The suggestion that Marijuana is a “gateway drug”, where use leads to the use of “hard drugs like cocaine or heroin,  has long been dismissed as old school and a vestige of the Just Say No era.[i]. It’s not that simple because there is evidence that adolescent smoking, drinking, and vaping, whether tobacco-nicotine or cannabis-THC, is a gateway event making other drug use more compelling and likely. But the entire concept itself isn’t that simple. In an influential cross-sectional study by Harvard Professor Dr. Bertha Madras, parental marijuana use was associated with an increased risk of substance use among adolescent and young adult offspring living in the same household. Rather than this as modeling, it has been shown that second-hand smoke is first-hand smoking without consent. [ii] Screening household members for substance use and counseling parents on risks posed by current and past marijuana use are warranted[iii]. Prenatal THC exposure induced increased motivation for food, heightened learned helplessness and anhedonia, and altered stress sensitivity.[iv]

Studies have found that Marijuana can lead to cross-sensitization[v], as can tobacco, cocaine, and alcohol use. “Cross-sensitization” refers to extreme responses to one substance after earlier use of a different drug. This is an observable scientific fact that some drug experiences make other drugs more reinforcing and addicting. This heightened responsiveness may be limited to a critical time window, 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. Pre-exposure to THC has been shown to change increase heroin taking and alter some pharmacological effects of heroin [vi]. Evidence from the lab has also shown that exposure to cannabinoids during adolescence makes cocaine more rewarding throughout lifetime.It is as if the change in cocaine interest, once switched on, persists .  Responses to cocaine are regulated by epigenetic mechanisms in the brain’s reward regions, such as DNA methylation. When given cocaine, THC-exposed rats exhibited expected increases in locomotion. Still, they avoided the center of the open field, suggesting that this THC pre-exposure regimen enhances the anxiogenic effects of cocaine.[vii]

Cannabis use is increasing, age of first use is decreasing, frequency of use is increasing and dose of THC has been increasing suggesting to scientists delta-9-tetrahydrocannabinol (THC), might increase future reinforcing effects of other abused drugs such as cocaine or heroin are contribute to the overdose epidemic. Up to this point, this “gateway”  research on marijuana has been descriptive and cross-sensitization research has mainly been behavioral. Research from Columbia University tried to define the underlying brain mechanisms behind adolescent cross-sensitization from marijuana use, Scherma[viii] et al. exposed rats to Marijuana and cocaine and studied their responses and brain changes. The results were published in the prestigious Proceedings of the National Academy of Sciences. In addition, this study looked at the sensitizing effects of Marijuana on cocaine liking and attachment. They showed 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. In other animal studies, researchers have used this synthetic, which produces results like THC 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 seven 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. Moreover, they were susceptible to its effects. But adult rats were not. So Scherma et al. 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.

Studies show that Marijuana has adverse effects [ix] or that medicinal marijuana is more hype than reality at this point[x]—but this study is not 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 for calling teen substance use a “gateway” event. Still, 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 using rodents, a synthetic cannabinoid instead of smoking rats or THC, the lack of “self-administration” for the drugs, and relying on tissue instead of cell type for neurobiological changes. 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 hijacking[xi] or changing the brain through the mesocorticolimbic reward pathways usually activated after the 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 indirectly affect normal development as substance 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’s sensitivity to heroin, making it much more compelling. NIDA supported scientists led by Dr. Jasmine Hurd at Mt Sinai Medical School in NY  conclude that cannabis use during adolescence may also change motivation and addiction liabilities in the next generation. Typically, we do not know the substance use history for the father or mother . We also do not know the second and third hand early life exposure histories . Use may have time bomb, unintended neurodevelopmental implications produced by the increased use of cannabis during pregnancy. Simply using high potency  Δ9-tetrahydrocannabinol today by pregnant women, young mothers, and teens may have these unintended consequences.[xii]This is an entirely new area of scientific study but marijuana may be sensitizing for cocaine, heroin, and other substances is real and may explain so called gateway phenomenon.[xiii] . Other researchers have studied at-home or environmental exposures, like second and third-hand smoking[xiv]– essentially first-hand use without “consent.” Smoking in the home might have sensitizing effects on children and adolescents.

Legalization and widespread use of cannabis use, vaping THC, high potency THC products for sale in cannabis clinics and earlier us mean we will be field testing cannabis over the next decades. Marijuana affects different people in different ways, causes cannabis use disorders and other problems, changes future drug use, polydrug use, depression [xv], and trauma.  Drs. Denise and Nobel Laureate 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 becoming very hard to ignore.

Marijuana-related questions are complicated. Cannabis-derived psychoactive compounds such as Δ9-tetrahydrocannabinol and synthetic cannabinoids directly interact with the reward system and thereby have addictive properties[xvi]. Cannabinoids induce their reinforcing properties by an increase in tonic dopamine levels through a cannabinoid type 1 (CB1) receptor-dependent mechanism within the ventral tegmental area. Cues conditioned to cannabis smoking induce drug-seeking responses (i.e., craving) by eliciting phasic dopamine events. A dopamine-independent drug-seeking mechanism involves an endocannabinoid/glutamate receptor system within the corticostriatal reward system. Basic research has led to the conclusion that a pharmacological blockade of endocannabinoid signaling should reduce drug craving and subsequently reduce relapse behavior in addicted individuals.

Regular or heavy cannabis use was associated with an increased risk of using other illicit drugs, abusing or becoming dependent upon other illegal drugs, and using a wider variety of illicit drugs. The dangers of use, abuse/dependence, and use of a diversity of other drugs declined with increasing age. The findings may support a general causal model such as the cannabis gateway hypothesis[xvii].   Animal and human studies show that cannabis or its derivatives can increase relapse to cocaine seeking following withdrawal. Moreover, cannabis use in humans is associated with impulse control deficits, and animal studies implicate endogenous cannabinoids (ECB) in several impulsivity constructs. However, the brain areas where cannabinoids might control impulsivity or cocaine seeking are mainly unknown. [xviii]

Cannabis exposure during adolescence is associated with emotional and motivational alterations that may increase the risk of developing psychiatric disorders. In rodent models, exposure to cannabinoids during adolescence leads to increased self-administration of opiates and cocaine. However, the psychological and neural mechanisms and the sex-specificity of this phenomenon are largely unknown[xix]

In small studies, CBD has also been shown to have promise as a treatment for patients with opioid use disorders and is being tried as a treatment of precipitated craving and anxiety.[xx]. Despite the belief that cannabis is relatively harmless, exposure during adolescence is associated with an increased risk of developing several depression, psychosis and psychopathologies in adulthoodit is not just that use has increased with legalization among teens, but the dose has increased as well as the frequency of use. The potency of ∆-9-tetrahydrocannabinol (THC) has increased more than four to 10 times and potency surely will influence the addiction, sensitization, and emergence of other use-related behaviors. We will need to carefuly understand prenatal, post natal and early life adolescent THC exposure at todays  exceptionally high dosesto understand the brain and molecular changes that are induced and underly  psychiatric risk.[xxi]



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[xiii] 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.

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