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It’s time to acknowledge “marijuana’s” racism-steeped past by transitioning back from “marijuana” to “cannabis”.

1930’s…

It was always cannabis. In plant taxonomy terms, Cannabis sativa is a plant that has been used for the strength of its fibers and medicinal properties for thousands of years. Even into the early 1930’s, cannabis was being consumed regularly for the treatment of migraine, nausea, and other ailments.

But in 1934, Harry Anslinger took over the Federal Bureau of Narcotics and made it his mission to criminalize marijuana possession. His strategy: scare the American public by associating it with Mexican immigrants, and make it evil. After all, Mexican immigrants were using cannabis recreationally. But they called it marijuana.

The term “marijuana” was introduced to the US by Mexican immigrants who came to the US during the Mexican Revolution, a period of great political turmoil between 1910 and 1920. One of the most common versions of the famous La Cucharacha, sung by soldiers and civilians supporting Pancho Villa included marijuana in its lyrics:

Spanish	English
La cucaracha, la cucaracha,	The cockroach, the cockroach,
ya no puede caminar	can’t walk anymore
porque no tiene, porque le falta	because it doesn’t have, because it’s lacking
marihuana que fumar.	marijuana to smoke.

When Anslinger went on the attack against cannabis, he didn’t call it cannabis. It was a deliberate strategy to avoid using the words “cannabis” or “hemp”, two innocent and soft sounding words, in favor of the unknown and harsher sounding “marijuana”. It gave him the opportunity to make the fresh association to the American public: marijuana and immigrants were linked. And not only that, it made them dangerous.

William Randolph Hearst, media mogul and father of yellow journalism, was Anslinger’s megaphone. Through Hearst, Anslinger generated fear in this alien drug called marijuana. It was turning good people evil; it created thieves, and killers; it made Mexicans and African Americans lust for white women. Marijuana was at the heart of immigrant crime.

And it worked. By 1937, Anslinger was in front of Congress to support a bill that would criminalize the possession of “marijuana” (the Marijuana Tax Act essentially criminalized its possession by creating unreasonably high tariffs on its possession). Despite claims by a representative from the American Medical Association that 1) marijuana has not been proven to be harmful in the ways claimed by Anslinger, and 2) most physicians didn’t even know marijuana and cannabis were the same thing, the bill overwhelmingly gained approval.

Today… 

The number of cannabis-related arrests are vastly weighted towards minority populations despite ubiquitous use patterns throughout the population. Many have died because of cannabis, not through overdose or its harmful impacts on the body, but in gang-related killings in the cannabis drug trade. Simple possession charges have broken families, disproportionately affecting African Americans and minority men, in part a holdover from cannabis’ racially-tinged history over the last 80 years.

And the negative social stigma has been pervasive. Nancy Regan’s Just Say No campaign solidified marijuana’s stigma in a new generation of Americans; cannabis’ medicinal abilities were of course never discussed. Many are surprised to learn about cannabis treatment for pain, migraine, nausea. But our American ancestors at the turn of the 20th century would be surprised that cannabis is no longer associated with medicine, and instead, it’s considered dangerous to the same order of magnitude (be federal government definition) as heroin, quaaludes, and LSD.

Does this stigma impact its treatment potential? Work by prominent UCLA Psychiatrist, Dr. Thomas J. Ungerleider, described how important “set” and “setting” are in cannabis’ effects in his commentary of his career’s work in Marijuana: A Signal of Misunderstanding (1999). It extends what we know about the importance of expectation in medicine; our brains are powerful regulators of drug success.

Even though cannabis has been repeatedly demonstrated to be therapeutically effective for a host of disorders and ailments in rodents (presumably with no expectation), children (little to no expectation), and adults, a negative expected outcome based on social stigma and expectation of harm from decades of anti-marijuana campaigns can hinder its success. If a positive expectation can drive treatment success with minimally-effective drugs or placebos, then it stands to reason that one tainted in social stigma could impede maximal treatment outcomes. Indeed, there’s a well-documented medical phenomenon called the “nocebo” effect in which there’s a detrimental effect on health caused by negative expectations. The brain can override some of cannabis’ positive effects, if we let it. We need to wipe away the social stigma attached to medicinal cannabis use.

So let’s start by moving away from marijuana and returning to cannabis.

We can even retain the alliteration! “Medicinal marijuana” sounds nice, but why not “clinical cannabis”? Let’s perpetuate the latter.

Years ago, I sat in D.A.R.E. class as teachers warned of the harm of cannabis. Not only would it destroy your brain, but it would lead to harder and more dangerous drugs (side note: I find it funny that cannabis is listed as a Schedule I drug in part out of fear that it would lead to the use of Schedule 2 drugs, like cocaine and morphine). Is this true? Does cannabis itself alter the brain in such a way that makes users more likely to graduate to other drugs?

Well, no.

The political history

Cannabis is not a “gateway drug”. Even those who toiled to make it illegal admitted that it was not the gateway to heroin. The Federal Bureau of Narcotics chief, Harry Anslinger, made it his mission to prohibit cannabis (which he deliberately called “marijuana” to associate it with Mexican immigrants). Throughout the 1930s, he cajoled newspapers, Hollywood, and politicians in a grand effort to make cannabis illegal. His efforts culminated with the passing of the 1937 Tax Act, which essentially made cannabis illegal to possess. In these hearings before the Committee on Ways and Means (75th Congress, 1st Session: House Marijuana Hearings), Anslinger was was asked if cannabis users graduate to heroin or cocaine.

“No sir,” he responded. “I have not heard of a case of that kind. I think it is an entirely different class. The marijuana addict does not go in that direction.”

12 years later, as the Cold War was heating up, Anslinger changed his view. He likened cannabis to a falling domino stating that cannabis addicts graduate to heroin once the thrill of weed is gone. This resonated with people of the era who were familiar with the idea of Communism toppling one country after the other, like a domino.

The idea stuck and persisted through the Nancy Reagan, “Just Say No” era.

What does the science say? 

The science in unclear, at best. On one hand, studies show that cannabis use precedes other drug use. But this by no means indicates that cannabis causes other drug use. Instead, it is commonly believed that the reason cannabis precedes other drug use is that it is more easily accessible. Under this reasoning, nicotine, tobacco, and alcohol would also be considered “gateway drugs”. It’s clear that accessibility plays a major role individual use patterns.

Of concern is the impact of cannabis (mainly THC-rich cannabis) on the developing brain. Adolescent exposure to THC impairs dopamine signaling in the brain in response to other rewards. This affects the strength of drug-associated reward, and hypothetically, lead to the use of harder drugs in order to achieve a strong high. Consistent with this idea, rats exposed to large amounts of THC (or just their parents!) are more likely to seek heroin in adulthood.

But this doesn’t mean people behave like this in the real world. For one, we’re given more choices for how to live our lives than rats in a cage. And just because there may be some shift in brain chemistry, it’s unlikely to sufficiently alter reward perception to the point that heroin is the only means of living a pleasurable life.

To date, there haven’t been any studies linking adolescent cannabis use to harder drug use that aren’t confounded by genetic, environmental, or socio-economic factors. So given our current level of scientific and political understanding, the simplest answer to the question, is cannabis a gateway drug? is NO. The main reasons being: 1) an historical perspective reveals that this stance was taken for political reasons, and not based on science; 2) confirmational bias leads us to confirm our belief that cannabis is a gateway drug because “hard drug” is often preceded by cannabis, even though cannabis is merely the more easily accessible and economic choice.

Original posting date: February 17, 2018

A recent article published in the journal, Addiction, looked at the impact of adolescent alcohol and cannabis use on brain structural characteristics. The scientists used a brain imaging technique called MRI (yes, the same thing used to diagnose your torn ACL) and looked at numerous characteristics relating to number of brain cells and how they connect across different brain areas.

To the excitement of the cannabis community, alcohol use was associated with numerous abnormal structural characteristics, while cannabis appeared to have no effect. “See, cannabis is safe!” I read on numerous cannabis sites. I got emails, “what do you think of this? Exciting, huh?”

Let’s pump the breaks. Yes, adolescent alcohol exposure is bad. That’s not surprising. Not only does alcohol perturb normal brain function when it’s in the system, leading to shifts in the way brain cells act, but it also increases inflammation in the brain leading to a host of long-term consequences such as the changes in brain structure reported in this article. But THC, the high-inducing chemical in cannabis, is known to cause detrimental effects on the developing brain even in the absence of overt structural changes.

THC has been shown in numerous studies to affect the manner in which brain cells connect to one another and synchronize their activity. This shift in what’s known as “functional connectivity” can lead to long-term consequences on cognitive function and psychology health. Adolescent THC exposure is also associated with increased risk for developing schizophrenia. THC can cause 1) an acute psychotic episode, 2) one that persists beyond THC’s action in the brain, and 3) long lasting psychosis that requires clinical intervention.

Some of the negative effects of cannabis on the developing brain are thought to result from perturbation to the connections between the brain’s cortex, which controls everything from decision making to sensory perception, and the thalamus, which acts as an important relay station in the brain. By impairing the connections between the cortex and the thalamus, cannabis can lead to impairments in cognitive and executive functioning, and disorganized thinking associated with schizophrenia. It’s noted however that this particular mechanism is up for debate.

There are numerous disorders that often don’t have overt structural signatures including depression, anxiety, and PTSD. Instead, many symptoms result an imbalance in the chemicals brain cells use to communicate, called neurotransmitters. Shifts in neurotransmitters levels, and the sensitivity of their receptors, can be altered by cannabis exposure. This effect has long-term consequences in the developing brain of an adolescent.

While we can be excited about cannabis’ wide scope of therapeutic benefits, let’s not let that cloud the reality of its potential risk. THC-rich cannabis may not have as detrimental effects on the developing brain as alcohol, but it’s not accurate to say that it’s safe. For both drugs, it’s best to wait until the brain is fully developed to mitigate any long-term adverse consequences.

In 1971, Congress created the National Commission on Marijuana and Drug Abuse, now called the Schaffer Commission. A reluctant President Richard Nixon appointed 13 members to the group that consisted of senators, congressmen, and physicians. One of these members, Dr. Thomas Ungerleider was a psychiatrist and researcher at UCLA. Nearly 30 years after the commission was formed, Dr. Ungerleider reflected on the experience in a paper titled: Marijuana: Still a “Signal of Misunderstanding”. This title alludes to the title of their first year’s report: “Marijuana, Signal of Misunderstanding”, in which the commission unanimously recommended that cannabis be decriminalized. Notably, they did not recommend legalization, but they felt strongly that possession should not be grounds for imprisonment. In the end, the commission’s recommendation was opposed in Congress, and the Nixon administration failed to implement its recommendations. Consequently, 25 years after the report was issued, there were still nearly 600,000 arrests for personal possession.

One of the commission’s task’s was to travel around the world to study cannabis laws and use patterns in various countries. These experiences revealed the global pervasiveness of the United State’s anti-marijuana agenda. The United States had a major influence in the 1961 Single Convention on Narcotic Drugs, which established an international treaty for outlawing specific drugs, including cannabis.

Adhering to the treaty’s policy against cannabis exposed a country’s bias against certain ethnic and socioeconomic groups. Just as the United States justified cannabis’ illegality by tying its use to crime among immigrant populations, Dr. Ungerledier recalls several instances in which the stated justification for a country’s cannabis policy diverged from the truth. These stories were divulged to members of the commission in unofficial meetings and social events, often after the consumption of “free-flowing use of alcohol”.

Global reach

In India, there were two types of cannabis: 1) the stronger smoked cannabis (called charas), which was illegal, and 2) the legal weaker cannabis beverage (called bhang). The official reason charas was illegal was because it was reported to be more like heroin, whereas bhang was like coffee. But Dr. Ungerleider reports that the real reason charas was illegal was because it was used mainly by the lower class while bhang was commonly used by the upper class. By making charas illegal, India complied with the international treaty established at the Single Convention on Narcotic Drugs that was strongly supported by the US, while preserving its use among the upper class.

In South Africa, marijuana, or dagga as it was called, was illegal for the official reason that it harmed the nation’s youth. But dagga was mainly used by the Bantu natives suppressed by the apartheid regime. After centuries of use by the Bantu, there was a growing market for dagga among the white middle class. It was feared that the money used to purchase dagga from the Bantu would be used to buy weapons to overthrow apartheid. This fear was revealed to the commission in unofficial meetings with government officials, adding to the number of countries that used cannabis laws to suppress minorities and the lower classes.

Iran adopted a policy of capital punishment for cannabis smuggling. Of the 160 smugglers who were executed, all were Afghans, thereby preserving the cannabis smuggling operation for Iranians citizens.

Dr. Ungerleider recalls heavy skepticism of the commissioners wherever they visited. Some foreign agents assumed they were on a secret mission with the CIA, or investigating other drugs like heroin or cocaine. Most couldn’t fathom that the United States would invest resources towards the study of cannabis alone. He remembers statements like, “You are not really a marijuana commission; no one would appoint a commission to study just marijuana. How gullible do you think we are?”

The commission was not on a mission for the CIA, nor were they secretly investigating other drugs, but they did discover ways in which a US-led international drug treaty was used to suppress minorities, immigrants, and the lower-class. What they couldn’t find was the serious harm their own government claimed cannabis caused. Instead, cannabis’ greatest harm seemed to stem from the way it was handled by the governments themselves.

Note: this was originally published on May 3, 2018 by Josh Kaplan

By Kaylee Martig

Many disorders, including Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), and mood disorders have a neurological basis in the body’s endocannabinoid system. The endocannabinoid system (further discussed in each disorder’s section) is comprised of cannabinoid type I and type II receptors (CB1 and CB2, respectively) which are activated by compounds known as cannabinoids. Types of cannabinoids include endogenous cannabinoids, which are produced by the body and include neurotransmitters 2-AG and anandamide, phyto-cannabinoids, which are produced by plants, and synthetic cannabinoids, which are produced artificially. Cannabis, commonly known as marijuana, contains over 100 phyto-cannabinoids, some of which act on the body’s natural cannabinoid receptors as well as other relevant targets for therapeutic use in disorders including ASD, ADHD, and mood disorders. The two most prominent phyto-cannabinoids produced by cannabis are tetrahydrocannabinol (THC) and cannabidiol (CBD).

THC is intoxicating and is responsible for the euphoric “high” associated with cannabis use. It often causes drowsiness and increased appetite, which can sometimes be beneficial. CBD, however, is non-intoxicating, and is responsible for many of the therapeutic benefits associated with cannabis. Many studies have demonstrated CBD’s anti-inflammatory, neuroprotective, anxiolytic (anti-anxiety), and antipsychotic properties (1). One way CBD works in the brain by inhibiting the reuptake and enzymatic degradation of anandamide, increasing plasma anandamide levels, which may compensate for the low levels associated with disorders such as ASD (2). This is one mechanism by which cannabis may mediate the effects of such disorders in the brain.

Different strains of cannabis have differing ratios of THC to CBD, which can be used to target specific symptoms. For example, in ASD, the drowsiness and increased appetite associated with THC may improve symptoms of comorbid sleep and feeding disorders. Meanwhile, the anxiolytic and antipsychotic properties of CBD may improve anxiety and self-injury. In bipolar disorder, the antidepressant-like effects of THC may improve mood, while the antipsychotic properties of CBD may prevent cannabis-induced psychosis. Many treatments use a combination of CBD, THC, and other phyto-cannabinoids, which are more effective when used in combination. One study which compared five strains of CBD-rich cannabis, all with similar amounts of CBD, found different strains produced different effects, demonstrating different combinations of phyto-cannabinoids can be more effective than CBD or THC alone (3, 4). This is called the “entourage effect,” and supports the use of whole-plant products over CBD/THC extracts.

Another result of the entourage effect is a wider therapeutic window. Purified CBD extracts yield a bell-shaped dose-response, in which too-low and too-high doses are ineffective, producing a narrow therapeutic window (5). The therapeutic dose may differ depending on the desired effect (e.g., a lower dose may be effective for anxiety whereas a higher dose is effective for epilepsy), but means it may be difficult to treat multiple symptoms simultaneously. However, one study found a wider therapeutic window for a whole-plant product over a purified CBD extract, due to the entourage effect (5). Finally, the entourage effect may cause CBD to lessen the intoxicating effect of THC, permitting the administration of higher doses without a “high” and with a lower risk of cannabis-induced psychosis (4, 6).

Cannabis’ current clinical utility is limited by a relative lack of research on both efficacy and safety, particularly regarding long-term use. There is evidence that THC-rich cannabis can harm the developing brain. However, the long-term effects of CBD-rich cannabis use in children are not well known, despite promising short-term results. Adverse effects in short-term use include sleep disturbances, drowsiness, irritability, and changes in appetite (7, 8). However, most of the research on cannabis use for ASD and other disorders study only short-term use (weeks to months), meaning we do not know potential long-term effects. Some studies have shown that adolescents may be more vulnerable to adverse effects caused by cannabis, relative to adults, due to ongoing neuromaturation (9). However, these adverse effects appear to be linked primarily to THC, rather than the CBD-rich strains which are being used to treat these disorders (2).

Another factor to consider is interactions between medical cannabis and other drugs used to treat the disorders. In one study, 82% of children being treated with cannabis were receiving another drug concurrently, such as antipsychotics (72%), mood stabilizers (17%), benzodiazepines (12%) and SSRI antidepressants (7%) among others (10). One mechanism through which CBD interacts with prescription drugs is the temporary deactivation of cytochrome P450 liver enzymes, which affects the metabolism of other drugs (7, 11). Some drugs may rise to toxic levels when administered in conjunction with cannabis, because the deactivation of the P450 enzyme prevents the breakdown and removal of the drug in the body, causing it to remain more potent for longer than intended. Anti-epileptic medications, CNS depressants, SSRIs, tricyclic antidepressants, and lithium, all commonly used to treat ASD and mood disorders, are just a few drugs which fall into this category (12, 13, 14). Other drugs, however, may become less effective when administered in conjunction with cannabis, as the deactivation of the P450 enzyme can prevent the drug from being broken down and used in the body, making it less potent than intended (11). Risperidone, an antipsychotic used to treat schizophrenia, bipolar disorder, and behavioral disorders associated with autism, falls into this category (7).

More research must be conducted on interactions between cannabis and prescription drugs before they are considered safe for use, as research to date has been inconclusive (14). Some studies report no described interactions between prescription drugs and cannabis, when low to moderate doses of cannabis were used. However, doses upwards of 20mg CBD per kilogram of body weight may be used to treat disorders such as epilepsy, and could increase the risk of interactions (15). Geffrey et al. (12) emphasize the importance of monitoring drug levels in patients who are using CBD. Drug interactions can increase the risks associated with treatment using cannabis, although 24% of the children in the aforementioned study by Aran et al. (10) were able to stop taking the other prescription drugs following the cannabis treatment. Treatment with cannabis is becoming more common for a variety of disorders, but safety and efficacy are dependent on a number of factors, including strain, dose, mode of ingestion, and personal factors, and long-term outcomes are largely unknown.

 

 

References

1. Devinsky, O., Cilio, M. R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., . . . Friedman, D. (2014). Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 55. doi:10.1111/epi.12631
2. Poleg, S., Golubchik, P., Offen, D., & Weizman, A. (2018). Cannabidiol as a suggested candidate for treatment of autism spectrum disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 89, 90-96. doi:10.1016/j.pnpbp.2018.08.030
3. Berman, P., Futoran, K., Lewitus, G. M., Mukha, D., Benami, M., Shlomi, T., & Meiri, D. (2018). A new ESI-LC/MS approach for comprehensive metabolic profiling of phytocannabinoids in Cannabis. Scientific Reports, 8. doi:10.1038/s41598-018-32651-4
4. Russo, E., & Guy, G. W. (2006). A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Medical Hypotheses, 66, 234-246. doi:10.1016/j.mehy.2005.08.026
5. Gallily, R., Yekhtin, Z., & Hanus, L. O. (2014). Overcoming the bell-shaped dose-response of cannabidiol by using Cannabis extract enriched in cannabidiol. Pharmacology & Pharmacy, 6, 75-85. doi:10.4236/pp.2015.62010
6. Iseger, T. A., & Bossong, M. G. (2015). A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophrenia Research, 162, 153-161. doi:10.1016/j.schres.2015.01.033
7. Barchel, D., Stolar, O., De-Haan, T., Ziv-Baran, T., Saban, N., Fuchs, D. O., . . . Berkovitch, M. (2019). Oral cannabidiol use in children with autism spectrum disorder to treat related symptoms and co-morbidities. Frontiers in Pharmacology. doi:10.3389/fphar.2018.01521
8. Porter, B. E., & Jacobson, C. (2013). Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior, 29, 574-577. doi:10.1016/j.yebeh.2013.08.037
9. Tapert, S. F., Schweinsburg, A. D., & Brown, S. A. (2008). The influence of marijuana use on neurocognitive functioning in adolescents. Current Drug Abuse Reviews, 1, 99-111. doi:10.2174/1874473710801010099
10. Aran, A., Cassuto, H., Lubotzky, A., Wattad, N., & Hazan, E. (2018). Brief report: Cannabidiol-rich cannabis in children with Autism Spectrum Disorder and severe behavioral problems – a retrospective feasibility study. Journal of Autism and Developmental Disorders, 1-5. doi:10.1007/s10803-018-3808-2
11. Devitt-Lee, A. (2015). CBD-drug interactions: Role of cytochrome P450. Project CBD. Retrieved from https://www.projectcbd.org/science/cannabis-pharmacology/cbd-drug-interactions-role-cytochrome-p450
12. Geffery, A. L., Pollack, S. F., Bruno, P. L., & Thiele, E. A. (2015). Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia, 56, 1246-1251. doi:10.1111/epi.13060
13. Lindsey, W. T., Stewart, D., & Childress, D. (2012). Drug interactions between common illicit drugs and prescription therapies. The American Journal of Drug and Alcohol Abuse, 38, 334-343. doi:10.3109/00952990.2011.643997
14. Rong, C., Carmona, N. E., Lee, Y. L., Ragguett, R., Pan, Z., Rosenblat, J. D., . . . McIntyre, R. S. (2017). Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents. Expert Opinion on Drug Safety, 17, 51-54. doi:10.1080/14740338.2017.1397128

15. Devinsky, O., Patel, A. D., Thiele, E. A., Wong, M. H., Appleton, R., Harden, C. L., . . . Sommerville, K. (2018). Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology, 90, 1204-1211. doi:10.

By Kaylee Martig

Mood disorders are a category of psychiatric disorders characterized by changes in affect. Two common mood disorders are depression and bipolar disorder. Symptoms of depression include “depressed mood” or “loss of interest or pleasure,” which may be accompanied by an increase or decrease in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness, or suicidal ideation (1). Symptoms of bipolar disorder include mania, which is described in the DSM-5 as “a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity and energy,” that may cycle with depressive symptoms. Although multiple classifications of bipolar disorder exist, it will be discussed as a single inclusive disorder in this paper.

There is accumulating research demonstrating the influential role of the endocannabinoid system in mood disorders. As previously described, the endocannabinoid system is comprised of CB1 and CB2 receptors which are activated by endogenous cannabinoid neurotransmitters. While it is not known exactly how the endocannabinoid system is related to mood disorders, two hypotheses include inhibition/excitation and regulation of the serotoninergic system. It is well established that the endocannabinoid system regulates inhibition and excitation in the brain; and when this system is dysfunctional, extreme inhibition or excitation of the brain may lead, respectively, to depression or mania (2, 3). Furthermore, CB1 receptors may play a role in the regulation of the serotoninergic system, which is dysregulated in depression (4).

Dysregulation of inhibition/excitation in the brain is associated with many psychiatric disorders, including schizophrenia, anxiety, and depression (2, 3). In a postmortem investigation, researchers found lower concentrations of CB1 receptors in the anterior cingulate cortex of individuals with unipolar depression than in healthy brains (5). Clinical observations suggest the endocannabinoid system and CB1 receptors may be similarly implicated in depression associated with bipolar disorder (2). The association between reduced CB1 activity and depression suggests drugs which increase CB1 activation may compensate for decreased CB1 activity and improve depressive symptoms. Animal studies have found that cannabinoids which increase CB1 activation elicit antidepressant effects in small doses, although they actually appear to have the opposite effect in high doses, with the potential to worsen depressive symptoms (6, 7). This supports the utility of cannabinoids as treatment for depression through the regulation of inhibition/excitation of the endocannabinoid system, although more research is needed to identify optimal dosing.

Conventional treatments for depression, including SSRI and tricyclic antidepressants, work in the brain by increasing the availability of serotonin. A number of studies in mouse models of depression found the administration of CBD increased serotonin levels, and CBD, THC, and other phyto-cannabinoids reversed depressive behaviors (7, 8, 9). In humans, THC (5-10mg) administered through smoking herbal cigarettes has been shown to decrease subjective ratings of depression and improve sleep under placebo-controlled conditions (2). The endocannabinoid system may be implicated through the activation of CB1 receptors and through regulation of the serotoninergic system. Clinical studies are needed to establish efficacy and determine a therapeutic dosing window, however anecdotal evidence indicates that a number of patients have found cannabis useful in treating symptoms of both depression and mania, sometimes more so than conventional treatments (10).

Still, there are risks associated with cannabis use, particularly in bipolar disorder. Cannabis use disorders are frequently diagnosed in people with bipolar disorder, with yearly incidence of 7.2% in people with bipolar disorder, compared to 1.2% in the general population (11). This may result from self-medication practices. The self-medication theory is supported by slightly worse symptomology in people with bipolar disorder who used cannabis compared to those with bipolar disorder who did not use cannabis, including higher levels of depressive and manic symptoms (12). The symptomology was worse prior to cannabis use, and improved within several hours of cannabis use. While anecdotal evidence has endorsed cannabis use in mania, research suggests THC use may induce or exacerbate mania. Those who used cannabis recreationally or for self-medication exhibit higher levels of illness severity, mania, and psychosis compared with nonusers (11; 13).

One of the major concerns about cannabis use is that it can trigger mania in people who are diagnosed with or are predisposed to bipolar disorder. High doses or rapid administration of THC, common in recreational use, can induce acute psychosis with hypomanic features in subjects without a mood disorder (2). One study found that intravenous administration of THC (2.5mg) induced positive psychotic symptoms in healthy adults (14). However, in people with bipolar disorder, cannabis use is associated with the onset and exacerbation of manic symptoms, as well as younger age of onset of mania and more frequent manic and depressive episodes (15, 16). These effects are likely caused by THC. CBD has antipsychotic properties and may actually lower the risk of cannabis-related psychosis (17). Therefore, psychotic and manic symptoms may be reduced by using cannabis products with substantial CBD levels.

Intriguingly, a study of adults found those with bipolar disorder who were also diagnosed with a cannabis use disorder demonstrated better neurocognitive performance than those without a diagnosis of a cannabis use disorder (18). Bipolar disorder, especially during manic episodes, is associated with neurocognitive deficits including deficits in attention, working memory, verbal learning, delayed verbal and nonverbal memory, and executive function (19). Results from the aforementioned research included better performance on measures of attention, working memory, verbal learning, processing speed, and executive functioning in cannabis users (18, 20). Cannabis (CBD alone and 1:1 CBD:THC) is known to have some neuroprotective properties against neurodegenerative conditions, such as Huntington’s disease (21). These areas of improved neurocognitive performance suggest cannabis use may also counteract some of the neurocognitive deficits associated with bipolar disorder. The information regarding recreational use of cannabis for people with bipolar disorder is inconclusive, and individuals with this disorder should use caution when deciding whether to use cannabis.

It is important to note that the use of cannabis for mood disorders have only been studied in adults, and cannot be directly generalized to children and adolescents. While cannabis appears to have some benefits for adults with mood disorders, it is unknown whether the neuroprotective properties of CBD would apply to children and adolescents, or whether cannabis would be an effective treatment for mood disorders in children. Furthermore, recreational cannabis use, specifically the use of THC, during adolescent development has been shown in numerous studies to increase the risk of psychiatric disorders including mood and psychotic disorders (22). Even adult recreational use may be unwise for people with bipolar disorder, due to the risk of psychosis. To date, research regarding the safety and efficacy of cannabis use in bipolar disorder is inconclusive, and may be impacted by factors including dose, mode of ingestion, and personal factors (12). As a whole, more research is needed to demonstrate long-term safety and efficacy of cannabis use, particularly in children.

References

1. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5^th ed.). doi:10.1176/appi.books.9780890425596
2. Ashton, C. H., & Moore, P. B. (2011). Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatrica Scandinavica, 124. doi:10.1111/j.1600-0447.2011.01687.x
3. Micale, V., Di Marzo, V., Sulcova, A., Wotjak, C. T., & Drago, F. (2013). Endocannabinoid system and mood disorders: Priming a target for new therapies. Pharmacology & Therapeutics, 138, 18-37. doi:10.1016/j.pharmthera.2012.12.002
4. Haj-Dahmane, S. & Shen, R. (2011). Modulation of the serotonin system by endocannabinoid signaling. Neuropharmacology, 61, 414-420. doi:10.1016/j.neuropharm.2011.02.016
5. Koethe, D., Llenos, I. C., Dulay, J. R., Hoyer, C., Torrey, E. F., Leweke, F. M., & Weis, S. (2007). Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression. Journal of Neural Transmission, 114, 1055-1063. doi:10.1007/s00702-007-0660-5
6. Bambico, F. R., Katz, N., Debonnel, G., & Gobbi, G. (2007). Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex. Journal of Neuroscience, 27, 11700-11711. doi:10.1523/JNEUROSCI.1636-07.2007
7. El-Alfy, A. T., Ivey, K., Robinson, K., Ahmed, S., Radwan, M, Slade, D., . . . Ross, S. (2010). Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Pharmacology Biochemistry and Behavior, 95, 434-442. doi:10.1016/j.pbb.2010.03.004
8. Linge, R., Jimenez-Sanchez, L., Campa, L. Pilar-Cuellar, F., Vidal, R., Pazos, A., . . . Diaz, A. (2016). Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: Role of 5-HT1A receptors. Neuropharmacology, 103, 16-26. doi:10.1016/j.neuropharm.2015.12.017
9. Zanelati, T. V., Biojone, C., Moreira, F. A., Guimaraes, F. S., & Joca, S. R. (2010). Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT1A receptors. British Journal of Pharmacology, 159, 122-128. doi:10.1111/j.1476-5381.2009.00521.x
10. Grinspoon, L., & Bakalar, J. B. (1998). The use of cannabis as a mood stabilizer in bipolar disorder: Anecdotal evidence and the need for clinical research. Journal of Psychoactive Drugs, 30, 171-177. doi:10.1080/02791072.1998.10399687
11. Lev-Ran, S., Le Foll, B., McKenzie, K., George, T. P., & Rehm, J. (2013). Bipolar disorder and co-occurring cannabis use disorders: Characteristics, co-morbidities and clinical correlates. Psychiatry Research, 209, 459-465. doi:10.1016/j.psychres.2012.12.014
12. Sagar, K. A., Dahlgren, M. K., Racine, M. T., Dreman, M. W., Olson, D., P., & Gruber, S. A. (2016). Joint effects: A pilot investigation of the impact of bipolar disorder and marijuana use on cognitive function and mood. PLoS One, 11. doi:10.1371/journal.pone.0157060
13. Van Rossum, I., Boomsms, M., Tenback, D., Reed, C., van Os, J., & the EMBLEM Advisory Board (2009). Does cannabis use affect treatment outcome in bipolar disorder? The Journal of Nervous and Mental Disease, 197, 35-40. doi:10.1097/NMD.0b013e31819292a6
14. Morrison, P. D., Zois, V., McKeown, D. A., & Lee, T. D. (2009). The acute effects of synthetic intravenous Δ9-tetrahydrocannabinol on psychosis, mood and cognitive functioning. Psychological Medicine, 39, 1607-1616. doi:10.1017/S0033291709005522
15. Bally, N., Zillino, D., & Aubry, J. (2014). Cannabis use and first manic episode. Journal of Affective Disorders, 165, 103-108. doi:10.1016/j.jad.2014.04.038
16. Gibbs, M., Winsper, C., Marwaha, S., Gilbert, E., Broome, M., & Singh, S. P. (2015). Cannabis use and mania symptoms: A systematic review and meta-analysis. Journal of Affective Disorders, 171, 39-47. doi:10.1016/j.jad.2014.09.016
17. Iseger, T. A., & Bossong, M. G. (2015). A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophrenia Research, 162, 153-161. doi:10.1016/j.schres.2015.01.033
18. Braga, R. J., Burdick, K. E., DeRosse, P., & Malhotra, A. K. (2012). Cognitive and clinical outcomes associated with cannabis use in patients with bipolar I disorder. Psychiatry Research, 200, 242-245. doi:10.1016/j.psychres.2012.05.025
19. Kutz, M. M., & Gerraty, R. T. (2009). A meta-analytic investigation of neurocognitive deficits in bipolar illness: Profile and effects of clinical state. Neuropsychology, 23, 551-562. doi:10.1037/a0016277
20. Ringen, P. A., Vaskinn, A., Sundet, K., Engh, J. A., Jonsdottir, H., Simonsen, C., . . . Andreassen, O. A. (2010). Opposite relationships between cannabis use and neurocognitive functioning in bipolar disorder and schizophrenia. Psychological Medicine, 40, 1337-1347. doi:10.1017/S0033291709991620
21. Campos, A. C., Fogaca, M. V., Sonego, A. B., & Guimaraes, F. S. (2016). Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacological Research, 112, 119-127. doi:10.1016/j.phrs.2016.01.033
22. Chadwick, B., Miller, M. L., & Hurd, Y. L. (2013). Cannabis use during adolescent development: Susceptibility to psychiatric illness. Frontiers in Psychiatry, 4. doi:10.3389/fpsyt.2013.00129

By Kaylee Martig

Autism Spectrum Disorder (ASD) is characterized by persistent social, communicative, and locomotor deficits across multiple contexts. Symptoms may include deficits in social-emotional reciprocity, nonverbal communicative behaviors, and relationships; and restricted, repetitive patterns of behavior, interests, or activities, such as stereotyped or repetitive movements, insistence on sameness, fixated interests, or sensory processing differences (1). Comorbidities of ASD may include sleep disorders (54.7% prevalence), Attention Deficit Hyperactivity Disorder (ADHD; 88.7% prevalence), self-injury (88.7% prevalence), anxiety (49.1% prevalence) and epilepsy (2, 3). As many as 1.6% of 8-year-old children are diagnosed with ASD. Currently, there are no treatments for its core symptoms, including social and communication deficits, only for its comorbid symptoms, such as self-injury and anxiety, which are often treated with drugs including antipsychotics and antidepressants (4). Because conventional treatments are not always effective, and often have adverse side-effects, more parents are turning to less conventional treatments, including using medical cannabis, to treat severe symptoms.

There are many neurological underpinnings of ASD, including excess cortical excitation and impaired anandamide signaling, which are based in the body’s endocannabinoid system. As previously described, the endocannabinoid system is comprised of CB1 and CB2 receptors which are activated by endogenous cannabinoid neurotransmitters 2-AG and anandamide. Through various mechanisms, the endocannabinoid system controls emotional responses, contextual behavioral reactivity, social interaction, and circadian rhythms (4). This suggests that many of the symptoms and comorbidities of ASD, including deficits in social-emotional reciprocity, anxiety, and sleep disturbances, may be mediated by the endocannabinoid system.

One function of the endocannabinoid system is to regulate levels of cortical inhibition/excitation. Excess cortical excitation can cause hyper-sensitivity and hyper-reactivity, which are related to many of the symptoms and comorbidities of ASD. The inhibition/excitation balance could be restored by decreasing excitation or increasing inhibition. A recent study found CBD to contribute to this regulation in people with ASD (5). Additionally, decreased levels of the cannabinoid anandamide in the endocannabinoid system may contribute to symptoms of ASD. The first study of anandamide in children with ASD found significantly lower plasma levels of anandamide in children with ASD, supporting impaired anandamide signaling as a key factor in ASD (6). These connections are promising in considering treatment with cannabis, which can regulate inhibition/excitation and increase levels of anandamide.

A report from one early-stage clinical trial found improvement in “at least one of the core symptoms of ASD” in most cases of children being treated with cannabis with various THC:CBD ratios (7). This study also noted improvement in comorbid symptoms, including sensory difficulties, feeding and sleep disorders, and seizures. Additional studies have focused on using CBD-rich cannabis (1:20 ratio of THC:CBD) to treat comorbid symptoms, including behavioral outbreaks/self-injury, hyperactivity, anxiety, and feeding and sleep disorders in children with ASD (2, 8). Improvement was noted in the majority of children, with minimal adverse effects, which included sleep disturbances, drowsiness, irritability, and changes in appetite. These findings suggest non-inferiority of treatment with CBD (see table 1.1), although more research is needed to establish efficacy in treating core symptoms.

 

Table 1.1 Comparison of Cannabis to Conventional Treatments

Symptom	Improvement with cannabis (1:20 THC:CBD)	Improvement with conventional treatment
hyperactivity	68.4%	80% (methylphenidate)
self-injury	67.6%	82% (aripiprazole)
sleep problems	71.4%	60% (melatonin)
anxiety	47.1%	55-73% (SSRIs)

In all comorbid symptoms of ASD, non-inferiority of CBD was observed (2).

 

The benefits of cannabis for epilepsy, another common comorbidity of ASD due to similar neural mechanisms that reflect decreased inhibition, are also being increasingly researched, and have appeared effective in preventing seizures preclinical models as well as numerous case studies (9, 10). Extensive research supports the use of CBD-rich cannabis to reduce seizure frequency in cases of treatment-resistant epilepsy, particularly in children with Dravet Syndrome and Lennox-Gastaut Syndrome (11, 12). One recent study found that in a group of children with drug-resistant Dravet Syndrome, 62% of children experienced improvement in their overall condition while using CBD-rich cannabis (13). While it is difficult to ascertain the prevalence of cannabis use for ASD or its comorbidities, it appears more parents are administering cannabis to their children, especially in cases where conventional drugs have failed. One mother credits cannabis for reducing self-injurious and violent behavior in her 12-year-old son with low-functioning ASD who, even while taking antipsychotics, could have as many as 300 violent episodes in a day (14).

In summary, more research is required to establish whether cannabis is an effective and safe treatment for ASD in children. Abnormalities in the endocannabinoid system likely contribute to ASD symptoms and comorbidities, making CBD a plausible treatment by increasing anandamide to normal levels. In preclinical and early clinical studies, adverse effects appear to be limited. However, more research should be conducted to demonstrate long-term safety of cannabis use, particularly in children. It is important to note that any drug should be used only when benefits outweigh the potential risks, and as such conversation surrounding the use of cannabis to treat ASD should be for the treatment of severe symptoms, such as severe feeding disorders and self-harm, rather than neurodivergence. The goal is not to eradicate diversity but to improve functioning and quality of life.

References

1. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5^th ed.). doi:10.1176/appi.books.9780890425596
2. Barchel, D., Stolar, O., De-Haan, T., Ziv-Baran, T., Saban, N., Fuchs, D. O., . . . Berkovitch, M. (2019). Oral cannabidiol use in children with autism spectrum disorder to treat related symptoms and co-morbidities. Frontiers in Pharmacology. doi:10.3389/fphar.2018.01521
3. Poleg, S., Golubchik, P., Offen, D., & Weizman, A. (2018). Cannabidiol as a suggested candidate for treatment of autism spectrum disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 89, 90-96. doi:10.1016/j.pnpbp.2018.08.030
4. Chakrabarti, B., Persico, A., Battista, N, & Maccarrone, M. (2015). Endocannabinoid signaling in autism. Neurotherapeutics, 12, 837-847. doi:10.1007/s13311-015-0371-9
5. Pretzsch, C. M., Freyberg, J., Voinescu, B., Lythgoe, D., Horder, J., Mendez, M. A., . . . McAlonan, G. M. (2019). Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology. doi:10.1038/s41386-019-0333-8
6. Karhson, D. S., Krasinska, K. M., Dallaire, J. A., Libove, R. A., Phillips, J. M., Chien, A. S., . . . Parker, K. J. (2018). Plasma anandamide concentrations are lower in children with autism spectrum disorder. Molecular autism, 9. doi:10.1186/s13229-018-0203-y
7. Kuester, G., Vergara, K., Ahumada, A., & Gazmuri, A. M. (2017). Oral cannabis extracts as a promising treatment for the core symptoms of autism spectrum disorder: Preliminary experience in Chilean patients. Journal of the Neurological Sciences, 381, 932-933. doi:10.1016/j.jns.2017.08.2623
8. Aran, A., Cassuto, H., & Lubotzky, A. (2018). Cannabidiol based medical cannabis in children with Autism – a retrospective feasibility study. Neurology, 90. Retrieved from http://n.neurology.org/content/90/15_Supplement/P3.318
9. Devinsky, O., Cilio, M. R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., . . . Friedman, D. (2014). Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 55. doi:10.1111/epi.12631
10. Porter, B. E., & Jacobson, C. (2013). Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior, 29, 574-577. doi:10.1016/j.yebeh.2013.08.037
11. Elliot, J., DeJean, D., Clifford, T., Coyle, D., Potter, B. K., Skidmore, B., . . . Wells, G. A. (2018). Cannabis-based products for pediatric epilepsy: A systematic review. Epilepsia, 60. doi:10.1111/epi.14608
12. O’Connell, B. K., Gloss, D., & Devinsky, O. (2017). Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy & Behavior, 70, 341-348. doi:10.1016/j.yebeh.2016.11.012
13. Devinsky, O., Cross, H., Laux, L., Marsh, E., Miller, I., Nabbout, R., . . . Thiele, E. A. (2017). Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome. New England Journal of Medicine. doi:10.1056/NEJMoa1611618
14. Myung-Ok Lee, M. (2017). I made my son cannabis cookies. They changed his life. The Washington Post. Retrieved from https://www.washingtonpost.com/opinions/i-made-my-son-cannabis-cookies-they-changed-his-life/2017/01/06/699b1d20-d1ef-11e6-a783-cd3fa950f2fd_story.html?noredirect=on&utm_term=.a8c07e3c9bc6

Cannabis and Attention Deficit Hyperactivity Disorder

By Kaylee Martig

Attention Deficit-Hyperactivity Disorder (ADHD) is characterized by symptoms of inattention and hyperactivity/impulsivity which begin before age 12, are present in multiple settings, and interfere with daily functioning. ADHD can be classified as predominately inattentive presentation (previously known as Attention Deficit Disorder), predominantly hyperactive-impulsive presentation, or combined presentation (1). Extensive research has demonstrated the role of abnormal dopamine transmission and dopamine deficiency in ADHD, which may implicate the endocannabinoid system. As previously described, the endocannabinoid system is comprised of CB1 and CB2 receptors which are activated by endogenous cannabinoids 2-AG and anandamide. Dopamine and the endocannabinoid system have a bidirectional relationship, in which dopamine affects the endocannabinoid system, and cannabinoids affect the dopamine system. Animal models have demonstrated the role of dopamine in modulating the endocannabinoid system, resulting in reduced sensitivity of CB1 receptors and increased anandamide levels in people with ADHD (2). This suggests drugs which restore CB1 function may be effective in treating ADHD (3). However, any associations between cannabinoids and ADHD are only speculative at this point.

While CBD has been shown to significantly improve hyperactivity in children with Autism Spectrum Disorder (ASD; 4), there is no evidence from randomized controlled studies to support cannabis as treatment for ADHD. Conventional ADHD medications, including amphetamine and methylphenidate (Ritalin), work by increasing dopamine and norepinephrine activity (5). Acute THC ingestion may similarly increase dopamine release (6). One study found nominally significant improvement in symptoms of hyperactivity/impulsivity in 30 adults with ADHD who used a cannabinoid medication (1:1 THC:CBD; 7). However, in chronic use, THC actually blunts the dopamine system, which could worsen ADHD (6). Additionally, CBD increases anandamide levels, already high in people with ADHD (this is opposite of ASD). The lack of research on cannabis use in ADHD makes it difficult to know the potential long-term effects. Presently, the majority of research surrounding ADHD and cannabis focuses on the co-occurrence of ADHD and cannabis use disorders.

People with ADHD are more likely to engage in cannabis use earlier, become a heavy user, and develop a cannabis use disorder (8). It is unclear whether early cannabis use causes ADHD symptoms, or whether the heavier cannabis use is caused by self-medication of ADHD symptoms. The self-medication theory is supported by findings that daily cannabis users were more likely to experience hyperactive-impulsive symptoms when not using cannabis (9). However, until there is more research on the association between ADHD symptoms and the endocannabinoid system and cannabis use, it is not advisable to use cannabis to treat hyperactivity associated with ADHD.

References

1. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5^th ed.). doi:10.1176/appi.books.9780890425596
2. Castelli, M., Federici, M., Rossi, S., De Chiara, V., Napolitano, F., Studer, V., . . . Centonze, D. (2011). Loss of striatal cannabinoid CB1 receptor function in attention‐deficit / hyperactivity disorder mice with point‐mutation of the dopamine transporter. European Journal of Neuroscience, 34. doi:10.1111/j.1460-9568.2011.07876.x
3. Bracci, E. (2011). The endocannabinoid system misfires in ADHD mice (Commentary on Castelli et al.). European Journal of Neuroscience, 34. doi:10.1111/j.1460-9568.2011.07917.x
4. Barchel, D., Stolar, O., De-Haan, T., Ziv-Baran, T., Saban, N., Fuchs, D. O., . . . Berkovitch, M. (2019). Oral cannabidiol use in children with autism spectrum disorder to treat related symptoms and co-morbidities. Frontiers in Pharmacology. doi:10.3389/fphar.2018.01521
5. Faraone, S. V. (2018). The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neuroscience & Behavioral Reviews, 87, 255-270. doi:10.1016/j.neubiorev.2018.02.001
6. Bloomfield, M. A. P., Ashok, A. H., Volkow, N. D., & Howes, O. D. (2017). The effects of Δ9-tetrahydrocannabinol on the dopamine system. Nature, 539, 369-377. doi:10.1038/nature20153
7. Cooper, R. E., Williams, E., Seegobin, S., Tye, C., Kuntsi, J., & Asherson, P. (2017). Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial. European Neuropsychopharmacology, 27, 795-808. doi:10.1016/j.euroneuro.2017.05.005
8. Wright, N. E., Maple, K. E., & Lisdahl, K. M. (2017). Effects of cannabis use on neurocognition in adolescents and emerging adults. In V. R. Preedy (Ed.), Handbook of Cannabis and Related Pathologies (pp. 151-159). doi:10.1016/B978-0-12-800756-3.00017-X
9. Loflin, M., Earleywine, M., De Leo, J., & Hobkirk, A. (2013). Subtypes of Attention Deficit-Hyperactivity Disorder (ADHD) and cannabis use. Substance Use & Misuse, 49, 427-434. doi:10.3109/10826084.2013.841251