Contrary to popular belief, a study conducted by researchers at Johns Hopkins Medicine revealed that relatively high doses of CBD may exacerbate the negative effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis that can alter mood or produce a “high” feeling. The results indicate that CBD in edible cannabis products prevents THC from being broken down or metabolized, which could lead to more potent and prolonged pharmacological effects.
The study’s findings, which were released on February 13 in JAMA Network Open, showed that, despite the same 20 mg of THC in each brownie, the maximum amount of THC detected in participants’ blood samples was nearly twice as high after consuming a brownie containing THC with CBD as after consuming a brownie with only THC. Furthermore, after consuming the brownie with the high CBD extract as opposed to the one with the high THC extract, there was a 10-fold increase in the maximum amount of 11-OH-THC, a metabolic byproduct of THC that produces drug effects similar to THC.
The study compared the effects of cannabis extracts with varying concentrations of THC and CBD on pharmacokinetics—the body’s process of absorbing and eliminating drugs—and pharmacodynamics—the body’s reaction to a drug.
Lead author of the study Austin Zamarripa, Ph.D., a postdoctoral research fellow at the Johns Hopkins University School of Medicine, says, “The fact that THC and CBD were administered orally was essential for the study, and played a large role in the behavioral effects and drug interactions we saw.”
In controlled human studies assessing these interactions, THC and CBD were primarily administered intravenously or by inhalation, or not at the same time. Since the intestine and liver metabolize edible cannabis products like baked goods, candies, and gummies, a large portion of the data currently available regarding interactions between THC and CBD may not apply to them.
“When the same dose of THC was given in a high CBD cannabis extract, compared with a high THC extract with no CBD, we saw stronger subjective drug effects, greater impairment of cognitive [thinking] and psychomotor [moving] ability, and greater increase in heart rate,” notes Zamarripa.
What Does The New Study Reveals?
The new study was carried out from January 2021 to March 2022 at the Behavioral Pharmacology Research Unit at Johns Hopkins Bayview Medical Center. Rather than using different subjects for each drug type, the study tested each type of cannabis extract and placebo within the same subjects. Eighteen adult participants—seven women and eleven men—who had abstained from cannabis use for at least thirty days were chosen by the researchers to participate in the study.
The study participants’ three sessions were spaced out by at least a week. Participants ate a brownie containing 20 mg of THC, 20 mg of THC, and 640 mg of CBD, or no THC or CBD (placebo) during each session. The ingredients of the brownie consumed during a particular session were unknown to the participants and investigators beforehand. Thirty minutes after consuming each brownie, participants were also given a drug cocktail that included five cytochrome (CYP) probe drugs: 100 mg caffeine, 25 mg losartan, 20 mg omeprazole, 30 mg dextromethorphan, and 2 mg midazolam.
These medications will assist the scientists in determining the effects of THC and CBD on participants’ bodies’ metabolism of dietary supplements and other commonly used medications (in analyses that will be published separately).
Prior to each session, baseline blood samples, vital signs (heart rate and blood pressure), and assessments of cognitive and psychomotor function were taken from every participant in order to establish a baseline for comparison. After completing the drug dosage, participants gave blood and urine samples at scheduled intervals for 12 hours, and then once more around 24 hours later. The Drug Effect Questionnaire (DEQ), a standardized instrument used to evaluate various aspects of subjective experiences following the administration of a psychoactive drug such as THC or cannabis, was used to measure self-reported drug effects.
There were significant differences between the two extracts, even though participants experienced the usual effects of cannabis with both the THC and CBD extracts. These differences are probably due to the increased concentration of THC and 11-OH-THC in the blood following the consumption of the CBD extract.
Participants scored subjective drug effects on a 0–100 scale, where 0 represented “not at all affected” and 100 represented “extremely affected,” using the DEQ tool. Subjective ratings showed that participants experienced higher increases in feeling sick (12 [THC] vs. 26 [THC + CBD]), dry/red eyes (16 [THC] vs. 29 [THC + CBD]), overall drug effects (59 [THC] vs. 73 [THC + CBD]), and difficulty performing routine tasks (30 [THC] vs. 47 [THC + CBD]). Compared to when they ate the brownie with the high THC extract, participants’ performance on tests of memory and attention was noticeably worse after consuming the brownie with the high CBD cannabis extract.
Heart rate increased more after consuming the high CBD extract brownie, going from a baseline increase of 10 beats per minute [THC] to a baseline increase of 25 beats per minute [THC + CBD]. Neither the performance on any cognitive or psychomotor tasks nor the subjective drug effect ratings were affected by the placebo brownie.
Senior author of the study Ryan Vandrey, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, says, “We have demonstrated that there can be significant metabolic interactions between THC and CBD, such that the THC effects are stronger, longer-lasting, and tend to reflect an increase in unwanted adverse effects] with a relatively high oral dose of CBD [640 mg].
Vandrey mentioned that incorrect labeling of CBD products was discovered in another recent study conducted by his team. Our new research indicates that “people should be aware that taking a high-dose CBD extract may cause interactions with other medications.” If a person is also taking CBD, they should talk to their doctor about whether they should think about adjusting the dosage of THC and other medications, according to Vandrey.
Future research, according to the researchers, is required to fully comprehend the effects of THC and CBD dosage, relative concentrations, usage frequency, and individual health variations on how our bodies metabolize prescription drugs. In order to support clinical and regulatory decision-making about the therapeutic and nontherapeutic use of cannabis products, this kind of research is required.
Zamarripa and Vandrey were not the only researchers who contributed to the study: Mary F. Paine from Washington State University and the Center of Excellence for Natural Product Drug Interaction Research; Jashvant D. Unadkat from the University of Washington and the Center of Excellence for Natural Product Drug Interaction Research; Tory Spindle, Renuka Surujunarain, and Elise Weerts from the Johns Hopkins University; and Sumit Bansal from the University of Washington.
The National Center for Complementary and Integrative Health of the National Institutes of Health, namely the National Institute on Drug Abuse (T32 DA007209, and P01 DA032507) and the Center of Excellence for Natural Product Drug Interaction Research (U54 AT0008909), provided funding for this study.
Vandrey has received compensation for her services as a scientific advisory board member or consultant for the following companies: Radicle Science Inc., MyMD Pharmaceuticals, Syqe Medical, WebMD, MyMD Pharmaceuticals, and Canopy Health Innovations. Spindle has worked as Canopy Health Innovations’ paid consultant. Weerts has agreements with MyMD Pharmaceuticals and Mira Pharmaceuticals to fund preclinical research. The other writers have disclosed no conflicts of interest.
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