-COOH (11-carboxy-THC), is inactive but lingers much longer, which is why it is the usual target of drug tests. Heart rate, blood pressure and temperature were tracked at the same points.
The Surprise: Occasional Male Users Reacted Most Strongly
Active cannabis, as expected, raised the feeling of being high and relaxed positive feelings compared with placebo. The interesting part was who reacted most.
At the 4% THC strength, occasional-use men rated their high 32.3 mm higher on the 100 mm scale than occasional-use women (95% CI: 9.8 to 54.9) and 29.2 mm higher than frequent-use men (95% CI: 7.5 to 50.8). Sedation and impairment rose above placebo only in the occasional group, and in a sex-split exploratory analysis only in occasional-use men, with an increase of 22.3 mm at 4% THC (95% CI: 13.5 to 31.1). The same pattern held for dysphoric arousal, which rose by 20.4 mm at 4% THC in occasional-use men (95% CI: 13.0 to 27.8) and in no other group. Ratings of a “bad effect” mirrored that finding.
The body told the same story. In the model adjusted for blood THC levels, heart rate increased under active cannabis only in the occasional group, by 20.4 beats per minute at 4% THC (95% CI: 7.0 to 33.8). When split by sex, this rise was confined to occasional-use men, at 32.5 beats per minute (95% CI: 15.6 to 49.4). So yes, smoking cannabis can raise heart rate, and in this trial the biggest jumps came in the people least used to it.
What makes this striking is that occasional-use men did not carry more THC in their blood. Their peak plasma THC and 11-OH-THC were similar to those of occasional-use women. Something other than the amount of drug reaching the bloodstream was driving the difference.
Frequent Users: More THC in the Blood, Less Felt, More Wanted
Tolerance is the body’s way of turning down the volume on a drug it meets often. A useful image is a smoke alarm in a kitchen where someone cooks every day: eventually the household stops reacting to every beep. In this trial, frequent users showed exactly that kind of muted response to the unpleasant effects, yet they had the most THC in their blood.
At 4% THC, the frequent-use group reached a peak plasma THC level 42.3 ng/mL higher than the occasional group (95% CI: 8.9 to 75.7). Within the frequent group, men peaked 57.1 ng/mL higher than women (95% CI: 9.8 to 104.3), a finding from exploratory follow-up. For 11-OH-THC, men had higher levels than women and frequent users had higher levels than occasional users, again concentrated at the 4% strength.
The difference was visible even before anyone lit up. At baseline, frequent-use women had a plasma THC level of 6.6 ng/mL against 2.0 ng/mL in occasional-use women. Occasional-use men had undetectable baseline 11-OH-THC across all sessions, compared with 1.3 ng/mL in occasional-use women, and their baseline THC-COOH was 3.7 ng/mL against 34.1 ng/mL in frequent-use men. Those leftovers from regular use are a reminder of how long THC and its metabolites can stay in the system.
The reward side ran in the opposite direction from the unpleasant effects. Across the sample, 9 participants (20.5%) chose extra puffs of placebo, 10 (22.7%) of 4% cannabis and 15 (34.1%) of 10% cannabis. Among frequent users, self-administration climbed with strength, from 20.8% at 0% THC to 37.5% at 4% and 54.2% at 10%. Among occasional users there was no such climb, and the placebo was actually the most chosen option, at 20%. Frequent users also showed rises over placebo in liking the effect and wanting to take it again, and none of these patterns depended on sex.
This fits earlier evidence. A 2009 study by Ramaekers and colleagues in the Journal of Psychopharmacology found certain THC-related cognitive impairments in occasional but not heavy users, despite serum THC concentrations more than 50% lower in the occasional group, as the UCLA authors point out. More THC in the blood, it turns out, does not straightforwardly mean more impairment, a theme we have also covered in our piece on whether doubling your THC dose gets you higher.
Why This Contradicts Earlier Research on Women and Cannabis
Rodent studies have long pointed to females being more sensitive to THC’s rewarding effects and developing tolerance faster, possibly because of estradiol and because female animals produce more 11-OH-THC. Human studies, though, have been mixed. A 2023 analysis by the same UCLA group in Addiction Biology found signs of greater sensitivity in women who smoked cannabis near-daily, while a laboratory study of young adults led by Justin Matheson, published in Psychopharmacology, found few sex differences overall, with women smoking less of the cigarette. A preprint from the Centre for Addiction and Mental Health, posted on Research Square in May 2026 and not yet peer reviewed, also reported a lack of consistent sex differences across several THC potencies.
The new trial adds a missing variable: how often people use. The authors suggest that men and women may cross the threshold into tolerance at different levels of use. In plain terms, women using “only” up to four days a week may already have built up more tolerance than men with the same habits. The paper also offers simpler alternatives. The occasional-use women in this sample were slightly older and had been using cannabis for more years, which could also explain their calmer response. And if their muted reaction were purely about tolerance, they might have been expected to like and want the cannabis more, which they did not.
One more twist concerns dose. On most measures, the 10% cigarette did not produce a bigger effect than the 4% one. The likely reason is self-titration: people unconsciously take smaller or more diluted puffs of stronger cannabis. The 10% cigarettes needed more puffs to finish, 12.4 against 7.8, despite the fixed puffing routine.
Limitations: A Small Trial With Many Exploratory Findings
This is a well-designed study, but it is a small one, and the authors are frank about that. With 44 people split into four groups, the trial had roughly 80% power to detect moderate effects of cannabis itself (Cohen’s d of 0.40 or more), but needed much larger effects to reliably detect two-way (d of 0.70 or more) and three-way (d of 1.0 or more) interactions. Most of the sex-specific findings, including those on the high, sedation, heart rate and blood THC in frequent-use men, came from an exploratory follow-up protocol. The researchers did not apply corrections for multiple comparisons, so some of these results could be false positives.
There are other caveats. The cannabis strengths of 4% and 10% THC are far below what US dispensaries typically sell, where flower often tests at 20% THC or more, according to an analysis of 30 million sales in Washington state. Only peak values were analyzed in detail, puff volume was not measured, and the extra-puff choice had to be reduced to a simple yes or no because most people picked either zero or three puffs. Occasional-use men also had a lower body mass index than frequent-use men (22.5 against 26.5 kg/m²), though adjusting for it did not change the findings. Finally, “occasional” here still meant up to four days a week, so true first-timers were not studied.
The work was funded by the US National Institutes of Health. The senior author declares, outside this work, receiving study drug from cannabis companies and grant funding from several public bodies, and is an associate editor of the journal.
What It Means for THC Blood Levels, Driving and Use Disorder
The findings matter beyond the lab, starting with the roads. Several US states judge cannabis-impaired driving partly by a fixed concentration of THC in the blood. This trial shows how weak that link can be: the people with the most THC on board were among the least impaired by their own account, while those with less THC reported the most sedation and impairment. Plasma values measured in a lab are also not directly comparable with the whole-blood figures used in law, so the numbers in this study cannot be read against legal limits.
The second lesson concerns use disorder. Frequency of use is one of the strongest known predictors of cannabis use disorder, and the authors cite data showing daily or near-daily use carries a 19% higher risk than use one to four days a week and a 28% to 32% higher risk than less frequent use. In this trial, frequent users of both sexes were the ones who liked cannabis more and chose to keep smoking, a pattern consistent with our coverage of weekly THC thresholds linked to addiction risk. Sex still matters on the treatment side, as a trial of varenicline for cannabis use disorder suggested.
Context also matters. Women have historically used cannabis less than men, but the gap has narrowed. The study cites the UN estimate of about 244 million cannabis users worldwide in 2023, and the latest UNODC global cannabis figures put the number higher still. Men and women also tend to consume differently, with men favoring smoking and women more often choosing edibles and topicals, as a federal survey on gender differences in marijuana use showed. Since this trial looked only at smoked cannabis, its findings cannot be stretched to edibles, vapes or concentrates.
The take-home message is less a rule than a correction: sex alone does not predict how strongly someone will react to smoked THC. Sex combined with use history may, and science is only beginning to map how the two interact.
FAQ
Yes. In this trial, active cannabis raised heart rate compared with placebo, but the rise was clear only among occasional users, at 20.4 beats per minute at 4% THC. When the researchers looked at men and women separately, the jump was concentrated in occasional-use men, at 32.5 beats per minute. Frequent users showed a much smaller response, consistent with tolerance to some of THC’s effects on the body.
11-hydroxy-THC is the main active metabolite the liver makes from THC. Unlike THC-COOH, the inactive metabolite that drug tests usually look for, 11-hydroxy-THC is psychoactive in its own right. Animal studies suggested females produce more of it, but in this human trial men had higher levels than women, and frequent users higher levels than occasional users.
There is no single answer, because tolerance depends on how much and how often someone uses, and possibly on sex. This trial did not track tolerance over time; it compared people who already used more or less than four days a week. Those using more often felt fewer unpleasant effects and less impairment despite having more THC in their blood. The authors suggest that men and women may reach tolerance at different levels of use, which still needs to be tested.
Not necessarily, and the rules differ by state. Several states set a per se limit, a THC concentration in blood above which driving is illegal regardless of behavior, for example 5 ng/mL in Washington and Montana, 2 ng/mL in Nevada and Ohio and 1 ng/mL in Pennsylvania. Colorado treats 5 ng/mL as a permissible inference that a driver can challenge, some states have zero-tolerance rules, and others, including California and New York, require proof of actual impairment. Because regular users can carry measurable THC long after the effects fade, these limits remain scientifically contested. Driving under the influence of cannabis is illegal in every state.
Legal Disclaimer
This article is for informational and educational purposes only and does not constitute medical, legal or professional advice. It summarizes published scientific research and does not recommend the use of cannabis or any cannabis product. Cannabis laws vary by country and by US state, and the federal legal status of cannabis in the United States has been changing; readers are responsible for knowing the laws that apply to them. Cannabis can impair judgment, reaction time and coordination, and should never be used before driving or operating machinery. Anyone considering cannabis for health reasons, or concerned about their own use, should speak with a qualified healthcare professional.
