Monday, July 21, 2014

Hunting For the Marijuana-Dopamine Connection

Why do heavy pot smokers show a blunted reaction to stimulants?

Most drugs of abuse increase dopamine transmission in the brain, and indeed, this is thought to be the basic neural mechanism underlying the rewarding effects of addictive drugs. But in the case of marijuana, the dopamine connection is not so clear-cut. Evidence has been found both for and against the notion of increases in dopamine signaling during marijuana intoxication.

Marijuana has always been the odd duck in the pond, research-wise. Partly this is due to longstanding federal intransigence toward cannabis research, and partly it is because cannabis, chemically speaking, is damnably complicated. The question of marijuana’s effect on dopamine transmission came under strong scrutiny a few years ago, when UK researchers began beating the drums for a theory that chronic consumption of strong cannabis can not only trigger episodes of psychosis, but can be viewed as the actual cause of schizophrenia in some cases.

It sounded like a new version of the old reefer madness, but this time around, the researchers raising their eyebrows had a new fact at hand: Modern marijuana is several times stronger than marijuana in use decades ago. Selective breeding for high THC content has produced some truly formidable strains of pot, even if cooler heads have slowly prevailed on the schizophrenia issue.

One of the reports helping to bank the fires on this notion appeared recently in the Proceedings of the National Academy of Sciences (PNAS). Joanna S. Fowler of the Biosciences Department at Brookhaven National Laboratory, Director Nora Volkow of the National Institute on Drug Abuse (NIDA), and other researchers compared brain dopamine reactivity in healthy controls and heavy marijuana users, using PET scans. For measuring dopamine reactivity, the researchers chose methylphenidate, better known as Ritalin, the psychostimulant frequently prescribed for attention-deficit hyperactivity disorder (ADHD). Ritalin basically functions as a dopamine reuptake inhibitor, meaning that the use of Ritalin leads to increased concentrations of synaptic dopamine.

In the study, heavy marijuana users showed a blunted reaction to the stimulant Ritalin due to reductions in brain dopamine release, according to the research. “The potency of methylphenidate (MP) was also reported to be stronger by the controls than by the marijuana abusers." And in marijuana abusers, Ritalin caused an increase in craving for marijuana and cigarettes.

 “We found that marijuana abusers display attenuated dopamine responses to MP including reduced decreases in striatal distribution volumes,” according to the study’s conclusion. “The significantly attenuated behavioral and striatal distribution volumes response to MP in marijuana abusers compared to controls, indicates reduced brain reactivity to dopamine stimulation that in the ventral striatum might contribute to negative emotionality and drug craving.”

Down-regulation from extended abuse is another complicated aspect of this: “Although, to our knowledge, this is the first clinical report of an attenuation of the effects of MP in marijuana abusers, a preclinical study had reported that rats treated chronically with THC exhibited attenuated locomotor responses to amphetamine. Such blunted responses to MP could reflect neuroadaptations from repeated marijuana abuse, such as downregulation of DA transporters.”

 Animal studies have suggested that these dopamine alterations are reversible over time.

Another recent study came to essentially the same conclusions. Writing in Biological Psychiatry, a group of British researchers led by Michael A.P. Bloomfield and Oliver D. Howes analyzed dope smokers who experienced psychotic symptoms when they were intoxicated. They looked for evidence of a link between cannabis use and psychosis and concluded: “These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.” And again, the higher the level of current cannabis use, the lower the level of striatal dopamine synthesis capacity.  As for mechanisms, the investigators ran up against similar causation problems: “One explanation for our findings is that chronic cannabis use is associated with dopaminergic down-regulation. This might underlie amotivation and reduced reward sensitivity in chronic cannabis users. Alternatively, preclinical evidence suggests that low dopamine neurotransmission may predispose an individual to substance use.”

The findings of diminished responses to Ritalin in heavy marijuana users may have clinical implications, suggesting that marijuana abusers with ADHD may experience reduced benefits from stimulant medications.

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Derek Williams said...

"Drugs of abuse". Sorry, comments like that indicate an innate bias. I would have hoped we'd moved on from such emotionally loaded terminology by now.

Dirk Hanson said...

Every locution has its drawbacks. I tend to stick with "addiction" mostly, but "dependence," "craving" "abuse" all carry baggage of various kinds as well. If you know of any un-emotionally loaded terminology, feel free to suggest it.

Chris R. said...

Nice post, Dirk.

Am I the only person skeptical of the statistical significance presented in that figure? P=0.016, but with n=19 and the relatively large SDs it seems slightly "off" to me... not to mention the psych fields are notoriously less than stellar when it comes to statistics. I wonder if the raw data is available anywhere.

Dirk Hanson said...

Here's the reference for author data:

Ian said...

Benzodiazepines also blunt response to amphetamines, but I don't think we would have read the same study conducted with benzodiazepines reported as causing the loss of pleasure, centers in the brain. An alternate way to look at this study (if you don't work for NIDA) would be to note that cannabis decreases the response to amphetamines, and given past animal research (Castelli PLOS One, Mayt 20, 2014) might be the more correct interpretation

Dirk Hanson said...

Hi Ian:

I thought the post made it clear that cannabis decreases the response to amphetamines in humans, according to the research. I agree that this is one of the take-home points of the studies.

Chris R. said...

Thanks, Dirk. I still don't see the raw data that was used to make that figure, which isn't surprising, given that raw data usually isn't included in the published works... The plot doesn't seem a bit "off" to you? With respect to the means and SDs? It's tough to say without seeing the raw data and re-analyzing, but I'm skeptical of their claim of statistical significance there.

Dirk Hanson said...

You could be right. It could be that researchers are still hunting for that connection.

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