Quotations from Scientific Articles on the Adverse Effects of Marijuana

Compiled by J. Strayhorn, M.D.

 

        The following is a summary of some scientific writings on the adverse effects of marijuana. I’ve written a brief summary of some of the information in 10 articles. After that, there are passages copied from the articles. The information about how to look up or cite each article comes before the quotations from it.

Cannabis and marijuana are the same thing. THC is the chemical in cannabis that gets people high and that produces a pleasurable feeling. CBD is another chemical in marijuana that has effects very different from THC. A preparation of CBD, available by prescription, has been approved by the U.S. Food and Drug Administration to treat a rare form of epilepsy.  All the following studies are really referring to the effects of THC. (However, one of the articles says that what is sold as CBD sometimes being contaminated with other substances, including THC.)

 

1.       Volkow and colleagues article, 2014.

This rated how confident scientists should be, as of 2014, that several bad effects of marijuana actually take place. There was “low” confidence for lung cancer; “medium” confidence for abnormal brain development,  progression to other drugs, schizophrenia, and depression or anxiety; and “high” confidence for addiction to marijuana and other substances, diminished lifetime achievement, motor vehicle accidents, and chronic bronchitis.

Lots of research has occurred since 2014, some of which is mentioned below.

2.       Dharmapuri and colleagues, 2020.

This cited problems with attention, memory, and impulse control in children whose mothers used marijuana during pregnancy.

This article also cited evidence for reduced “neurocognitive function,” meaning, really, how smart people are --  particularly for people who begin marijuana use earlier in life. It cites an article about reduced rates of high school graduation in users of marijuana. It cites findings of a higher rate of suicide attempts, higher rates of psychosis, more motor vehicle crashes. It points out the unknown content of “spice” or “spike” which in one study was found to be contaminated with rat poison. It speaks of the addictive nature of marijuana, lists withdrawal symptoms, and estimates 8% to 12% of users will develop moderate to severe Cannabis Use Disorder. Cannabis Use Disorder means about the same thing as addiction to marijuana. The following are listed as possible withdrawal symptoms: “1) irritability, anger, or aggression; (2) nervousness or anxiety; (3) sleep difficulty or insomnia; (4) decreased appetite or weight loss; (5) restlessness; (6) depressed mood; and (7) at least 1 of the following: abdominal pain, shakiness or tremors, sweating, fever, chills, or headache.” 

This article cites a 2017 study finding poor quality control in preparations of CBD purchased online – the CBD was often not in the concentration claimed on the label, and it was sometimes contaminated with other stuff such as THC.

3.       Fisher and colleagues, 2020.

This article mentions evidence for many of the same problems already listed. In addition, it speaks about the “reward function” of the brain – the brain events that make us feel good when good things happen. In the short run, cannabis stimulates the brain pathways that create a feeling of being rewarded, but in the long term, these pathways are “downregulated,” meaning that they are less sensitive than they would otherwise be. This is thought to result in less motivation (because feeling good about accomplishments, or anticipating feeling good, creates motivation). “Downregulation of reward pathways” is also thought to contribute to depression. The odds of suicide attempts are cited as about 3.5 times higher in adolescents who have used marijuana.

This article also mentions the danger of addiction to cannabis, and it cites a finding that 50% of adolescents who use cannabis every day ultimately become addicted to it.

The article cites a finding that heavy users of cannabis had a 4 fold higher risk of psychosis than nonusers.

This article also discusses findings on the effects of cannabis on IQ, or intelligence test score. It cites a longitudinal study (which is a study of the same people over time) finding that people who started using marijuana earliest in life had the biggest reductions in IQ, and there was not recovery of the IQ even one year after some of these people stopped using marijuana.

4.       Cannabis drug facts from NIDA (the US National Institute on Drug Abuse).

This website cites a study finding that  “People who started smoking marijuana heavily in their teens and had an ongoing marijuana use disorder lost an average of 8 IQ points between ages 13 and 38. The lost mental abilities didn't fully return in those who quit marijuana as adults. Those who started smoking marijuana as adults didn't show notable IQ declines.”

5.       NIDA web page on link between marijuana and psychiatric disorders.

This summarizes information about a certain gene that apparently makes people more likely to get psychotic from using marijuana.

It also mentions a study finding a certain type of cancer of the testicles more likely in males who have used marijuana.

6.       CDC web page on marijuana.

This speaks of a number of the problems already mentioned, and also mentions social anxiety as a possible bad effect of marijuana use.

7.       Krebs 2019. This article goes over the evidence for the effects of cannabis on learning and memory and thinking, but it also mentions an article that studied some twins, which did not confirm the hypothesis that marijuana lowered intelligence. Nonetheless, the authors are willing to conclude that “Verbal learning and memory, attention … are consistently impaired by exposure to cannabis.”

This article also reviews studies that have looked at the brains of users and non-users of marijuana. They say that “Regular cannabis users consistently exhibit reductions in grey matter volume.” The reduction in volume of the grey matter of the brain occurs especially in regions that have lots of receptors for cannabis. These include the hippocampus, prefrontal cortex, amygdala and cerebellum. This article also reviews the evidence about a higher risk of schizophrenia in users of cannabis. The article also reviews a number of brain changes in rats who have been given cannabis.

8.       Renard and colleagues, 2016. This article has to do with studies of rats given cannabis, and the negative effect on the functioning of the prefrontal cortex. The prefrontal cortex is a part of the brain that is thought to be central to planning, decision-making, self-discipline, and other “executive functions.”

9.       Zehra and colleagues, 2018. This article goes into some detail about how THC use reduces the brain response to reward, by reducing how much dopamine is released in response to rewarding stimuli.  The phrase “lower reward sensitivity” means, “good events don’t make you feel as good.”

10.   Marconi and colleagues, 2016. This was a meta-analysis, meaning a pooling of the results from a bunch of other studies, looking at the effect of marijuana use on the development of psychotic illness. The authors used 10 studies that had enrolled about 67 thousand people in all. Each of the 10 studies found a significant relationship between heavy marijuana use and increased risk of psychosis. There was a dose-response relationship found, where the risk of psychosis went up the more frequently people used marijuana. The odds of developing a psychotic illness were 3.9 times higher in heavy marijuana users than in nonusers.

 

 

Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014 Jun 5;370(23):2219-27. doi: 10.1056/NEJMra1402309. PMID: 24897085; PMCID: PMC4827335.

Level of Confidence in the Evidence for Adverse Effects of Marijuana on Health and Well-Being.

Effect

Overall Level of Confidence*

Addiction to marijuana and other substances

High

Abnormal brain development

Medium

Progression to use of other drugs

Medium

Schizophrenia

Medium

Depression or anxiety

Medium

Diminished lifetime achievement

High

Motor vehicle accidents

High

Symptoms of chronic bronchitis

High

Lung cancer

Low

*The indicated overall level of confidence in the association between marijuana use and the listed effects represents an attempt to rank the strength of the current evidence, especially with regard to heavy or long-term use and use that starts in adolescence.

 

 

Sadhana Dharmapuri, Kathleen Miller, Jonathan D. Klein; Marijuana and the Pediatric Population. Pediatrics August 2020; 146 (2): e20192629. 10.1542/peds.2019-2629

The majority of studies [of the children whose mothers used marijuana when pregnant] demonstrated a negative impact of marijuana during pregnancy, including deficits in neuropsychological functioning, decreased attention, memory problems, and poor impulse control.37

Endogenous cannabinoids have an important role in the control of neural circuits and structures in the prefrontal cortex and the hippocampus. During adolescence, these circuits mature and regulate attention, executive functioning, and memory. Studies have revealed that the development and maturation of these circuits can be affected by cannabis, causing impairment in neurocognitive functioning.43,44

… authors explored neurocognitive measures in adolescents with recent cannabis use disorder who were now abstaining and also found that younger onset was associated with lower overall neurocognitive function. Similarly, Meier et al45  found persistent neurocognitive changes 1 year after cessation of cannabis use.

In a recent longitudinal study on marijuana use and adolescent brain development, researchers found that cannabis use had adverse effects on IQ and executive functioning.46  This cross-sectional longitudinal study revealed differences in resting-state networks known to mediate executive functioning (left dorsolateral prefrontal cortex) and regulatory control (anterior cingulate cortex). Marijuana use was associated with declines in neural connectivity over time, especially in adolescents with cannabis use disorder.46  In an Australian longitudinal study, authors found that individuals who used before age 17 years old had a reduced odds of high school graduation and degree completion compared with nonusers. These individuals were more likely to have cannabis use disorder, were more likely to use other illicit substances, and had more suicide attempts.47 

Animal studies of cannabis use and psychosis have suggested a remodeling of brain structure due to effects on the endocannabinoid system. These changes are similar to changes seen in schizophrenia.48  In a recent study by Di Forti et al,49  the authors found that daily marijuana use and high-potency marijuana (THC content >10%) are the strongest independent predictors of whether an individual will have a psychotic episode. Initiation of marijuana use by age 15 years slightly increased the odds of having a psychotic episode, but this was not independent of potency and frequency of use. Individuals with daily use had a 3.2 times higher likelihood of developing psychosis compared with nonusers. Individuals who used high-potency marijuana were 1.6 times more likely to develop psychosis compared with nonusers.49  Individuals who had both daily use and high-potency use were almost 5 times as likely to develop psychosis compared with nonusers. Further studies exploring frequency and potency of use and gene expression may help elucidate the neurobiology behind the development of psychosis due to cannabis. Physicians should be aware of the increasing potency of legal marijuana products; for example, the average THC content of marijuana sold legally in Colorado is ∼18%.

 In 2018, the Insurance Institute for Highway Safety and the Highway Loss Data Institute reported an increase in motor vehicle crashes in states that had legalized marijuana use.

[SCs below stands for synthetic cannabinoids.]

SCs, (eg, Spice and K2) have become popular recreational substances among young adults. These substances are plant-derived material adulterated with substances similar to synthetic THC. These are readily available for purchase online or in shops specializing in marijuana and tobacco paraphernalia. SCs are often marketed as safe, natural, herbal blends not intended for human consumption in attractive packaging. However, these products are not naturally produced. They are typically mass produced outside of the United States. They are typically dissolved and mixed with dried vegetation in an imprecise process. The dosing of one product batch can vary greatly from that of another batch. These products can also be contaminated with heavy metals, bacteria, and chemicals. For example, in 2018, 70 individuals experienced serious drug overdose in Connecticut from using synthetic cannabis that was contaminated with rat poison. Unlike THC, which is a partial agonist at CB1 and CB2 receptors, SCs are full agonists at CB1 and CB2 sites, increasing the potency of SCs.66  This may account for the increased morbidity and mortality seen with the use of SCs compared with marijuana.67 

Serious adverse health effects have been documented with the use of SCs. Adverse effects include cardiac abnormalities, coagulopathies, and neurologic and psychiatric abnormalities.68  Cardiac effects include tachycardia and acute myocardial infarction.69,70  A cardiac fatality was reported in a young adult after smoking SCs.71  Hematologic abnormalities due to long-acting vitamin K–dependent antagonist contamination of SCs have been reported.71  In a review of SC use, reports of acute kidney injury were noted. All individuals required hospitalization, and one individual required dialysis.72  Neurologic abnormalities are also well documented. SCs have been linked to strokes, seizures, and psychiatric effects, including anxiety, agitation, suicidal ideation, and psychosis. The neuropsychologic effects of SCs, compared with marijuana, are enhanced because of the difference in SC action at CB1 and CB2 sites.

 

Many people purchase medical and recreational marijuana online. In a 2017 JAMA study, authors found that nearly 70% of CBD products sold online contained higher or lower concentrations of the drug than was on their label. Some CBD products contained significant amounts of THC. CBD products sold for vaping were mislabeled 88% of the time, and THC was detected in 18 of 84 samples, some with enough to produce intoxication.76  It is important to counsel patients and parents about the THC content in CBD products and to note that they lack regulation by the FDA. Pediatricians should also refer to individual state laws for further information concerning purchasing, use, and possession of marijuana.

Monitoring the Future survey data suggest that most adolescents do not perceive marijuana use as harmful, addictive, or associated with withdrawal.77,78  However, 8% to 12% of marijuana users will develop moderate to severe cannabis use disorders. … The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition describes cannabis withdrawal as having ≥3 of the following signs and symptoms within the 1 week of discontinuing use: (1) irritability, anger, or aggression; (2) nervousness or anxiety; (3) sleep difficulty or insomnia; (4) decreased appetite or weight loss; (5) restlessness; (6) depressed mood; and (7) at least 1 of the following: abdominal pain, shakiness or tremors, sweating, fever, chills, or headache.79 

 

Fischer AS, Tapert SF, Lee Louie D, Schatzberg AF, Singh MK. Cannabis and the Developing Adolescent Brain. Curr Treat Options Psychiatry. 2020 Jun;7(2):144-161. doi: 10.1007/s40501-020-00202-2. Epub 2020 Apr 18. PMID: 32714742; PMCID: PMC7380653.

The belief among many teens that marijuana is benign relative to other recreational drugs is in contrast to a preponderance of evidence that adolescent marijuana use is linked to psychiatric symptoms including psychosis and suicidality,[7, 8] as well cognitive impairment in learning, memory, and executive function.[7, 8] Cannabis use also results in compromised motor coordination contributing to an increased risk of motor vehicle collisions, which is a leading cause of morbidity and mortality in adolescents.[9]

Cannabis may acutely contribute to an increase in pleasure and decrease in perceived stress by increasing dopamine with reward circuitry and decreasing cortisol released by the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. Chronic cannabis use, however, results in cannabinoid receptor type 1 (CB1-R) downregulation and reductions in endocannabinoids levels [21] that impair sensitivity to reward and stress.[24] In animal models, disruption of ECS signaling results in a depressive phenotype with impaired reward sensitivity.[25, 26] In humans, the CB1-R antagonist rimonabant produced a significant increase in depressive symptoms in individuals with no history of mental illness in a double-blind placebo-controlled clinical trial. Depressive symptoms were so severe that they resulted in withdrawal of this medication from the European market, and prevented FDA approval.[27] 

CB1R agonist exposure acutely results in alterations in neurotransmitters that are similar to those produced by other drugs of abuse via attenuation of evoked GABA release that results in downstream increases in DA within fronto-limbic brain circuitry, especially within the nucleus accumbens (NAc), a central hub of reward processing.[28] Tolerance that develops with chronic cannabis exposure is attributed to disrupted reward-related signaling mechanisms in this system by reducing DA cell density in the ventral tegmental area (VTA), as well as decreasing VTA DA cell firing and downstream DA release in the NAc and the medial prefrontal cortex (PFC).[21, 29] Reductions in CB1-R expression and function as well as decreased DA are more pronounced with adolescent cannabis use (relative to use in adulthood), contributing to disrupted reward signaling, impaired reward sensitivity, and ultimately depressive symptoms of anhedonia, depressed mood and decreased motivation.

the co-occurrence of psychiatric symptoms and cannabis use are well documented, and should be a standard part of patient psychoeducation and motivational interviewing.

Cannabis use significantly increases risk for addiction,[50] with adolescents being four times as likely to develop cannabis dependence within two years after use onset.[51] About 20% of individuals who start using marijuana in adolescence and up to 50% of teens who smoke marijuana daily will develop an addiction.[9] Moreover, use of cannabis preparations with higher THC content show a dose-dependent increase in risk of developing a substance use disorder.[52] Recent cannabis use trends among adolescents raise concerns because they account for the majority of substance abuse treatment admissions in adolescence.[53, 54] Importantly, adolescent cannabis use also confers increased risk for other substance use disorders. A recent meta-analysis demonstrated significant associations between the frequency of adolescent cannabis use and increased risk of cannabis use disorder (adjusted OR = 4.2 monthly, 8.7 weekly, 17.9 daily use), as well as use of opiates and other illicit drugs (adjusted OR = 2.8, 4.7, 7.8) by young adulthood.[55] Cannabis has recently been proposed as a potential treatment for opioid use disorder based on a study that found that states with medical cannabis laws experienced slower increases in opioid analgesic overdose mortality (−21%).[56] However, the association between legalization of cannabis for medicinal purposes and opioid-related mortality has increased 23% on longitudinal follow up.[57]

While developing a substance use disorder is the most common long-term psychiatric diagnosis associated with adolescent cannabis use,[55] depressive symptoms are the most common psychiatric symptoms associated with cannabis use in adolescence.[58] Depressive symptoms in adolescence are particularly concerning given that suicide, often attributable to depression, is a leading cause of death in this age group.[59] A recent meta-analysis assessing the effects of adolescent cannabis use found an increased risk of major depressive disorder (OR 1.37, 95% CI 1.16–1.62), suicidal ideation (OR 1.50, 95% CI 1.11–2.03) and suicide attempts (OR 3.46 CI 1.53 – 7.83), but not anxiety symptoms by young adulthood.[8] A longitudinal study prospectively followed a community sample of 662 adolescents from 2003–2013 to examine the strength of association between cannabis use frequency and psychiatric symptoms. From ages 15–19 years, more frequent cannabis use lead to greater depressive, but not anxiety or psychotic symptoms, after controlling for age of onset of use, sex, socioeconomic status, and other drug use.[58] Of note, there were no reported changes in anxiety symptoms with more frequent cannabis use.[58] Notably, depressive symptoms during adolescence do not predict subsequent cannabis use in young adults, suggesting that this relation was not simply due to premorbid differences.[4, 60] In addition, reductions in cannabis use are associated with reductions in depressive symptoms.[61] In Colorado, the rate of increase in cannabis potency directly correlates with increased rates of cannabis related emergency department visits by adolescents.[50, 62] In a study of over 4,000 adolescents who presented for emergency and urgent care visits between 2005 and 2015, the most common ICD codes other than cannabis use were depression (39%) and unspecified mood disorder (22%), with a significant increase in marijuana-related visits following legalization of medicinal and recreational marijuana.[63]

A broad-based literature has established a link between adolescent cannabis use and risk of psychosis. Cannabis use is considered a preventative risk factor for psychotic disorders, including schizophrenia, especially in those with a pre-existing genetic vulnerability.[20] Epidemiological studies have consistently reported an association between cannabis use and schizophrenia in which cannabis use precedes psychosis independent of other substance use.[20] This effect, however, is not immediate with adolescent cannabis use, portending an increased risk of psychotic disorders that manifest primarily in young adulthood.[58] In a sample of 6,534 subjects from the general population Northern Finland Birth Cohort of adolescents that were prospectively followed until age 30, adolescent cannabis use was significantly associated with developing a psychotic disorder after controlling for baseline prodromal symptoms, daily smoking, alcohol and other substance use, with a significant ‘doseresponse’ effect with respect to frequency of cannabis use (HR = 3.0, 95% CI 1.1–8.0).[64] In a study of over 400 first episode patients with psychosis, adolescents who had started cannabis at age 15 or younger, daily cannabis users, and use of cannabis with higher THC content, significantly advanced the timeline of when they experienced first psychotic episode by 2–6 years.[65] Increasing evidence demonstrates a dose-response relation between cannabis use and risk for psychotic outcomes.[64, 66] In a recent meta-analysis of all available published studies examining the relation between cannabis use and psychosis, regular cannabis users had a 2-fold increased risk, and heavy cannabis users a 4-fold increase in risk, for psychosis relative to nonusers.[7] For a comprehensive meta-analytic review of the association between cannabis use and psychosis, please see Marconi et al. [7]

Cognition and academic performance.

Although some controversy exists in the adult literature with respect to the lasting effects of cannabis on cognitive function, regular cannabis use in adolescence is significantly associated with cognitive impairment within the domains of attention, processing speed, verbal learning and memory, and executive functioning.[67–69] Longitudinal studies have demonstrated that increased adolescent cannabis use significantly predicts poorer verbal memory[70] and attention.[71] These deficits are also more likely persist following abstinence with adolescent (as compared to adult) cannabis use.[72] Earlier age of onset of use and heavier use during adolescence are associated with increased rates of cognitive impairment in adulthood.[73] In a prospective longitudinal study of over 1000 youth followed from birth to adulthood, those who regularly used cannabis during adolescence demonstrated the greatest reductions in IQ.[74] Individuals that started using cannabis in early adolescence demonstrated the greatest reductions in IQ (i.e., from ‘average’ in childhood to ‘low-average’ in adulthood). Moreover, they did not return to their predicted intellectual trajectory, and cognitive impairments remained evident following over one year of abstinence.[74] It is also important to note that an earlier age of onset has also been associated with greater cognitive impairments even when the total duration of use is relatively short as demonstrated by Solowij and colleagues.[75] Of note, there is some evidence to suggest that greater CBD content may serve a protective role against some THC-induced cognitive deficits.[67] Long term functional consequences include poor educational outcome, with increased likelihood of dropping out of school, and diminished long term academic and occupational achievement.[9]

Indeed, meta-analyses have found that cannabis increases collision risk (pooled OR: 1.5 – 2.5). [84, 85] Simulated driving studies have demonstrated that driving under the influence of cannabis results in significantly poorer lane control and reduced driving speed, similar to effects observed when using a cell phone or texting while driving [85, 86]. This is particularly relevant to young drivers who are more likely to be involved in distraction related motor vehicle accidents. [87] While studies are lacking with adolescent drivers, simulated driving studies of young adult drivers have shown that driving performance in conditions of divided attention and increased driving complexity significantly worsened following cannabis use. Participants were significantly more likely to be classified as having a high crash risk (OR 4.31) after cannabis use lasting up to 5 hours after use. [88] Further research is needed to assess the impact of the cannabis on driving behavior and collision risk in youth, which to date has received little attention.

Cannabis (Marijuana) DrugFacts | National Institute on Drug Abuse (NIDA) (nih.gov)

For example, a study from New Zealand conducted in part by researchers at Duke University showed that people who started smoking marijuana heavily in their teens and had an ongoing marijuana use disorder lost an average of 8 IQ points between ages 13 and 38. The lost mental abilities didn't fully return in those who quit marijuana as adults. Those who started smoking marijuana as adults didn't show notable IQ declines.5

Is marijuana addictive?

Marijuana use can lead to the development of a substance use disorder, a medical illness in which the person is unable to stop using even though it's causing health and social problems in their life. Severe substance use disorders are also known as addiction. Research suggests that between 9 and 30 percent of those who use marijuana may develop some degree of marijuana use disorder.25 People who begin using marijuana before age 18 are four to seven times more likely than adults to develop a marijuana use disorder.26

Many people who use marijuana long term and are trying to quit report mild withdrawal symptoms that make quitting difficult. These include:

Is there a link between marijuana use and psychiatric disorders? | National Institute on Drug Abuse (NIDA) (nih.gov)

Recent research (see "AKT1 Gene Variations and Psychosis") has found that people who use marijuana and carry a specific variant of the AKT1 gene, which codes for an enzyme that affects dopamine signaling in the striatum, are at increased risk of developing psychosis. The striatum is an area of the brain that becomes activated and flooded with dopamine when certain stimuli are present. One study found that the risk of psychosis among those with this variant was seven times higher for those who used marijuana daily compared with those who used it infrequently or used none at all.63

A few studies have shown a clear link between marijuana use in adolescence and increased risk for an aggressive form of testicular cancer (nonseminomatous testicular germ cell tumor) that predominantly strikes young adult males.75,76 The early onset of testicular cancers compared to lung and most other cancers indicates that, whatever the nature of marijuana’s contribution, it may accumulate over just a few years of use.

Teens | Health Effects | Marijuana | CDC

Marijuana and the teen brain

The teen brain is actively developing and continues to develop until around age 25. Marijuana use during adolescence and young adulthood may harm the developing brain.3,4

Negative effects of teen marijuana use include3:

Difficulty thinking and problem-solving

Problems with memory and learning

Reduced coordination

Difficulty maintaining attention

Problems with school and social life

How marijuana can impact a teen’s life:

Increased risk of mental health issues. Marijuana use has been linked to a range of mental health problems, such as depression and social anxiety.3 People who use marijuana are more likely to develop temporary psychosis (not knowing what is real, hallucinations, and paranoia) and long-lasting mental disorders, including schizophrenia (a type of mental illness where people might see or hear things that aren’t there).5 The association between marijuana and schizophrenia is stronger in people who start using marijuana at an earlier age and use marijuana more frequently.

Impaired driving. Driving while impaired by any substance, including marijuana, is dangerous and illegal. Marijuana negatively affects several skills required for safe driving, such as reaction time, coordination, and concentration.3,6

Potential for addiction. Approximately 3 in 10 people who use marijuana have marijuana use disorder.7 Some signs and symptoms of marijuana use disorder include trying but failing to quit using marijuana or giving up important activities with friends and family in favor of using marijuana.8 The risk of developing marijuana use disorder is stronger in people who start using marijuana during youth or adolescence and who use marijuana more frequently.9

Krebs MO, Kebir O, Jay TM. Exposure to cannabinoids can lead to persistent cognitive and psychiatric disorders. Eur J Pain. 2019 Aug;23(7):1225-1233. doi: 10.1002/ejp.1377. Epub 2019 Mar 19. PMID: 30793421.

There is now no doubt that long-term cannabis use can lead to addiction. Approximately one in 11 people who experienced cannabis will become dependent in their lifetime, but this risk is almost doubled if use starts in adolescence. 25% to 50% of daily users will become dependent (Englund, Freeman, Murray, & McGuire, 2017). In more recent US national data (2012–2013), among 9.52% of US adults using cannabis in the past year, 2.9% had a diagnosis of DSM-IV CUD, i.e., three out of 10 cannabis users (Hasin, 2018). Moreover, extending analyses of DSM-5 diagnoses of CUD, 19.5% of lifetime users met criteria for DSM-5 CUD, of whom 23% were symptomatically severe (>6 criteria). 

3 CANNABIS USE AND PSYCHIATRIC DISORDERS, EPIDEMIOLOGICAL EVIDENCE

The first prospective study that demonstrated an association between cannabis use and schizophrenia in later life was conducted in young conscripts to the Swedish Military and published in 1987 by Andréasson, Allebeck, Engström, and Rydberg (1987). The authors found that “heavy” cannabis use at age 18 (more than 50 times, approximately corresponding to once a week for 1 year) led to a sixfold increased risk of schizophrenia 15 years later. Extending the sample (more than 50,000 persons), the duration of the follow-up and the analysis to address all possible confounders, they confirm an increased risk of schizophrenia after cannabis exposure, even after eliminating potential unravelled prodromal psychosis, association of other drugs, family vulnerability, etc. This study also revealed that early cannabis consumption (i.e., at age 15) further increased the risk of developing schizophrenic symptoms at age 26 by a factor of four compared to cannabis consumption after age 18, even after controlling for predating psychotic symptoms (Arseneault et al., 2002). There are now 13 studies that consistently demonstrate that the use of cannabis increases the risk of schizophrenia-like psychosis (see for review Murray et al., 2017). A significant association was found in 10 studies and a trend in the three remaining studies. The psychotic syndrome induced by cannabis is diagnosed either cannabis-induced psychosis (when the symptoms rapidly regress after withdrawal) or schizophrenia, when the symptoms persist. This chronic condition requires antipsychotics medication for long periods (minimum 2 years, most of the time for decades if not lifetime). Noteworthy, approximately 40%–50% of patients with cannabis-induced psychosis will finally be diagnosed with schizophrenia within 3 years (Arendt, Rosenberg, Foldager, Perto, & Munk-Jørgensen, 2005), underlining the potential of cannabis to induce chronic, persistent psychotic symptoms.

5 CANNABIS USE, COGNITION AND BRAIN STRUCTURE

The majority of studies assessing the chronic effects of cannabis have shown that regular users exhibit poorer cognitive performance across a large range of domains compared to nonusers. Verbal learning and memory, attention and psychomotor function are consistently impaired by acute and chronic exposure to cannabis (Broyd, van Hell, Beale, Yücel, & Solowij, 2016). Acute effects of cannabis use include executive functions (especially inhibition) and memory (including working memory) while chronic effects are less consistent. The deficits are more important in early age at onset, heavy use and high THC/CBD ratio (Broyd et al., 2016). Processing speed is also affected. Findings regarding IQ are less consistent. In the large Dunedin birth cohort, persistent cannabis use was associated with decline in general functioning (IQ). The impairment was more important in adolescent-onset cannabis users (vs. in adult-onset users) and when the exposure persists (Meier et al., 2012). Nevertheless, in a limited sample of co-twins, short-term cannabis uses in adolescence did not appear to cause IQ decline or impair executive functions, even when cannabis use reaches the level of dependence (Meier et al., 2018). Impaired verbal memory, attention and psychomotor functions may persist after prolonged abstinence (Broyd et al., 2016) as well as IQ deficit in adolescent users, although discontinuation attenuates the deficit (Meier et al., 2012).

Overall, brain-imaging studies have shown that chronic cannabis exposure induces brain alterations, (reviewed in Gruber & Sagar, 2017; Murray et al., 2017). Lorenzetti, Solowij, & Yücel (2016) reviewed 23 anatomical neuroimaging studies and reported that regular cannabis users consistently exhibit reductions in grey matter volume especially in brain regions with high concentration of CB1R, that is in the hippocampus, prefrontal cortex, amygdala and cerebellum.

Cannabinoids act on the reward habit and cognition networks. Among other changes, acute use leads to increased firing of dopamine (DA) neurons and DA release, while chronic use results in decreased DA release in the ventral striatum (Curran et al., 2016). In addition, the eCB system modulates synaptic efficacy and plasticity (Castillo, Younts, Chávez, & Hashimotodani, 2012). The main eCBs, 2-AG and anandamide, are synthesized “on demand” from phospholipid precursors in the postsynaptic membrane by Ca2+-dependent and independent mechanisms and feedback in a retrograde manner onto presynaptic terminals, thus suppressing afferent neurotransmitter release via activation of CB1Rs (Ohno-Shosaku & Kano, 2014). Electrophysiological and biochemical data strongly support a model of postsynaptic synthesis and a presynaptic site of action. Retrograde eCB signalling promotes Long-term depression (LTD), but these eCB forms of synaptic plasticity after stress have also been found to promote long-term potentiation (LTP) for review Morena, Patel, Bains, and Hill(2016).

Adults rats that have been chronically exposed to CB1R agonists or THC during their adolescence display short-term memory impairment in the novel object recognition and novel-place recognition paradigms, as well as deficits in spatial working memory and reduced social interactions (Renard et al., 2014; Rubino & Parolaro, 2016). These deficits were milder or not significant when rodents were exposed during adulthood. Our studies and others reported a reduced expression of synaptic plasticity proteins (PSD95, synaptophysin, protein kinase C-dependent signalling), of cytoskeletal and structural proteins, and activity-regulated cytoskeletal-associated protein (Arc) as well as a reduced expression of CB1R in the hippocampus and/or prefrontal cortex in adult rats that were treated with CB1R agonists or THC during adolescence. (for review Curran et al., 2016; Renard et al., 2014). Those proteins have a close interaction with N-Methyl-D-aspartate (NMDA) receptors and determine the size and strength of excitatory synapses. A significant reduction of NMDA receptors was found in the hippocampus of adolescent treated rats as well as a reduced glutamic acid decarboxylase 67 (GAD 67) and basal gamma-Aminobutyric acid levels in the prefrontal cortex (Rubino & Parolaro, 2016). In addition, rats exposed to cannabinoids during adolescence have, when adults, reduced total dendritic length, arborization, and spine numbers in the dentate gyrus and the prefrontal cortex and an impaired synaptic plasticity in the prefrontal cortex as reflected by a decrease in LTP at hippocampal to prefrontal cortex synapses pathway (Renard et al., 2016). This glutamate dysregulation likely contributes to the altered plasticity and cognitive impairments observed in schizophrenia.

 

Renard J, Vitalis T, Rame M, Krebs MO, Lenkei Z, Le Pen G, Jay TM. Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex. Eur Neuropsychopharmacol. 2016 Jan;26(1):55-64. doi: 10.1016/j.euroneuro.2015.11.005. Epub 2015 Dec 3. PMID: 26689328.

In many species, adolescence is a critical phase in which the endocannabinoid system can regulate the maturation of important neuronal networks that underlie cognitive function. Therefore, adolescents may be more susceptible to the neural consequences of chronic cannabis abuse. We reported previously that chronically exposing adolescent rats to the synthetic cannabinoid agonist CP55,940 leads to impaired performances in adulthood i.e. long-lasting deficits in both visual and spatial short-term working memories. Here, we examined the synaptic structure and function in the prefrontal cortex (PFC) of adult rats that were chronically treated with CP55,940 during adolescence. We found that chronic cannabinoid exposure during adolescence induces long-lasting changes, including (1) significantly altered dendritic arborization of pyramidal neurons in layer II/III in the medial PFC (2) impaired hippocampal input-induced synaptic plasticity in the PFC and (3) significant changes in the expression of PSD95 (but not synaptophysin or VGLUT3) in the medial PFC. These changes in synaptic structure and function in the PFC provide key insight into the structural, functional and molecular underpinnings of long-term cognitive deficits induced by adolescent cannabinoid exposure. They suggest that cannabinoids may impede the structural maturation of neuronal circuits in the PFC, thus leading to impaired cognitive function in adulthood.

 

Zehra A, Burns J, Liu CK, Manza P, Wiers CE, Volkow ND, Wang GJ. Cannabis Addiction and the Brain: a Review. J Neuroimmune Pharmacol. 2018 Dec;13(4):438-452. doi: 10.1007/s11481-018-9782-9. Epub 2018 Mar 19. PMID: 29556883; PMCID: PMC6223748.

In rats, early-life exposure to THC blunts dopaminergic response to naturally rewarding stimuli that elicit DA release later in life (Bloomfield et al. 2016). Likewise in rats, adolescent exposure to THC resulted in increased self-administration of and blunted striatal DA response to CB1R agonists in adulthood (Scherma et al. 2016). Changes in reward-related circuitry after chronic cannabis use may be related to changes in the eCS after prolonged cannabis use. The eCS has been implicated in reward-processing and reward-seeking behavior given that CB1 receptors are densely expressed in areas associated with reward processing and conditioning including the amygdala, cingulate cortex, PFC, ventral pallidum, caudate putamen, NAcc, VTA, and lateral hypothalamus (Parsons and Hurd 2015; Volkow et al. 2017a). In animals, activation of CB1 receptors seems to influence the hedonic effects of natural rewards after THC administration, suggesting that cannabis can affect reward sensitivity via activation of CB1 receptors (Parsons and Hurd 2015).

Chronic THC exposure has further been shown to downregulate CB1Rs, providing a neurobiological basis for the development of tolerance and desensitization to the rewarding effects of THC (Colizzi et al. 2016). In rodents, chronic administration of THC or CB1R agonists leads to tolerance in most responses as well as a decrease in CB1R availability in many brain areas (Maldonado and Rodriguez de Fonseca 2002; Tanda and Goldberg 2003; Maldonado et al. 2011). In cannabis users, withdrawal symptoms have also been associated with reductions in CB1R availability as assessed by [11C]OMAR PET imaging (Curran et al. 2016; D’Souza et al. 2016). Hirvonen et al. (2012) found that cannabis use downregulates CB1R in cortical regions, potentially altering the brain’s reward system. However, they also found that after 4 weeks of abstinence, CB1R density returned to normal in cannabis users in all regions except the hippocampus. This suggests that some neurobiological changes of chronic cannabis use are reversible (Hirvonen et al. 2012).

Similar to animal models of chronic THC exposure, chronic cannabis use has been shown to blunt DA response to DA-releasing stimulant drugs in the striatum with both [11C]-(+)-PHNO and [11C]raclopride PET imaging (Volkow et al. 2014c; Bloomfield et al. 2016; van de Giessen et al. 2017) and to decrease DA synthesis as assess with PET imaging with [18F]DOPA (Bloomfield et al. 2014) (Fig. ​(Fig.2).2). This pattern of decreased stimulant-induced DA release is also seen with chronic use of other drugs of abuse such as alcohol, cocaine, and nicotine (Koob and Volkow 2016). However, cannabis users do not show lower baseline D2/D3 receptor availability in the striatum compared to healthy controls – a pattern seen in chronic alcohol, nicotine, cocaine, opiate and methamphetamine users (Volkow et al. 1996b, 2001, 2002, 2014b, 2017c; Wang et al. 1997; Martinez et al. 2012; Tomasi et al. 2015b; Wiers et al. 2016a, 2017; Ashok et al. 2017). Moreover, the stimulant challenge led to significantly lower self-reported ratings of feeling high (Volkow et al. 2014c), and decreased brain glucose metabolism in the striatum, thalamus, and midbrain (Wiers et al. 2016b) in cannabis users versus controls. Cannabis users had higher negative emotionality and lower positive emotionality personality scores than controls, and negative emotionality scores were inversely correlated with methylphenidate-induced dopamine increases in the ventral striatum (Volkow et al. 2014c; Wiers et al. 2016b). These findings offer an explanation for decreased dopamine reactivity in the striatum during abstinence that may contribute to negative emotionality, which is consistent with lower reward sensitivity in cannabis users during the withdrawal phase of addiction (Volkow et al. 2014c). In another study, a stimulant challenge also led to blunted brain glucose metabolism in striatal regions, which was associated with craving (Wiers et al. 2016b). Together these findings from stimulant challenges indicate functional changes in the dopaminergic reward system in chronic cannabis users.

a. Statistical group differences in the effect of methylphenidate on the distribution volume between controls and marijuana abusers. Methylphenidate-induced decreases in distribution volumes were stronger in controls than in marijuana abusers (p < 0.005). ...

Furthermore, fMRI studies have also revealed functional and structural changes in brain areas involved in reward processing after chronic cannabis use. In one study, participants in a cannabis-dependent group had greater activation in the ventral striatum in response to losses during a monetary incentive delay (MID) task compared to healthy controls (Yip et al. 2014). Compared to controls, the cannabis-dependent participants also had smaller putamen volumes, a brain region involved in habit formation. These differences seemed to be driven by participants who were unable to stay abstinent from cannabis and were comparable to findings in tobacco smokers suggesting similar changes in reward functioning in both tobacco and alcohol addiction (Yip et al. 2014). In another fMRI study with the MID task, cannabis users in withdrawal had greater activation in the ventral striatum in response to positive incentives compared to healthy controls during the MID task, similar to findings in alcohol users (Filbey et al. 2013). Persistent cannabis use also seems to be related to a blunted response to reward anticipation in the NAcc during the MID task: in this study, even after controlling for prior and current use of other drugs, greater cannabis use was related to decreased activation in the NAcc during reward anticipation at baseline, 2 year, and 4 year follow ups (Martz et al. 2016). Together, these findings suggest that chronic cannabis use produces functional alterations in areas involved in reward processing.

In addition, chronic cannabis use has been linked to impaired memory and IQ, suggesting changes in executive functioning after chronic cannabis use. However, IQ deficits appear to be present before initiation of cannabis use which may suggest that lower IQ could be a risk factor for cannabis addiction (Jackson et al. 2016).

Future studies should also investigate the specific neurocircuitry Koob and Volkow (2016) implicate in the three stages of addiction: specifically, how cannabis use impacts glutamate signaling in the VTA (disrupted during binge/intoxication) and PFC (disrupted during preoccupation/craving) and acetylcholine signaling in the habenula (disrupted during withdrawal/negative affect).

 

Marconi A, Di Forti M, Lewis CM, Murray RM, Vassos E. Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis. Schizophr Bull. 2016 Sep;42(5):1262-9. doi: 10.1093/schbul/sbw003. Epub 2016 Feb 15. PMID: 26884547; PMCID: PMC4988731.

Cannabis use has been reported to induce long-lasting psychotic disorders and a dose-response relationship has been observed. We performed a systematic review of studies that investigate the association between the degree of cannabis consumption and psychosis and a meta-analysis to quantify the magnitude of effect. Published studies were identified through search of electronic databases, supplemented by manual searches of bibliographies. Studies were considered if they provided data on cannabis consumption prior to the onset of psychosis using a dose criterion (frequency/amount used) and reported psychosis-related outcomes. We performed random effects meta-analysis of individual data points generated with a simulation method from the summary data of the original studies. From 571 references, 18 studies fulfilled inclusion criteria for the systematic review and 10 were inserted in the meta-analysis, enrolling a total of 66 816 individuals. Higher levels of cannabis use were associated with increased risk for psychosis in all the included studies. A logistic regression model gave an OR of 3.90 (95% CI 2.84 to 5.34) for the risk of schizophrenia and other psychosis-related outcomes among the heaviest cannabis users compared to the nonusers. Current evidence shows that high levels of cannabis use increase the risk of psychotic outcomes and confirms a dose-response relationship between the level of use and the risk for psychosis. Although a causal link cannot be unequivocally established, there is sufficient evidence to justify harm reduction prevention programs.