Neuroscience of Cannabis Use Disorder
Last Updated: 18 August 2019
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Substance Use Disorder CME Needs
Today’s post gets to the basic science of cannabis use disorder. As demand for treatment of substance use disorder increases, so does the demand for relevant, quality CME covering opioid use disorder, alcohol use disorder, cannabis use disorder, and other topics in addiction medicine for non-specialists.
If you are searching for addiction medicine CME for non-specialists, we’ve got you covered.
Cannabis Use Disorder and Nicotine Receptors
In 2019, scientists discovered an association between the prevalence of cannabis use disorder and a mutant nicotine receptor in the brain. What does it mean for diagnosis and treatment of substance use disorder, specifically cannabis use disorder? And what does it mean for science?
The thing is, we kinda know how marijuana works. The main psychoactive ingredient is tetrahydrocannabinol (THC), which itself can make people feel high and is known to interact with a dedicated system of receptors in the brain.
So when this study found that cannabis use disorder was linked to a mutant nicotine receptor, it made sense that the mutation was important for brain function. But why nicotine? Why not, say, a receptor that binds THC? At first glance, it’s a mystery, but the authors propose a pretty interesting idea.
To understand their explanation, we first have to understand dopamine. In the first half of the 20th century, dopamine played no role in the neuroscientist’s imagination. It was little more than a ‘who-cares precursor’ to the much more interesting fight-or-flight molecule, noradrenaline.
But then scientists developed a range of technologies to invasively study the living brain. Could scientists encourage certain behaviors by cranking up the dopamine? All the experiments seemed to work; tinkering with dopamine tinkered with reinforcement and reward.
For example, dopamine-spiked animals would find themselves mindlessly pulling levers or preferring one room over another identical room. Today, according to many neuroscientists, whether it’s opioid use disorder, alcohol use disorder, or gambling or overeating, reinforcement and addiction are all about the dopamine.
In the case of THC, the connection to dopamine was thought to be less direct. Maybe there’s a stop along the way, perhaps, the stimulation of a nicotine receptor, that mediates the link. In fact, supporting this idea, a 2001 study showed that THC inhibits other neurotransmitters that work on the nicotine receptor in question.
So it all comes together, the story goes: smoking marijuana impacts the function of nicotine receptors, affecting dopamine.
Dopamine Signaling in Cannabis Use Disorder
Where does the gene mutation come into play? How can alternative forms of this receptor make some people more susceptible to addiction? This part leads to a paradox because the mutation doesn’t actually affect the receptor itself. Instead, it affects the amount of the receptor that’s produced. People with cannabis use disorder have the version of the gene that produces fewer copies.
For those with the mutation, who therefore have fewer nicotine receptors, we might then expect a reduced impact of THC on dopamine. If that’s the case, we might then expect a reduced likelihood that THC would be addictive, which is the opposite of the narrative the authors were proposing. The lead author declined to comment on this apparent contradiction.
And the problems with this explanation aren’t strictly logical. Some experiments with rodents have actually shown that acute THC exposure doesn’t impact dopamine signaling at all. And an experiment in humans found that if THC does impact dopamine, the effect is minimal.
Given these issues, the explanation provided doesn’t seem to make a ton of sense. To the author’s credit, they have other ideas; for example, maybe there’s a previously underappreciated molecule in marijuana that’s directly interacting with the nicotine receptor. Maybe. Or maybe it’s one of the hundred other superficially plausible mechanistic links connecting marijuana and dopamine via a nicotine receptor.
Future Treatment of Cannabis Use Disorder
With medical and recreational legalization on the horizon in much of the U.S., attitudes towards marijuana use are becoming much more accepting. At the same time, four million Americans meet criteria for cannabis use disorder, a state of intense drug dependence that few would ask for.
The study clearly shows that people with this mutant nicotine receptor are about 30 percent more likely to develop cannabis use disorder.
It’s a finding that could perhaps argue for caution among those who are at an elevated risk.
Or, further down the road, it’s possible that this study will help identify a specific treatment of cannabis use disorder. We already block (different) nicotine receptors to help patients quit smoking tobacco; might we be able to help those with cannabis use disorder by targeting the same system?
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Castañeda E, Moss D, Oddie SD, Whishaw IQ. THC does not affect striatal dopamine release: Microdialysis in freely moving rats. Pharmacology Biochemistry and Behavior. 1991;40(3):587-591. doi:10.1016/0091-3057(91)90367-b.
Demontis D, Rajagopal V, Thorgeirsson T, et al. Genome-Wide Association Study Implicates Chrna2 In Cannabis Use Disorder. European Neuropsychopharmacology. 2019;29. doi:10.1016/j.euroneuro.2018.07.008.
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