By Alexander Beadle
Published: Feb 17, 2023
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Relatively high doses of CBD in edibles may increase the intoxicating and adverse effects of THC, a new study suggests.
Published in JAMA Network Open, researchers from the University of Washington and the Johns Hopkins School of Medicine found that individuals given brownies containing high doses of CBD experienced stronger subjective effects than those given brownies made from a THC-dominant strain, despite both edibles containing the same dose of THC.
At first, this finding might appear to contradict previous work, which has suggested that CBD works as a buffer for some of THC’s acute effects. However, the researchers behind this new trial believe that this discrepancy may be down to the fact that their study used edible cannabis products, while most other research has focused on inhalable cannabis or other methods of administration.
Edibles feel stronger when they have high CBD
This new randomized clinical trial involved 18 participants who took part in three distinct experimental sessions, each separated by at least one week. At each session, the participant was given a brownie that had been made with either a THC-dominant extract, a CBD-dominant extract, or a placebo containing neither cannabis compounds. In the case of the cannabis brownies, the THC doses in each brownie were both around 20 milligrams (mg); the CBD-dominant brownies also contained an additional 640 mg of CBD.
Before and at regular intervals lasting up until 24 hours after eating the brownies, participants completed questions from the standardized Drug Effect Questionnaire (DEQ), which asked them to rate various effects on a 0-to-100 effect scale. Specifically, participants were asked to rate the overall subjective drug effects, positive effects, negative or adverse effects, and any perceived impairment.
Participants then completed three computerized tasks that aimed to independently assess any impact on their cognitive performance and memory. Participants’ vital signs, such as their heart rate, were also monitored throughout.
The researchers found that participants consistently reported greater increases on the 0-100 drug effects scale after eating the high-CBD brownie, compared to the THC brownie, despite both containing the same amounts of THC.
Participants also reported higher ratings of unpleasant drug effects, feeling sick, dry eyes, and difficulties performing routine tasks after eating the high-CBD brownie. Their heart rates also slightly increased and their performances in the three computer tasks were also lower when given the high-CBD brownie compared to the others.
“Overall, we saw stronger subjective drug effects, greater impairment of cognitive [thinking] and psychomotor [moving] ability and greater increase in heart rate when the same dose of THC was given in a high CBD cannabis extract, compared with a high THC extract with no CBD,” lead author Austin Zamarripa, a postdoctoral research fellow at the Johns Hopkins University School of Medicine, said in a statement.
CBD may influence the metabolism of THC from edibles
Evidence from other clinical studies has shown that CBD and THC are capable of interacting with other drugs, and each other, through the inhibition of cytochrome P450 (CYP) enzymes.
Knowing this, the researchers behind this new clinical trial also asked participants 30 minutes after consuming the brownie to take an oral cocktail of five CYP probe drugs: caffeine, omeprazole, losartan, dextromethorphan, and midazolam. Participants provided blood samples before and after eating the brownies, which were analyzed with the aim of identifying any potential cannabinoid-drug interactions with these other drugs. The maximum concentrations of THC and its active metabolite 11-OH-THC in the blood were also assessed.
The researchers found that the peak levels of THC in the blood samples measured nearly twice as high after consuming the high-CBD brownie, compared to the brownies made from the THC-dominant extract. In addition, the peak level of 11-OH-THC, the metabolic byproduct of THC, which is also responsible for strong intoxicating effects, was a staggering 10-times greater.
In their paper, the researchers stated that the pharmacokinetic modeling and simulations resulting from this CYP drug cocktail analysis will be described in a subsequent paper, as “those outcomes are beyond the scope of a single manuscript.”
However, they do suggest that high doses of CBD when consumed orally appear to inhibit regular THC metabolism in the body, which could explain the observed increases in acute drug effects.
“We have demonstrated that with a relatively high oral dose of CBD [640 mg] 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,” said senior author Ryan Vandrey, a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.
Study contradicts some earlier work involving high-CBD strains
Previous work on cannabis strains containing high levels of CBD has generally suggested that CBD could attenuate some of the more adverse effects related to THC consumption.
For example, one fMRI (functional magnetic resonance imaging) study from researchers at University College London found less brain disruption when individuals consumed cannabis strains high in CBD, compared to strains with very little CBD but an equivalent amount of THC. An animal study performed by researchers at Western University, Canada, also found that CBD was able to mediate some of the adverse psychiatric effects associated with THC by affecting the extracellular-signal regulated kinase (ERK) pathway.
So, do the results from this new clinical trial contradict the findings of these past studies? Not necessarily. As the authors explain, edible cannabis products are metabolized in a very different way to the inhalable cannabis or cannabinoid infusions used in other studies. Edibles must undergo first-pass metabolism in the intestine and liver before reaching circulation, while other routes of administration do not. This could be a key difference, the researchers suggest.
“The fact that THC and CBD were orally administered was very important for the study, and played a large role in the behavioral effects and drug interactions we saw,” Zamarripa said.
