by Dr. Mark Gold
The suggestion that marijuana is a “gateway drug” has long been the butt of breezy jokes among its consumers, a chance to laugh at a frustratedly stern father’s weary search to justify a plea against use. It’s the last refuge of scolds, the tired maxim of bygone after-school specials, the cliché too risibly antique to merit a response. If you want to fret about marijuana, find something, anything else to say.
We all get this now, right?
It’s not that simple, because the concept itself isn’t that simple.
“Cross-sensitization” refers to extreme responses to one substance after earlier use of a different drug. This isn’t exactly “gateway” use—but it’s not the opposite, either. It’s an observable scientific fact that some drug experiences make other drugs more reinforcing and addicting. This heightened responsiveness may be limited to a window of time, like puberty. But it could be something that can occur throughout the life cycle. The increased response can also contribute to health risks from later substance use, and studies have found that marijuana can lead to cross-sensitization,1 as can tobacco, cocaine, and alcohol use. Up to this point, the research on marijuana and cross-sensitization is largely behavioral. To get a better sense of the underlying brain mechanisms behind adolescent cross-sensitization from marijuana use, Scherma et al. exposed rats to marijuana and cocaine and studied their responses and brain changes.2 The results were published in May in the prestigious Proceedings of the National Academy of Sciences.
What did this study find about rats, marijuana, and cocaine?
This study found that cross-sensitization to cocaine occurs in adolescent rats previously exposed to marijuana-THC-linked to changes in the rats’ brains. Scherma et al. collected two groups of rats: one adolescent group, and one adult group. They fed them, provided water, and stored them in cages in a climate-controlled room with alternating day and night light cycles. Then they injected them with a solution containing a synthetic cannabinoid, WIN 55,212-2. Researchers have used this synthetic, which produces results similar to THC, in other animal studies and discovered cross-sensitization and changes to chemical structures and withdrawal symptoms. Scherma et al. also ratcheted up the rats’ synthetic cannabinoid doses “to mimic heavy cannabis consumption in human adolescence,” they write. They let the rats rest in abstinence for 7 days before injecting them with cocaine.
By measuring the rats’ “distance traveled” over time—their propensity to scramble around in their cages after cocaine exposure—this study determined that adolescent rats were cross-sensitized to cocaine after earlier-in-life synthetic cannabinoid exposure. They were remarkably sensitive to its effects. But adult rats were not. Scherma et al. then flipped the experiment around: they injected the rats with cocaine twice a day for 11 days before another week of abstinence and exposure to the synthetic cannabinoid. This time, neither the adults nor the adolescents were cross-sensitized, suggesting that marijuana, but not cocaine, promotes cross-sensitization in adolescents. After the rats were killed, Scherma et al. checked them for brain changes and found different alterations. But what stood out the most were chemical changes to proteins in the prefrontal cortex, which helps regulate decision-making and judgment. It may be the case that these prefrontal cortex differences are the underlying cause of cross-sensitization in the rats.
Why is this important?
Studies show that marijuana has adverse effects 3—but this study is not really one of those. It does give pediatricians and child psychiatrists plenty to think about, and more to study in their patients. Marijuana is an undeniably powerful drug, like alcohol and tobacco, changing the brain and accelerating drug-reward learning. That may be a basis to call teen substance use a “gateway” event, but all young people will have different vulnerabilities informed by genes, age, and other risk factors, as well as the route of administration and dose.
While mounting behavioral evidence indicates that marijuana plays a role in cross-sensitization, this study finds the “how”: a neurochemical pathway by which the change occurs in the prefrontal cortex. Scherma et al. caution against overlooking limitations in their work, like the use of rodents, a synthetic cannabinoid instead of smoking rats4 or THC, the lack of “self-administration” for the drugs, and relying on tissue instead of cell type for neurobiological changes. These authors, including a Nobel-Prize winning researcher, also warn, “substance use disorders do not develop from a single drug encounter but require repeated exposures that result in enduring epigenetic and synaptic changes.” This research team studied the effects of a cannabinoid on cocaine cross-sensitization only, not on the development of cocaine use disorders. Further studies are needed and are in progress. And researchers, supported by NIDA, have also raised alarms about youth marijuana smoking and vaping.
Substance use has been described as hijacking5 the brain through the mesocorticolimbic reward pathways usually activated after performance of species survival behaviors like eating or sex. This system changes during child and adolescent development and parenting might be thought of as developing new connections and learning to modulate and control the search for reinforcement or pleasure. Direct effects of substance use during development can confuse and alter the brain’s reinforcement system. These drugs have indirect effects on normal development as use takes time, energy, and commitment, and preoccupation with substances is not easily reversed through treatment or new learning. Some of the most alarming and recent studies by NIDA researchers have warned that exposure to THC in utero can produce sensitizing effects and changes lasting after conception and birth. The most recent data shows that parental THC exposure alters male offspring sensitivity to heroin, making it much more compelling . NIDA scientists conclude that mild to moderate cannabis use during adolescence may also alter heroin abuse liability for males in the subsequent generation. Fathers passing on addiction liability to their sons is a completely new area of scientific study. Marijuana may be sensitizing for cocaine, heroin, and other substances.6
Drs. Denise and Eric Kandel have warned that early use of one drug is likely to sensitize and make other drugs more compelling, with less control over later use. This work, now replicated and extended in recent human studies, is very hard to ignore.
Other researchers have studied at-home or environmental exposures, like second and third-hand smoking. These are essentially first-hand use without “consent”. Smoking in the home might have sensitizing effects on children and adolescents. Smoking is both highly addictive as a route of drug administration and dangerous in itself, especially in the COVID-19 era. NIDA Director Dr. Nora Volkow has warned about heightened virus risks from Marijuana, tobacco, and vaping use.
Scherma et al. also say that their study should emphasize the importance of understanding marijuana’s effects “Given the current increase in permissive societal and legal attitudes toward cannabis use”. Cannabis laws, research, and opinions are colored by the existing availability of tobacco and alcohol and lack of national clarity on the medicinal and euphoric value of use. Whatever the merits of changing attitudes on an overall policy level, studies like this one help us remember that FDA scientific studies, like those insisted on for COVID cures and treatments, should be added to marijuana legalization discussions. Legalization and widespread use of cannabis means that we will be surprised but also find answers to questions through field testing experiments, such as how marijuana differentially affects different people, future drug use, polydrug use, depression 7 and trauma. We have learned a great deal and have more to learn about Cannabidiol, or CBD. CBD, a pharmacological preparation of marijuana, has already been proven safe and effective for some rare seizures and may be found through additional study to be “medication” for other diseases. CBD has also been shown to have promise as a treatment for patients with opioid use disorders in early studies of precipitated craving and anxiety.8
Marijuana-related questions are complicated. As we have learned during this COVID-19 pandemic, medications need careful evaluation before being considered for use. Ballot initiatives might have led to Chloroquine and Hydroxychoroquine approval for the treatment of COVID-19. Random assignment, prospective, double- blind placebo controlled studies are the gold standard, and medications should be considered dangerous until proven safe and effective. To answer complicated questions with more certainty, we’ll need human clinical trials like those submitted to the FDA for CBD and rare pediatric seizure disorders—studies including men and women, the old and young, pregnant women and fetuses, and children, adolescents, and young adults.
1. Melas, P. A., Qvist, J. S., Deidda, M., Upreti, C., Wei, Y. B., Sanna, F., Scherma, M., Fadda, P., Kandel, D. B., Kandel, E. R. (2018). Cannabinoid Modulation of Eukaryotic Initiation Factors (eIF2α and eIF2B1) and Behavioral Cross-Sensitization to Cocaine in Adolescent Rats. Cell Reports, 22(11), 2909–2923. https://doi.org/10.1016/j.celrep.2018.02.065
2. Scherma, M., Qvist, J. S., Asok, A., Huang, S. C., Masia, P., Deidda, M., Wei, Y. B., Soni, R. K., Fratta, W., Fadda, P., Kandel, E. R., Kandel, D. B., Melas, P. A. (2020). Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine. Proceedings of the National Academy of Sciences, 117(18), 9991–10002. https://doi.org/10.1073/pnas.1920866117
3. Volkow, N. D., Baler, R. D., Compton, W. M., Weiss, S. R. B. (2014). Adverse Health Effects of Marijuana Use. New England Journal of Medicine, 370(23), 2219–2227. https://doi.org/10.1056/nejmra1402309
4. Bruijnzeel, A. W., Qi, X., Guzhva, L. V., Wall, S., Deng, J. V., Gold, M. S., Febo, M., Setlow, B. (2016). Behavioral Characterization of the Effects of Cannabis Smoke and Anandamide in Rats. PLOS ONE, 11(4), e0153327. https://doi.org/10.1371/journal.pone.0153327
5. Volkow, N. (Updated 2020). Marijuana: Letter From the Director. National Institute on Drug Abuse (NIDA). Retrieved from https://www.drugabuse.gov/publications/research-reports/marijuana/letter-director
6. Hempel, B. J., Crissman, M. E., Imanalieva, A., Melkumyan, M., Weiss, T. D., Winston, C. A., Riley, A. L. (2020). Cross-Generational THC Exposure Alters Heroin Reinforcement in Adult Male Offspring. Drug Alcohol Depend [Epub ahead of print]. https://doi: 10.1016/j.drugalcdep.2020.107985.
7. Volkow, N. D., Wang, G.-J., Telang, F., Fowler, J. S., Alexoff, D., Logan, J. Jayne, M., Wong, C., Tomasi, D. (2014). Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proceedings of the National Academy of Sciences, 111(30), E3149–E3156. https://doi.org/10.1073/pnas.1411228111
8. Hurd, Y. L., Spriggs, S., Alishayev, J., Winkel, G., Gurgov, K., Kudrich, C., Oprescu, A.M., Salsitz, E. (2019). Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial. American Journal of Psychiatry, 176(11), 911–922. https://doi.org/10.1176/appi.ajp.2019.18101191
Dr. Mark S. Gold is a teacher of the year, translational researcher, author, mentor and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine and food.