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CBD Treats Cannabis Dependence By Stabilizing Endocannabinoids, Study Suggests

By Alexander Beadle

Published: May 02, 2023   
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Cannabis use disorder (CUD) is growing in prevalence. But unlike other substance use issues, there are currently no approved pharmacotherapies to assist people struggling with cannabis dependence.

One recent clinical trial had suggested that CBD, the major non-psychoactive component in cannabis, may help to encourage abstinence. However, little is known about how the cannabinoid might promote these effects.

Now, new research published in Translational Psychiatry by the same group behind that clinical trial, suggests that CBD could help to stabilize the levels of anandamide – an important endocannabinoid – in the body. This endocannabinoid has previously been linked to psychiatric issues, and so could be an important therapeutic target for CUD.

While the team behind this study did not see any significant effects of CBD on clinical outcomes, they believe that their preliminary findings suggest the need for further investigation of CBD as a treatment for CUD.

Anandamide levels fall among placebo users when trying to quit cannabis

This new paper comes out of a randomized, double-blind, placebo-controlled phase 2a clinical trial investigating CBD as a treatment for cannabis use disorder. As described in a previous publication in The Lancet Psychiatry by the same research group, eligible participants in the clinical trial were aged over 16 and met the DSM-5 criteria for a cannabis use disorder of at least moderate severity. All of the participants had also reported at least one prior failed attempt to quit their cannabis use.

For this trial, the participants were given either a placebo or CBD in doses of 200-, 400-, or 800 milligrams (mg). In addition, they also received six 30-minute sessions of motivational interviewing therapy, which is a type of talk therapy aimed at assisting people in making changes to their life.

Levels of anandamide were measured at baseline, then again on days 14 and 28 of the trial. This was done via a blood sample, with the blood plasma levels of anandamide determined using liquid chromatography tandem mass spectrometry (LC-MS/MS).

Researchers found that in the placebo group, overall anandamide levels fell from day 0 to day 28. However, there was no significant difference in those receiving the 800 mg CBD when adjusted for cannabis use.

“The finding of a reduction in anandamide levels over the 28-day-treatment period in the placebo group was unexpected, but illustrates the value of a matched placebo group when interpreting effects of CBD in this clinical population,” the researchers wrote.

Despite this observation, the researchers say that they did not find evidence suggesting that these changes in anandamide levels were meaningfully associated with any changes in cannabis use, withdrawal symptoms, anxiety, or depression symptoms recorded in the clinical trial.

Anandamide and substance use

The endocannabinoid system has been implicated in a range of different psychiatric disorders, from anxiety and depression to addiction. Recent trials have demonstrated that cannabinoid receptor 1 (CB1R) availabilitya predictor for greater cannabis withdrawal symptoms when individuals attempt to quit – is reduced in daily cannabis users

Because of this, endocannabinoid signaling is increasingly being considered as a therapeutic target when it comes to developing treatments to tackle such psychiatric disorders.

Anandamide is an endocannabinoid produced within the body and is a partial agonist of the CB1 receptor. Current research suggests that individuals who use cannabis frequently tend to have lower levels of anandamide in their cerebrospinal fluid compared to non-users; low anandamide levels have separately been found in the blood plasma of individuals with depression. Additionally, people who carry the FAAH 385A allele, which results in destabilized FAAH proteins and elevated anandamide levels, have been found to self-report lower anxiety levels compared to non-carriers.

As indicated by this latest study, blood plasma levels of anandamide also appear to fall when individuals with CUD initiate treatment and periods of abstinence. The researchers hypothesize that this could be down to changes in CB1 receptor density or other changes to the body’s endocannabinoid system upon the cessation of chronic cannabis use.

“These findings provide some support for the role of CBD in enhancing anandamide signaling, although further testing is needed,” the researchers wrote. “However, we did not find evidence that changes in anandamide levels were associated with changes in cannabis use, cannabis withdrawal, anxiety or depression during treatment.”

In one possible explanation for this, researchers note that anandamide is synthesized on demand within the body in a time- and context-dependent manner, so it is possible that future studies which take blood plasma measurements more frequently could return different results that may relate to clinical outcomes.

“Further research in other clinical populations and sampling from cerebrospinal fluid could advance our mechanistic understanding of CBD’s effects in treating psychiatric disorders,” the researchers added.


Looking outside the scope of anandamide levels, the clinical trial concerned in this study found that high doses of CBD could increase the number of cannabis-free days reported by CUD patients who were attempting to quit, compared to those given a placebo.

“The doses tested were higher than those available in over-the-counter CBD products,” Tom Freeman, an addiction researcher at the University of Bath and lead author of the study, told Analytical Cannabis after the publication of the trial’s first paper. “And it’s important to realize that the lowest dose was ineffective, and the highest dose was more effective. So, I wouldn’t recommend people self-medicate using over-the-counter CBD products.”

A previous study, authored by researchers at the University of Sydney, has also suggested that the CBD:THC oromucosal spray Sativex can help to combat cannabis withdrawal symptoms when attempting to quit.

“This is the first study with sufficient power to allow us to draw conclusions regarding the efficacy of cannabinoid medicines for outpatient treatment of cannabis dependence,” Nick Lintzeris, the study’s lead author and professor of addiction at the University of Sydney, told Analytical Cannabis at the time.

“The counseling and regular reviews had some benefits – but that these are enhanced when combined with active medication” he added. “This is a finding generally consistent with the evidence from other areas of health care – that combined medication and counseling is often more effective than either approach alone.”


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