High-Dose CBD Made Oral THC Effects Stronger in a Small Johns Hopkins Trial
A small randomized clinical trial from Johns Hopkins University found that a high dose of cannabidiol (CBD) substantially increased the amount and effects of orally consumed delta-9-tetrahydrocannabinol (THC). The findings, published in JAMA Network Open in 2023, suggest that CBD can inhibit the body’s breakdown of edible THC—but they do not establish that cannabinoids generally produce an “entourage effect.”
The study included 18 healthy adults—11 men and seven women—who had not used cannabis for at least 30 days before testing. Each participant attended three sessions at the Johns Hopkins Behavioral Pharmacology Research Unit in Baltimore between January 2021 and March 2022. The within-participant, double-blind design allowed researchers to compare the same people’s responses under different conditions.
During the sessions, participants ate one of three brownies: a placebo with no cannabinoids, a brownie containing 20 milligrams of THC, or a brownie containing the same 20-milligram THC dose plus 640 milligrams of CBD. The sessions were separated by at least one week.
Researchers collected blood and urine samples for approximately 24 hours and monitored vital signs, subjective drug effects, memory, attention and psychomotor performance. Participants also received a five-drug cytochrome P450 testing cocktail to help researchers assess how the cannabinoids affected drug-metabolizing enzymes.
When THC was combined with 640 milligrams of CBD, the peak THC concentration in the blood was almost twice as high as it was after THC alone. The peak concentration of 11-hydroxy-THC—an active THC metabolite produced during digestion—was approximately 10 times higher with the CBD-containing brownie.
The pharmacokinetic differences were accompanied by stronger reported effects. Compared with the THC-only brownie, the THC-and-CBD combination produced higher ratings for overall drug effects, unpleasant effects, feeling sick, dry or red eyes, memory impairment and difficulty carrying out routine tasks. Participants also performed worse on several measures of memory, attention and psychomotor function.
Heart rate increased by an average of about 10 beats per minute after the THC-only brownie and about 25 beats per minute after the combination brownie. The placebo did not produce meaningful changes in subjective effects or cognitive performance.
The results are consistent with a pharmacokinetic explanation: at the dose used in this experiment, CBD appears to have slowed the metabolism of THC and 11-hydroxy-THC, allowing more of these compounds to remain in the bloodstream. That is different from proving the broader claim that cannabinoids always work better—or more strongly—when consumed together.
The dose of CBD was also unusually high. A 640-milligram oral dose is not representative of many commercial CBD products, so the findings should not automatically be applied to lower-dose CBD products, inhaled cannabis or other ratios of THC to CBD. The small sample, short-term design and focus on infrequent cannabis users further limit how broadly the results can be generalized.
The study also raises a potential medication-safety concern. Because CBD can affect drug-metabolizing enzymes, it may alter the effects of some prescription or over-the-counter medicines. The U.S. Food and Drug Administration’s consumer guidance on CBD advises caution about interactions and recommends discussing CBD use with a health professional.
For consumers, the practical takeaway is that adding CBD to an edible should not be assumed to make THC milder. In this controlled study, a high oral dose of CBD made the THC experience stronger, longer-lasting and more impairing. Further research is needed to determine how the interaction changes with different doses, cannabinoid ratios, delivery methods and patterns of cannabis use.
