This post reviews the epidemiology and health consequences of cannabis use and Cannabis Use Disorder (CUD). Cannabis use is widespread with WHO estimates of 220 million users worldwide. Numbers of users are increasing with about 20% increase over the past decade as legal restrictions have been loosened in many locations.
The cell biology of the natural endocannabinoid system (EC) has been reviewed in more detail in earlier posts here.
The known effects and potential risks of cannabis use in adolescents and young adults is a particular concern given the central role of the EC system in brain development. The incidence of CUD in all age groups is also a concern and frequently overlooked and underestimated in the addiction recovery literature and industry.
Cannabis is by far the most commonly used “illicit” drug with the highest use rates concentrated in North America, Australia, UK, and Western Europe. There has been significant loosening of legal restrictions in recent decades. In the US cannabis is fully legal in 24 states and approved for medical use in an additional 18 states. It remains a category 1 restricted substance in US federal law.
The endocannabinoid system has been reviewed in more detail previously. It consists of two primary receptor types CB1 and CB2. These are widely distributed in the body and central nervous system. CB1 receptors are more concentrated throughout the brain. CB2 receptors are more peripheral and function in the immune system. Anandamide and 2-AG are the principle endogenous endocannabinoids.
While cannabis contains hundreds of cannabinoids and other chemicals Δ9-THC is the principle bio active component and acts as a CB1 receptor agonist. The other cannabinoid of primary interest is Cannabidiol (CBD) a non psychoactive compound. It acts as a weak CB1 receptor modulator and acts on other non cannabinoid pathways.
Over time both legal and illegal production has resulted in cultivation of cannabis strains containing much higher THC concentrations with increased THC:CBD ratios than in the past. Other preparations as vapes, oils, concentrated wax, edibles, and granules are also commercially available. One challenge in research is uncertainty concerning quantities and relative concentrations in the population given the wide variety of available products.
3D reconstructions demonstrating the structural similarities of THC and endogenous cannabinoids (EC). The native system does not act like classic neurotransmitters. They are neuromodulators acting to control and regulate the strength and timing of both excitatory and inhibitory neurons. The levels of ECs and receptors is very dynamic and fluctuates with local conditions and between individuals.
Chronic use of THC results in compensatory down regulation of CB1 receptors resulting in tolerance, dependance, and withdrawal symptoms.
Cannabis Use Disorder (CUD) has historically been under diagnosed. Based on the most recent data and DSM 5 criteria 6.27% of the US population will meet criteria for CUD in their lifetime.
This section focuses on the following in CUD:
– Clinical criteria and screening
– Epidemiology of CUD
– Co-occuring psychiatric disorders
– Associated pulmonary disease
– Structural brain changes
– Withdrawal symptoms
The DSM-5 lists 11 criteria for the diagnosis of CUD. These are grouped into four clinical features:
· Impaired control over quantity and frequency of use despite desire and efforts to limit consumption.
· Continued use despite negative consequences in relationships, responsibilities, and activities.
· Continued use in activities resulting in potential physical or psychological harm to self or others
· Pharmacological tolerance and withdrawal symptoms
As in other substance use disorders there is a spectrum grouped as mild, moderate, or severe. Six or more positive criteria is considered severe CUD or addiction.
The Cannabis Use Disorders Identification Test CUDIT-R has been developed as a useful clinical and research tool. It was originally developed using DSM-IV criteria. Using the cutoff score of 8 or more for hazardous use and 12 or more for probable disorder it has a DSM-V sensitivity of about 85% and lower specificity in the 75% range making it suitable for screening rather than specific diagnosis.
This study utilized the largest US survey to date the NESARC III adapted to DSM-V criteria. Prevalence rates are broken down by degree of severity, age, and race/ethnicity.
Out of the 2.54% of the population with CUD more than 50% have mild disease severity. The demographics are heavily weighted to the 18-29 age group and males have twice the risk compared with females.
Lifetime incidence rates may be a more useful indicator of individual risk. This data indicates that 6.27% of the population will experience some degree of CUD in their lifetime. This has strong implications for public health and policy. Two out of every hundred people will experience severe CUD at some point.
Based on the NESARC study from 2018 about 32% of adults with past year cannabis use will meet criteria for CUD.
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The same data in bar graph form illustrates at risk populations and degree of disease severity for each group.
Data from a large US longitudinal population study illustrating prevalence of psychiatric disorders in cannabis users vs the general population. Lighter orange reflects incidence of the disorder occurring in all cannabis users and not restricted to CUD. Note that the incidence is increased in every disease category.
This is more detailed data correlating cannabis use disorder with specific conditions. The results are expressed as an odds ratio. Odds ratios reflect the odds of an event occurring in an exposed group divided by the odds in an unexposed group. Odds ratios may overstate the risk in some circumstances.
Note the marked increase in Anxiety disorders and PTSD. Large increases are also present in certain externalizing personality disorders.
While there is consistent positive correlation between the incidence of CUD, major depressive disorder, and Bipolar Disorder cross sectional studies cannot demonstrate causal relationships. These may be unidirectional or bidirectional.
This longitudinal study looked at initiation of cannabis use in pre existing mood disorder and the reverse relationship using several different statistical models.
The authors found no evidence of a causal relationship between pre existing cannabis use and either MDD or BPD. There was evidence for initiation of cannabis use following onset of a mood disorder. Results are strongly suggestive of a self-medication hypothesis for the initiation of cannabis use in these disorders.
A number of studies have explored the possibly of structural changes in chronic cannabis use. This neuroimaging study compared grey matter volumes resulting from chronic use. The research found significant volume loss in the orbitofrontal cortex of users. This area of the brain is crucial for integration of sensory and emotional information and goal directed behavior.
The incidence of lung disease in cannabis users both with and without concurrent tobacco use is shown above. Findings indicate significantly increased risk for asthma, COPD, and pneumonia in regular cannabis users with or without tobacco use compared with controls in a matched cohort.
Physical withdrawal from cannabis can occur in moderate to severe disease. There are currently no medications available to treat withdrawal or maintenance in recovery. Excepted timeline of symptoms is charted above. There is considerable individual variance. Relapse rates are high and in the 70% range. Adolescents and young adults are particularly prone to relapse.
There are concerns specific to adolescents and young adults. 15-29 year olds form the largest bloc of users with the highest relapse rates. The cannabinoid system is critical in orchestrating brain development. Neural development is not complete until the early 20s. Because of this the potential for acute and delayed or permanent sequela in adolescent and young adult users are a significant concern.
This graph tracks daily or near daily alcohol and cannabis use in 19-30 year olds from 1988-2023. During that time several significant trends are identified. Beginning in 2010 daily cannabis use exceeds daily alcohol use. Daily cannabis use rises from 3.3% to 10.4%. In the same period daily alcohol use declined from 6.5% to 3.6%.
During this time period the average THC content has increased from around 4% in the 1990s to 18-24% in the 2020s.
This is from a meta analysis of 69 studies measuring neuro cognitive function in adolescent and young adult cannabis users. The mean age of subjects was 20.6 years. The studies used standard neuro cognitive testing in current and abstinent users,
There were marked decreases in neuro cognitive measures. The largest declines were seen in learning, memory, and attention based tasks. Minimal effects were seen in motor and visio-spatial function.
Neurocognitive deficits in required abstinence at zero, less than 72 hours, and greater than 72 hours. Effect size returns to near baseline with greater length of abstinence indicating temporary deficit. Other reported results have been mixed and inconclusive.
To address limitations in previous studies this was a large controlled longitudinal study with periodic neurocognitive testing and verification of THC metabolites in hair and urine samples. There are inflection points seen in memory based task performance. With younger age of use onset test score moves from higher than controls to decreased scores The trend begins at age 14 -16. This indicates a more chronic process tied to stage if development. No significant differences were found in verbal and control testing.
From the same study. Based of hair samples subjects were grouped as THC+, Controls, or CBD+. Again an inflection point is observed after which CBD subjects demonstrated higher memory based function and THC+ subjects decreased function relative to controls.
CBD use without THC demonstrates the reverse trend from that seen in THC users. These findings are suggestive of a protective effect resulting from use of CBD during development.
From a meta analysis of 69 studies looking at cognitive function in early age of onset cannabis users.
These results demonstrated a consistent decrease in cognitive function in individuals with early onset of cannabis use across studies of moderate to high quality. The effect size was consistent with an average decrease of 2 IQ points.
There have been multiple reports indicating a link between cannabis use, psychosis, and schizophrenia. As use patterns and THC content has changed over the past few decades there is insufficient data to evaluate effect sizes.
This is an often cited study which took place in South London from 2005 – 2011. The study recruited all patients showing up to hospitals with first episode psychosis. A case control design was employed. Subjects were grouped by frequency of use from 0-6. They were also stratified by type of cannabis used and available locally, either lower potency “hash” with a lower THC/CBD ratio or higher potency “skunk” with a higher THC content.
Demographics of first episode psychosis cannabis using subjects vs control subjects. The subjects were closely matched by age at first use, and mean duration of use.
Use patterns demonstrate a dose-response relationship. Users of more potent “skunk” were much more likely to present with psychosis increasing with frequency of use. The occurrence was infrequent in lower frequency lower potency “hash” users. Non users were evenly matched in incidence with population controls.
Dose – response relationships are often used to test a true drug response rather than a confounding factor when randomized clinical trials are impractical.
Odds ratios measuring risk of psychotic disorder adjusted for age and demographic variables. The pattern is highly suggestive of a protective effect in higher CBD content use. Everyday hash users had a lower risk than infrequent skunk users. Everyday high THC low CBD skunk users had greater than 5x increased risk compared to non cannabis users.
While precise measurement is not possible in uncontrolled conditions results are supportive of the hypothesis that the ratio of THC to CBD may be more important than total THC dose in people who use cannabis.
Schematic based on aggregate of studies looking at risk proposing a mechanism for psychotic symptoms in schizophrenia and Alzheimer’s disease. Lower CB1 receptor availability due to high THC ingestion results in endocannabinoid dysregulation. Increased levels of 2-AG and Anandamide with decreased receptor availability results in psychotic symptoms. CBD acts as a partial CB1 receptor agonist resulting in a protective effect in rebalancing endocannabinoid levels. This results in decreased psychotic symptoms.
Increased incidence of psychosis, cognitive deficits, and other neuropsychiatric conditions in chronic cannabis use particularly in young age of use onset is well documented. However little is known about the underlying mechanisms at the cellular level.
This preclinical study in a rat model of adolescence and schizophrenia looked at cellular architecture in layer 3 pyramidal cortical neurons following THC exposure. In the frontal cortex these calls are critical in integrating signals from sensory and internal pathways and cognitive function.
Experimental design is shown above in fig. A. Multiple THC infusions during adolescence were followed by analysis of cellular architecture at 24h delay, 2 week post infusion delay, and into young adulthood. Microdissection by laser microscopy was also performed with analysis of gene expression compared with control population injected with the vehicle solution.
Corresponding cortical layers from a human brain are shown in the right lowermost image taken from the H01 electron microscopic dataset linked to here.
Cortical cellular architecture normally changes with maturity. Neurons were examined for arborization, the formation of dendritic trees ar the cell apex and base. This was compared and calculated as increased or decreased dendrite growth compared to controls. Results (c and f) show marked decreases in arborization in THC exposed rats consistent with cellular denuding and lack of normal maturation due to adolescent THC administration.
Like other substance use disorders CUD has a strong heredity component. This section focuses on genetics of CUD and the shared genetic components (pleiotropy) with other neuropsychiatric conditions.
This is taken from a large meta analysis combining genome wide association studies (GWAS) looking at polymorphisms statistically correlated with CUD. The two peaks highlighted by red arrows above have been consistently identified across studies.
These correspond to the genes FOXp2 located on chromosome 7 and CHRNA 2 located on chromosome 8.
On the left a composite map of all genetic variants found to be correlated with CUD. Closeup of chromosomes 7 and 8 showing locations of FOXp2 and CHRNA2.
FOXp2 codes for a transcription factor and has an essential role in learning and neuroplasticity. CHRNA2 codes for a subunit of the acetylcholine receptor and is also involved in nicotine dependance. These genes code for products with plausible roles in substance use disorders, an important criteria in identifying candidate genes.
The strength of association of cannabis use and CUD with co occuring disorders can be measured by linkage disequilibrium. This measures the statistical probability that two traits are inherited in a non random distribution. This happens when they are shared or physically close in the same stretch of DNA.
In this study the most closely related traits to CUD were found for ADHD, PTSD, and schizophrenia. There was also close genetic correlation with cocaine, alcohol, and nicotine dependance.
These along with other lines of evidence are consistent with shared inherited vulnerability for these conditions.
The next study utilized a design known as Mendelian Randomization (MR) to investigate a causal link in the association between cannabis use disorder and schizophrenia. MR can be used as a means of randomization when controlled trials are not possible. It utilizes a strongly associated genetic SNP for a trait as the control. Because the SNP (exposure) is assumed to be inherited free of any confounding factors a causal link between the exposure and the outcome can be inferred,
Multiple SNPs for both cannabis use and schizophrenia exist and could be used to investigate causality in both directions,
Using cannabis initiation as the exposure a moderately strong causal relationship (p value 0.019) was observed. Using schizophrenia as the exposure a strong causal link to cannabis use was identified (p value 2.64 x 10-5).
These findings are consistent with a bidirectional causal link between cannabis use initiation and schizophrenia.
There are currently no effective treatments for CUD or withdrawal from cannabis. Cannabidiol – CBD is a non psychoactive cannabinoid found in the cannabis plant. It is a weak partial agonist at CB1 receptors and acts in non cannabinoid cellular pathways.
CBD acts to partially counteract THC effects by acting as a negative allosteric modulator. At common doses near equal to THC content it does not block intoxicating effects of THC. Commercially available CBD preparations are in the 10-15mg range and of uncertain purity.
This was a randomized clinical trial using high doses 200, 400, and 800 mg of synthetic CBD for the treatment of cannabis use disorder. Subjects all received weekly motivational interviewing along with oral CBD or placebo for a total of 4 weeks. The 200mg arm was dropped in mid trial due to lack of identifiable effect.
Subjects reported days abstinent. Quantity of THC used was assessed by concentration of the THC metabolite in urine samples at the weekly sessions.
Results are as shown above. A Bayesian model was used to generate expected effect sizes. At the 400mg and 800mg daily dose modest yet significant reductions in measured THC levels were observed along with increase in days abstinent. This was a small sample size from a single center and positive findings warrant larger controlled studies.
This post is a brief overview of risks associated with of cannabis and cannabis use disorder. Increased daily or near daily use and THC content of cannabis preparations particularly in younger people including adolescents still in the neurological developmental stages is cause for concern. Increased incidence of cannabis use is present in neuropsychiatric disorders including mood, anxiety, and substance use disorders. There may be bidirectional effects complicating clinical management. There is strong evidence for a causal role of cannabis in psychosis and schizophrenia.
Cause and effect relationships in co-occurring conditions are coming more into focus with advances in technology and may guide development of more effective treatment. Cannabis use disorder has been under diagnosed and under treated in large part due to public misperception. Development of more effective treatment options remains a major challenge.
Thank you for taking the time to review this post. This post and website are for education and information purposes only and should not be considered medical or professional advice.No commercial or institutional interest, Images and data are taken from sources freely available in the World Wide Web.
Comments and suggestions are always welcome.
Jeff Kay jeffk072261@gmail.com
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