A study in human volunteers has found that some individuals may be genetically more predisposed to cannabis addiction than others. The research, headed by a team at University College London (UCL), linked specific variants in the cannabinoid receptor 1 (CNR1) gene and in the fatty acid amide hydrolase (FAAH) gene with behavioral measures of addiction predisposition, or endophenotypes, which are typical of cannabis use disorders (CUD).
“We were interested in asking whether these genetic markers could predict addiction-related responses after inhaling doses of cannabis, such as how much our attention is drawn to cannabis-related pictures,” said lead researcher Chandni Hindocha, PhD, a post-doctoral research associate at UCL’s Clinical Psychopharmacology Unit. The researchers report on their studies in Addiction Biology, in a paper titled, “Acute effects of cannabinoids on addiction endophenotypes are moderated by genes encoding the CB1 receptor and FAAH enzyme.”
About 9% of people who start using cannabis will develop CUD, the authors wrote. Problematic use of drugs is influenced by both environmental and genetic factors, which in the case of cannabis may include genetic differences in the body’s endocannabinoid system, on which the drug acts. As attitudes towards cannabis use are becoming generally more relaxed, the imperative to investigate differences in vulnerability and resilience to the harmful effects of the drug is increasingly evident. “This is particularly important because cannabis currently stands poised to join alcohol and tobacco as a legal drug across the globe, meaning rates of cannabis use disorders (CUDs) may also rise.”
The main psychoactive component in cannabis is tetrahydrocannabinol (THC), which activates the cannabinoid receptor type 1 (CB1R), which is encoded by the CNR1 gene. The second most abundant cannabinoid found in cannabis plants is cannabidiol (CBD), but this component doesn’t have psychoactive effects, and in fact has psychopharmacologically opposing effects to THC, although the mechanisms of action aren’t wholly understood. Importantly, CBD may actually protect against the development of CUD and the psychotic-like effects of THC, so the ratio of THC to CBD in cannabis is particularly important, the researchers stated.
Interestingly, they noted, the relative amount of THC in cannabis has been increasing over the last two decades, in parallel with higher rates of treatment requests for CUD. As well as acting on CB1R, CBD also increases inhibition of the FAAH, an enzyme that is involved in endocannabinoid signaling, which indirectly regulates the activity of CB1R. “FAAH inhibition is a mechanism that is currently being investigated as a treatment of CUD in humans, the team added.
Previous studies have linked variations in the CNR1 gene with addiction to cannabis, alcohol, nicotine, and cocaine, and possibly with CUD endophenotypes, such as reward-related brain activity when individuals are exposed to cannabis cues. “As such, genetic influences may, therefore, alter other mechanisms related to CUD—such as craving, satiation, and drug-cue salience,” the researchers commented.
The team devised an experiment to investigate whether any of three genetic variations in the genes encoding CB1R and FAAH impacted on individuals’ responses to acute cannabinoid administration. Forty-eight volunteers who were carriers of the genetic variations were enrolled, and each took a controlled dose of cannabis compounds using a vaporizer. Over four sessions the participants were given either a controlled dose of THC, CBD, a combination of CBD + THC, or placebo. The researchers then assessed measures of three different endophenotypes of CUD while the participants were under the influence. These included cue salience—effectively how far the participants’ attention was biased towards to images containing cannabis-related stimuli, compared with very closely matched images that contained food-related stimuli. Participants also filled in a short questionnaire to assess cannabis craving, and were tested for satiety using the Bodily Symptoms Scale.
While the results highlighted differences to drug cue salience and state satiety for all three genetic variants, participants who carried one of the single nucleotide polymorphism (SNP) variants in the CB1R gene tended to want more cannabis after having used it, and continuing to be drawn to the cannabis-related imagery while under the influence of their administered inhaled dose. The finding suggests that people with this genetic marker could be more prone to cannabis addiction.
“ … we report for the first time that the genes that code for the CB1 receptor and FAAH enzyme are implicated in the acute CUD related response to acute consumption of cannabinoids,” the authors stated. “This was found for the salience of appetitive cues and state satiety but not for craving. These results have important pharmacogenetic implications in regard to recreational users of cannabis who may be more vulnerable to the effects of THC and who may, therefore, be at greater risk of transitioning into CUD.”
The team acknowledges that their experiments will need to be replicated in much larger numbers of individuals to confirm their findings. “… it is important to consider these results as preliminary,” the team wrote. “Given the small cell sizes, this study was only powered to detect small-to-medium effect sizes. It would be important to replicate these findings with a larger sample size allowing for analysis of a dose-response relationship between genotype and risk.”
“We hope that our findings could lead to the development of a test that could inform clinicians who are considering prescribing a cannabis-derived medication, as we learn more about which genes affect how people react to cannabis,” Hindocha said. “Our findings have the potential to inform precision medicine targeting the rising clinical need for treatment of cannabis use disorders,” added co-author Tom Freeman, PhD, senior lecturer, department of psychology at the University of Bath.
In parallel with Hindocha et al.’s publication in Addiction Biology, a separate UCL team has published the results of studies indicating that the CBD in cannabis can help to offset the degree of psychoactive actions of THC. “We have now found that CBD appears to buffer the user against some of the acute effects of THC on the brain,” commented Matt Wall, PhD, at UCL’s Clinical Psychopharmacology Unit, who is lead author of the work, which is published in the Journal of Psychopharmacology (“Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity.”)
As well as generating the cannabis-related “high,” THC can also affect memory, and produce effects that increase anxiety and cause psychotic-like behavior, while studies have suggested that CBD has opposite effects to THC, and is anti-psychotic, and potentially anxiolytic. There is increasing concern, however, that today’s cannabis strains contain high levels of THC, and only minimal, if any counterbalancing CBD. “This high-strength cannabis (often referred to as ‘skunk’) is popular with users, but is also hypothesized to be responsible for the dramatic increase in reporting of cannabis-related health issues in recent years; most notably addiction, and cannabis-induced psychosis,” the researchers noted.
They reasoned that the potentially opposing psychological and pharmacological effects of CBD might render cannabis that contains higher levels of CBD a safer option than low-CBD cannabis, on the basis that “CBD may buffer the user against the main negative effects of THC.” To investigate more directly the effects on the brain of cannabis with different levels of THC and CBD, Wall’s team used functional magnetic resonance imaging (fMRI) technology to monitor brain activity at rest in 17 participants who had taken strains of cannabis equivalent to those used commonly in society today. Two of the strains had equal levels of THC, but while one also had high levels of CBD, the other, known as skunk, contained only negligible levels of CBD. A third, placebo contained neither compound.
The imaging results showed that the low-CBD cannabis impaired functional connectivity in the brain’s default mode (notably in the posterior cingulate cortex) and salience networks. In contrast, the high-CBD strain wasn’t associated with large disruption to these brain areas.
Disruption to functional connectivity in the posterior cingulate was also linked with the degree of how ‘high,” or “stoned” the participants felt after taking cannabis, and this was, again, dampened by high CBD levels. The researchers say their findings add weight to the suggestion that cannabis strains with greater CBD content may be less harmful, which suggests that it may be prudent to regulate the CBD content of cannabis in countries where the drug is legal. “As cannabis is becoming legal in more parts of the world, people buying cannabis should be able to make an informed decision about their choice of cannabis strain and be aware of the relative risks,” Wall noted.
The findings also provide some insights into why CBD holds potential for medicinal uses. “If CBD can restore disruption to the salience network, this could be a neuroprotective mechanism to explain its potential to treat disorders of salience such as psychosis and addiction,” added senior study author Val Curran, PhD, professor of psychopharmacology at the UCL Clinical Psychopharmacology Unit.
