The Psychopharmacology of Cannabis and its Impact on Mental Health – A Primer

CANNABIS USE - EPIDEMIOLOGY

Cannabis is the most commonly used illicit drug in the world with approximately 13 million people estimated to be cannabis dependent. [1]

When reviewing epidemiological data through population surveys and cannabis dependence data, the disability-adjusted life years was shown to account for two million years lost to disability or premature mortality, globally.

An area of current concern is that the plant product is becoming more and more potent in terms of THC content, with high-THC strains being grown and cultivation methods (e.g. hydroponic) increasing THC content.

Concomitantly, there has been a reduction in CBD content so the natural ‘buffering’ effect has been reduced and plant product is much more likely to induce psychotic symptoms. Regular users attest to how different the potency is to the ‘natural’ cannabis they used to use.

An arguably even more disturbing issue is the creation of synthetic THC analogues: these are highly potent and carry a much higher risk of psychosis and other psychiatric effects than any product of the Cannabis sativa plant.

Despite the high prevalence of cannabis use, transitioning from cannabis use to cannabis dependence is relatively low with under 10% of users becoming dependent.

This rate is lower than what is typically reported for dependency to alcohol (15%) or tobacco (32%) use.

However, the DSM-IV and ICD-10 list heavy cannabis use as a dependence disorder that meets their criteria for drug dependence.

Note that DSM-5 has – rather stupidly, in our view – stepped away from the notion of ‘dependence’, despite it being a well accepted and validated construct.

There is no doubt that THC is a drug of dependence, with animal models and human studies attesting to a withdrawal syndrome, with sleep disturbance, autonomic arousal, irritability and cravings being some of the cardinal features.

One of the complexities, however, is that it THC is highly lipophilic so accumulates in the brain of heavy users and is released only gradually upon cessation: this process can take some weeks and thus a more acute withdrawal state such as that seen with nicotine or alcohol, is not manifest.

Another complexity is that cannabis is often consumed with other drugs, including being mixed with tobacco, so withdrawal effects that might be attributed to cannabis might be compounded by the withdrawal of such other substances.

Also, tolerance is not usually found to the extent of many other drugs, and habitual users often have a ‘usual dose’ which satisfies them.

Cannabis has a rich and complex political and cultural history with a range of judgements and attitudes existing—cannabis is legalised in the Netherlands, but trafficking in Saudi Arabia often comes with a capital punishment sentence.

In contrast, public awareness of its association with mental and substance use disorders is poor.

This review attempts to elucidate the psychoactive effects of THC as well as the pharmacological benefits and harms of cannabis use.

PHARMACOLOGY OF CANNABIS

The primary compound with psychoactive properties is delta-9-tetrahydrocannabinol (THC).

The cannabinoid system in the brain consists of exogenous and endogenous cannabinoids along with their receptors.

Exogenous cannabinoids:

• THC and synthetic cannabinoids are exogenous cannabinoids.
• THC acts via the cannabinoid receptor (CB1), which is found diffusely throughout the brain and spinal cord but also in the periphery throughout the body. [2]
• A second cannabinoid receptor (CB2) is expressed only in the peripheral tissues, principally in the immune system. To some extent, THC and synthetic cannabinoids act as agonists at the CB2 receptor.
• The other cannabinoid of particular interest to psychiatry is cannabidiol (CBD), which appears to have antipsychotic properties: its mechanism of action is not fully understood but encompasses actions at the CB1 receptor as well as impacting the metabolism of anandamide, the naturally occurring substrate for the CB1 receptor.

Endogenous cannabinoids (endocannabinoids):

• Anandamide and 2-arachidonylglyceryl (2-AG)

CELLULAR MECHANISMS OF ACTION OF CB1 AND CB2 RECEPTORS

Both CB₁ and CB₂ receptor types inhibit adenylyl cyclase via Gi, and both types stimulate MAPK activity. Only the CB₁ receptor has been shown to signal via ion channels.

Ultimately, these pathways regulate important cellular functions necessary for synaptic plasticity and long-term changes in neuronal function. Thus, endocannabinoid agonists may be critical in the formation and maintenance of interneuronal communication.

An alternative receptor that is stimulated by anandamide has been pharmacologically described, and it is coupled to the Gi family of signal transduction proteins. [3]

RISK FACTORS FOR CANNABIS USE AND MENTAL HEALTH DISORDERS

Cannabis use at an early age is a consistently good predictor of the risk for developing a mental health disorder in later life.

Exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life, and the risk is dose-related. [4]

At an early age, frequent use can accelerate the first appearance of mental health issues by 3 to 7 years.

A major risk factor that affects younger users is that they have less resistance to social and group pressures.

Other known risk factors that increase the risk of mental health disorders with cannabis are:

• Smoking
• Prior mental health issues
• School difficulties
• Low socioeconomic status
• Negative family atmosphere

For those who start at the age of 14-15 years old these risk factors are not as strongly associated with mental health disorder as those aged 11-12 years old.

This is suggestive of cannabis use affecting the functional and psychological development of a child, which could then mediate lasting psychological damage.

There is particular concern regarding the heavy use of potent cannabis products by young people, as THC can impact cognitive functioning and by extrapolation, affect the developing brain at key developmental phases.

IS CANNABIS CAUSALLY RELATED TO MENTAL HEALTH DISORDERS?

There are a number of confounding factors that need to be considered when interpreting any association between cannabis exposure and mental health outcomes.

In a number of cohort studies, for example, it has been shown that the association between cannabis use and depression is confounded by numerous psychosocial issues as well as the use of other substances.

Also, longitudinal modelling suggests that mostly it is depression driving cannabis rather than vice versa: this is known as ‘reverse causality’.

In terms of psychotic disorders, whilst a ‘brought forward’ effect of cannabis is well accepted (i.e. that people who would develop schizophrenia irrespective of cannabis use, manifest the disorder some 5 or more years earlier than they would if they hadn’t used cannabis), causality (i.e. that cannabis actually acts as an independent cumulative causal factor in schizophrenia) is more complex.

In longitudinal cohort studies, an association between use of cannabis in teen years and later schizophrenia or schizophreniform disorders has been replicated, the effects are small (population attributable fraction around 5-8%) and seem to be pertinent mostly for individuals who had already experienced (subclinical) psychosis-like symptoms.

This is called ‘statistical interaction’ and speaks to cannabis ‘unmasking’ rather than ‘causing’ schizophrenia.

Also, people who later develop schizophrenia often have a long prodrome of negative-type symptoms, depression, anxiety and so forth, and these independently drive cannabis use (i.e. people might be ‘self-medicating’ these prodromal symptoms with cannabis).

Finally, it has been shown that some of the genes that predispose to schizophrenia also predispose to cannabis abuse.

Individuals with polymorphisms of COMT and AKT1 genes may be at increased risk for psychotic disorders in association with cannabinoids, as are individuals with a family history of psychotic disorders or a history of childhood trauma. [4]

Hence, causality between cannabis exposure and schizophrenia is difficult to establish definitively, but it seems reasonable to conclude at least some contribution of cannabis to schizophrenia in individuals with an underlying – probably largely genetic – predisposition. [4]

MENTAL HEALTH DISORDERS ASSOCIATED WITH CANNABIS USE

In 1995, The Lancet published an editorial that stated cannabis use was not harmful to mental health and that there were currently no clear causalities. [5]

Since 1995, researchers have investigated the fundamental factors that may exist and how cannabis use could contribute to mental health disorders in vulnerable populations.

PSYCHOTIC DISORDERS

THC can induce hallucinations and delusions even in individuals who have shown no previous signs of mental health problems.

Cannabis users can also show transitory psychotic reactions although Arendt suggests that this is an early expression of schizophrenia in vulnerable populations.[6]

Certainly, the symptoms of cannabis-associated psychosis are not too dissimilar from schizophrenia.

The risk of developing psychosis after cannabis use has been reported to be 12.5% in individuals who have shown prodromal symptoms and 3.1% in those not showing any prior symptoms. [7]

Frequency of cannabis use is also an important variable with subjects who have chronically used cannabis having a 50-200% higher risk of developing a psychotic disorder than regular cannabis users. [8]

The potency of product in terms of absolute THC content as well as THC:CBD ratio also needs to be considered (see above): work from researchers in London, UK, for example, point to the particular perniciousness of high potency ‘skunk’ in this context.

So, what is the relationship between cannabis use and psychotic disorders?

Self-medication and Affect Regulation Hypothesis

• Cannabis use is often used as a coping mechanism to relieve or reduce negative psychotic symptoms. Many people (40-60%) of people with schizophrenia use cannabis, often habitually and often at high doses. In determining the reasons for use, most will say they use it for non-specific symptoms such as nervousness, sleep problems, and other factors that can be called ‘negative affect’.
• Most cannabis users with schizophrenia acknowledge it exacerbates the positive symptoms of psychosis [9]. Hence, if there is an element of ‘self-medication’ it is largely related to negative symptom amelioration.

Co-occurrence

• Cannabis users with schizophrenia tend to have a lower negative symptom burden than those who have never used, and this has been suggested to increase the risk of exposure to other substance abuses. [10]
• Therefore, cannabis use often co-occurs with addiction to other psychoactive substances that together can act additively and contribute to the development of mental health issues.

Neurobiological

• As outlined above, schizophrenia and cannabis use share some aetiological factors. [11]
• This is suggested to happen due to the interactions between the endocannabinoid system and dopaminergic activity. This is supported by observations of cannabis use being shown to alter the onset, course, and relapse rates in schizophrenia.

Risk factor

• The Diathesis-Stress hypothesis suggests that cannabis use can accelerate and aggravate schizophrenia in vulnerable populations.
• As outlined above, although causality is difficult to establish in heavy users and early-age users who have latent psychotic problems, there is a probable relationship between cannabis use and psychosis in these vulnerable individuals.
• This is a crucial clinical point as people with a psychotic predisposition (through having a family history of psychosis or having a psychotic disorder such as schizophrenia) should be warned very emphatically that cannabis is likely to cause an exacerbation of symptoms and contribute to relapse and hospitalisation.
• In a recent study involving a cohort of individuals, the results indicate a notable association between emergency department (ED) visits related to substance use and an elevated likelihood of developing a schizophrenia spectrum disorder. Specifically, among ED visits linked to psychosis, cannabis use demonstrated the highest probability of transition, with an adjusted hazard ratio (aHR) of 241.6. [Myran et al., 2023]
• Furthermore, among ED visits not associated with psychosis, cannabis use ranked as the third-highest risk factor for transitioning, with an aHR of 14.3.
• The study revealed that younger age and male gender were both associated with an increased risk of transitioning, with male gender showing a more pronounced effect in younger individuals, particularly in cases involving cannabis use.

Contributor

• Cannabis use itself has previously been suggested to increase the risk of developing a psychotic disorder.
• In comparison to non-users, the adjusted probability ratio of developing schizophrenia was shown to be 6.7-fold greater for those who have used cannabis >50 times when compared to only 2.4-fold greater for those who have used cannabis just once. [12]
• Again, the associations are complex, and numerous confounding and reverse causality factors need to be considered in the interpretation of the data.
• Also, there is the simple fact that, while rates of cannabis use show large variation across the world, the rates of schizophrenia are fairly uniform at a country-by-country level, speaking to there being no major effect at a population level.

DEPRESSIVE AND ANXIETY DISORDERS

Most research into cannabis use and its association with mental health disorders has analysed the connection between THC and psychotic disorders.

Currently, there is very little literature on the consequences of cannabis use and affective disorders such as major depressive disorder, bipolar disorder, and anxiety-related disorders.

Many cannabis users say they like it because it makes them feel calm and assists sleep.

However, some people experience panic when they use cannabis, probably related to the profound tachycardia which invariably accompanies intoxication.

In terms of affective, there is evidence of an association between depression and cannabis consumption, but as detailed above, much of this association is confounded by other factors and reverse causality is also at play.

Early reports of cannabis being useful as an antidepressant have not been supported in scientific studies.

There is very little literature on cannabis and bipolar disorder, despite many people with bipolar using it, again mostly for non-specific effects such as assistance with sleep.

Some people with bipolar disorder manifest psychotic relapses upon exposure to cannabis, but the delineation of which individuals are likely to experience this is difficult.

A general approach to cannabis use amongst people with bipolar is to counsel against it but to try to understand individual reasons for use and tailor prescribed medications to deal with those features (e.g. using sedative mood stabilisers for sleep disturbance).

AMOTIVATIONAL SYNDROME

The ‘amotivational syndrome’ is associated with long-term use of cannabis and is characterised by apathy, lack of interest and general indifference.

This putative syndrome, as articulated by Schwartz (1987) includes the following parameters [13]:

• Loss of interest in things in general, with associated apathy and passivity
• Loss of desire to work, and loss of concern with work performance, resulting in loss of productivity
• Loss of energy and easy fatigability
• Moodiness and irritability
• Impaired concentration
• Lack of concern for personal appearance and hygiene
• A lifestyle that prioritises cannabis procurement and consumption.

The veracity of this syndrome as a clinical entity has been contested, and a number of confounding factors need to be considered.

Anhedonia

• Amotivational syndrome could be a subclinical symptom of anhedonia that is associated with cannabis use.

Depressive disorder

• Amotivational syndrome could instead be related to the underlying presence of depression.

Cannabis intoxication

• The characteristics of amotivational syndrome could be a natural biological consequence of cannabis use.

Personality issues

• Or, the symptoms of the amotivational syndrome are instead related to dysfunctional personality traits that are revealed with cannabis use in a population subset.

On balance, all of these factors might operate at an individual level to contribute to an apathetic syndrome which is well described by the term ‘amotivational’.

A key question is whether cessation of cannabis results in restitution of premorbid functioning and it seems that the answer is largely in the affirmative.

COGNITIVE DETERIORATION

Acute and chronic cannabis use comes with neuropsychological and cognitive performance issues that may even persist after discontinuing usage. [14]

Although if the period of abstinence is long enough then most neurocognitive functions should return to normal levels with no clinically significant deficits remaining.

What parts of cognition are directly affected by cannabis use?

Attention disorders

• The psychoactive compound THC activates CB1 receptors in the frontal cortex and hippocampus. This has been suggested to cause cognitive functioning deficits in working memory that then has a disruptive effect on attention processes.

Short-term memory

• When performing neuropsychological tasks, cannabis users showed an increase in forgetfulness and a remarkable impairment in learning ability. These data show that cannabis use has an acute and significant effect on short-term memory.

Processing speed

• In one study it showed that heavy cannabis use was associated with deficits in information processing speed abilities. This impairment in processing speed was also evident for several weeks after cessation of use.

Estimation of time

• One of the most interesting cognitive functioning impairments that are specifically associated with long-term cannabis use is time estimation. This impairment has been shown to worsen with the number of years of regular cannabis use and can endure well beyond the cessation of use.

Executive functions

• Deficits in executive functioning and cognitive control of behaviour have been shown to persist in tests carried out on 28-day abstinent heavy cannabis users.
• Moreover, 12-weeks of abstinence may still be associated with continued worsening of executive function abilities in some individuals.

Motor control

• In a randomised controlled trial, psychomotor control deficits were observed in a linear dose-response relationship with increasing THC content.
• However, these motor impairments were not observed in every subject, which could be due to tolerance and blunting of the pharmacological effects normally observed on motor skills with cannabis use.

It has generally been thought that once the cannabinoids are cleared from the aliphatic brain cells (and this can take up to a month in chronic heavy users), the individual will exhibit few –if any – enduring sequelae.

A recent systematic review and meta-analysis of 2152 cannabis-using individuals (mean age 20.6 years) across 69 studies, supports this view. [15]

In essence, there was a small effect size for reduced cognition associated with heavy cannabis use (d = 0.25; 95% CI -0.32- -0.17)), but that this almost disappeared in studies where a sufficient time was allowed (at least 72 hours): there were 15 such studies including 928 people, and the effect size was -0.08; 95%CI -0.22-0.07): ie. this was not significant at the 95% level and was thus a null effect.

Overall, it should be stressed that residual cognitive symptoms after all THC has ‘washed out’ of the brain is very subtle and would not usually be considered clinically relevant.

This is in contrast to other drugs of abuse, including alcohol and methamphetamines. However, as described above, the use of cannabis at crucial stages of cognitive development is likely to impact learning.

This is particularly important when considering the consequences of diminished learning capacity in younger users and its negative effect on maturation and neurological development at this critical time.

CONCLUSION

Cannabis sativa is a complex plant with numerous constituent chemicals.

In psychiatry, of most interest are THC, which is psychotomimetic, and CBD, which seems to have some antipsychotic properties.

Cannabis use has been associated with mood and psychotic disorders but understanding causal pathways is difficult, and many early studies used plant product which is highly variable in terms of its constituent chemicals.

What is clear is that THC can exacerbate psychosis is people with an underlying predisposition and such individuals need to explicitly counselled in this regard: understanding individual reasons for use is an important part of engagement in such discussions and motivating people to quit.

Cognitive effects of cannabis are usually short-lived, but heavy accumulative use can result in impaired cognition across a number of domains and is especially worrying during adolescence as the brain is still developing and the bedrocks of learning are being laid down.

Learn more:

What Is the Role of Cannabinoids in Psychiatry By Prof Martin Katzman?

Synthetic Cannabinoids – Myths Vs Science – Dr Raimondo Bruno

Synthetic Cannabinoids – Harms and General risk – Dr Raimondo Bruno

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