From Cannabis to Cocaine?

A recent study found that prolonged exposure to high doses of synthetic cannabinoid WIN 55,212-2 (WIN) in adolescent rats changes how their brains react to later cocaine exposure (1). The researchers monitored the brains of rats given cocaine for the first time - adolescent (but not adult) rats previously exposed to WIN showed unique molecular and epigenetic responses to cocaine. The research has generated some heated headlines, but does the study really prove that “cannabis is a gateway drug”, as The Daily Mail claims?  To find out more, we spoke to co-author Philippe Melas.

How does this study build on previous work?

A number of human epidemiological studies have found that cannabis use in adolescence is associated with increased risk for later substance abuse and other neuropsychiatric problems. Epidemiological studies have also shown that a person’s initial response to a drug can have a large impact on whether they continue to use it – a positive first experience with cocaine is associated with shorter time to second use and a higher risk of cocaine dependence. However, epidemiology cannot distinguish correlation from causation.

Meanwhile, rodent studies have provided convincing evidence of a role for endocannabinoids in modulating reward and cognition. The endocannabinoid system is involved in modulating neural activity and has a significant role in neurodevelopment. 

The combination of epidemiological and preclinical evidence led us to a hypothesis: cannabis exposure during critical neurodevelopmental periods (in utero or in adolescence) can reprogram the brain to increase susceptibility to neuropsychiatric disorders, including substance abuse. To our knowledge, our study is the first to map the molecular and epigenetic changes that occur when cocaine interacts with adolescent brains already exposed to cannabinoids.

Why use WIN for this study, rather than THC?

Animal studies have shown that plant cannabinoids (such as THC) or synthetic analogs (such as WIN or CP-55,940) result in similar neurochemical changes in the brain. However, while rodents can learn to self-administer most drugs of abuse used by humans, they do not readily self-administer THC – a partial agonist for cannabinoid receptors. Rodents do self-administer synthetic cannabinoid analogs, including WIN, which act as full agonists and so are more potent. We opted to work with WIN initially so that we could complement our studies with self-administration procedures. However, we plan to use THC in future experiments to verify the molecular and epigenetic changes we reported in this study.

What were the most interesting results?

To our surprise, we found that exposure to cocaine caused a number of unique molecular changes in brains already exposed to WIN, compared to brains that had not been exposed to cannabinoids. Even more interesting was the fact that both behavioral and molecular changes were confined to adolescent animals only, and not adults. The most extensive changes were in the prefrontal cortex, which plays a major role in executive functions, such as long-term planning and self-control, and is one of the last regions of the brain to reach maturity. This “underdeveloped” prefrontal cortex is thought to be behind adolescents’ propensity for risky behavior, including drug use. 

If our findings hold true in humans, it would suggest that adolescents who use cannabis will be more likely to have a favorable initial reaction to cocaine. However, cannabis use on its own will never cause someone to seek out cocaine – the progression to new drugs is the result of a combination of social, psychological, and environmental factors. And although favorable first encounters with a drug of abuse are known to predict repeated use of that drug in the future, we need to remember that additional vulnerabilities, such as genetic predispositions, are needed for an addiction to develop. We should also emphasize that our study was conducted using animals exposed to a drug regimen designed to model heavy cannabis use over an extended period of time in adolescence so the findings may not apply to occasional cannabis use or low THC doses.

How easily can results in rodents be extrapolated to humans? 

Most molecular and imaging studies to date support the association between early cannabis use and alterations in neurochemical and neurodevelopmental systems in both animals and humans. Rodents and humans use the same neurochemical systems in their brains, such as the endocannabinoid and the dopaminergic signaling systems, which we know are involved in the development of substance use disorders. Nonetheless, we should always be cautious when interpreting results originating from rodents and should not directly extrapolate them to humans, especially when studying complex psychiatric disorders such as drug abuse.  

What’s next?

We want to discover whether our molecular findings in rats translate into humans. To do so, we have partnered with the NIH NeuroBiobank to study postmortem brain samples from people who had been dependent on substances such as cannabis and cocaine. 

Moreover, we know that although cannabis use predicts later use of cocaine, few of these individuals actually become addicted to either drug, so we plan to study the genetic and environmental factors that influence progression to problematic drug use. To examine this question, we are collaborating with Swedish human epidemiological projects that have access both to genetic and environmental data.