Medicinal Cannabis – Psychopharmacology and Clinical Application

ENDOCANNABINOID SYSTEM

The endocannabinoid system is a ubiquitous lipid signalling system with a broad array of regulatory functions in the body.

The system consists of the cannabinoid 1 (CB1) and 2 (CB2) receptors and the endogenous signalling ligands, N-arachidonyl-ethanolamide (AEA) and sn-2-arachidonoyl-glycerol (2-AG).

The CB1 receptor

• The most abundant G protein-coupled receptor in the brain is mainly located in the axons and presynaptic nerve terminals.
• The receptor is present at particularly high levels in the neocortex, hippocampus, basal ganglia, cerebellum and brainstem.
• Also, present on some non-CNS sites (see diagram below)

The CB2 receptor

• Principally found in the periphery where they influence cytokines and cell migration.
• In the CNS, CB2 receptor expression is associated with inflammation, and it is primarily localised to microglia.

Activation of CB1 receptors in the presynaptic nerve terminal results in [Battista N et al., 2012], [Grant I et al., 2012]:

1. Activation of potassium channels and closure of voltage-dependent calcium channels;
2. Hyperpolarisation of the presynaptic terminal (known as depolarisation-induced suppression of inhibition (DSI))
3. Hyperpolarisation directly inhibits the release of inhibitory and excitatory neurotransmitters such as glutamate, acetylcholine, and dopamine.
4. Indirect suppression of other neurotransmitters, including serotonin, N-methyl-D-aspartate (NMDA), opiate, and γ-aminobutyric acid (GABA).
5. Inhibition of the over-activation of the above neurotransmitters thus, providing neuroprotection against excitotoxicity.

At present, endocannabinoids have been observed to, directly and indirectly, regulate several important physiological processes [Aggarwal, 2013], [Serrano and Parsons, 2011], [Rodriguez de Fonseca F et al., 2005], [Maccarrone M et al., 2010], [Greco R et al., 2010], [Howlett, 2004]:

• Appetite and digestion
• Energy metabolism
• Thermogenesis
• Immune function and inflammation
• Cardiovascular function,
• Neural development
• Synaptic plasticity, learning and memory
• Pain and nociception
• Movement and psychomotor behaviour
• Sleep/wake cycles
• Regulation of stress and emotion

CLINICAL PHARMACOLOGY OF CANNABINOIDS

Much of the information on cannabinoid clinical pharmacology has been carried out using the exogenous cannabinoid, Δ9-THC, and its effects during recreational cannabis use.

Pharmacodynamics

The cannabinoids studied primarily include Δ9-THC, but there has been some research on CBD, cannabinol (CBN), cannabigerol (CBG), and tetrahydrocannabivarin (THCV): [Pertwee, 2008]

Δ9 -THC (THC) :

• Δ9-THC resembles anandamide in its CB₁ affinity and is a partial agonist at CB₁ receptors, albeit with less efficacy than anandamide
• Even lower efficacy at CB2 than at CB1 receptors
• As a partial agonist, depending on these receptors’ expression level and coupling efficiency, THC will either activate them or block their activation by other cannabinoids.
• It is responsible for the psychoactive effects of marijuana. Psychoactive properties are mediated through the CB1 receptor.
• It also has strong antioxidant properties that are more potent than α-tocopherol and ascorbate.
• It also has neuroprotective qualities.

CBD: 

• It does not have detectable psychoactivity and has a low affinity to CB1 or CB2 receptors.
• Even though it has a low affinity for these receptors, recent evidence suggests its role as a CB2 antagonist via inverse agonism at the CB2 receptor. The CB2 antagonism contributes to the anti-inflammatory activity through inhibition of immune cell migration.
• It is suggested to have anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, and anxiolytic activity.

11-hydroxy-▵^9_ THC (11-OH-THC): 

• The primary active metabolite of THC and, in part, responsible for the psychoactive effects of THC. [Lemberger et al., 1973]

CBN:

• It is produced from the oxidative reaction of Δ9 -THC and shows some immunosuppressive properties.

CBG :

• It has partial CB1 and CB2 receptor agonist activity and is associated with analgesic and anti-inflammatory properties.

THCV

• Acts as a CB1 receptor antagonist and CB2 receptor partial agonist and may have some anticonvulsant properties.

Cannabichromene – No psychoactive properties

Although THC and CBD act through CB1 and CB2 receptors, several additional pharmacological actions are likely.

Pharmacokinetics

Pharmacokinetic information on cannabinoids, however, refers almost entirely to its major constituent, Δ9-THC. It has partial agonist activity at both CB1 and CB2 receptors and has activity at non-CB receptors and other targets throughout the body. [Sharma et al., 2012]

• Smoking – More rapid onset of action (within minutes), higher blood levels of cannabinoids, and a short duration of pharmacodynamic effects.
• Vapourisation – Comparable plasma concentrations to those obtained by smoking cannabis; however, absorption is somewhat faster.
• Oral administration – The slower onset of action, lower peak blood levels of cannabinoids, and a much longer duration of pharmacodynamic effects.
• Δ9-THC  is highly lipophilic and gets distributed in adipose tissue, liver, lung, and spleen.
• However, the amount of Δ9-THC delivered from cannabis products is not uniform, and this is a significant variable in the assessment of drug pharmacokinetics.
• The half-life of Δ9-THC for an infrequent user is 1.3 days, and 5-13 days for frequent users.
• The distribution of Δ9-THC throughout the body is also time-dependent but does begin immediately after absorption.
• Most cannabinoid metabolism occurs in the liver, and different metabolites are produced; however, this will depend on the preparation quality and route of administration. For example, Δ9-THC is metabolized in the liver by microsomal hydroxylation and oxidation catalyzed by cytochrome P450 (CYP) complex enzymes.

MEDICINAL CANNABIS PRODUCTS

Approximately 150 unapproved medicinal cannabis products are present on the market and must abide by the Australian standard for medicinal cannabis.

• CBD-dominant products (≥98% pure CBD) are Schedule 4 [prescription-only medications when prescribed to patients with conditions that require medical oversight].
• In contrast, THC products are Schedule 8 controlled medications [meaning prescriptions require state or territory health department approvals as THC is classified as a drug of dependence].

Many products contain different ratios of CBD and THC, for example, 10:1, 20:1 or 50:1.

Some products will contain CBD or THC alone as a highly purified active pharmaceutical ingredient (API)- containing formulations, often referred to as isolates. These formulations do not contain other cannabinoids, terpenes or flavonoids.

Other products contain CBD and/or THC with a full spectrum of cannabis plant constituents, including other phytocannabinoids (e.g. cannabichromene, cannabigerol, ∆9-tetrahydrocannabinolic acid or cannabidiolic acid) as well as terpenes and flavonoids, all of which may have therapeutic effects.

To ascertain precisely what the medicinal cannabis product contains, a request can be made to the manufacturer for a certificate of analysis.

Therapeutic daily doses of CBD are typically between 50 mg and 1500 mg, which are greater than those for THC, which are between 5 mg and 20 mg.

The only cannabis-based medicines registered by the Australian TGA are Nabiximols (Sativex) and CBD (Epidyolex).

Nabiximols (Sativex) [PI]:

• This specifically formulated extract comes as an oro-mucosal spray with a mean peak plasma concentration within 2 – 4 hours.
• 80 mg of extracts (nabiximols) in peppermint oil from Cannabis sativa L., folium cum flore (Cannabis leaf and flower), corresponding to 27 mg delta-9- tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD) and lesser amounts of other cannabinoids (56 mg total cannabinoids).
• It is indicated for treating spasticity associated with multiple sclerosis.

Epidyolex: [PI]

• Orally via syringe.
• Indicated to treat intractable childhood epilepsies
• Epidyolex contains 100 mg CBD/ml of sesame oil and is devoid of THC.
• Epidyolex was recently listed on the Pharmaceutical Benefits Scheme (PBS), and the Australian Government subsidises its cost.

Other cannabis medicines that have been registered by regulators outside of Australia, but are not registered in Australia, include:

Dronabinol (Marinol®): 

• An isomer of THC that comes as an oil-based preparation that can then be delivered as a capsule or liquid. The name ‘dronabinol’ is used for pure, synthetically-derived delta-9- tetrahydrocannabinol rather than the extracted delta-9-tetrahydrocannabinol present in Sativex.
• Registered by FDA for the treatment of anorexia in patients with AIDS and for managing chemotherapy-induced nausea and vomiting where standard anti-nausea treatments have failed.

Nabilone (Cesamet®): 

• Synthetic cannabinoid analogue for oral administration that reaches peak plasma concentration in 1 to 4 hours.
• Synthetically manufactured and registered in the US by the FDA for the management of chemotherapy-induced nausea and vomiting.

MEDICINAL CANNABIS IN PSYCHIATRIC DISORDERS - THE EVIDENCE

Anxiety Disorders:

Interaction with the CB1 receptor has a modulating effect on

• GABAergic and Glutamatergic transmission
• Hypothalamic-pituitary-adrenal (HPA) axis
• Immune system activation
• Neuroplasticity.

• Anxiolytic (and antidepressant effects) may also be mediated via CBD’s serotonergic effects via 5-HT1A receptor activation and THC’s CB1 receptor agonism.
• Modulation of limbic and paralimbic brain areas is also postulated.
• CBD may partially inhibit the psychoactive effects of THC resulting in anxiolysis.
• Studies show no causal relationship between anxiety and cannabis use
• A small study showed benefits in social anxiety disorder.
• In social anxiety, pre-treatment with CBD significantly reduced anxiety, cognitive impairment, and discomfort in the social anxiety group’s speech performance and significantly decreased hyperalertness in their anticipatory speech compared to the placebo group. [Bergamaschi et al., 2011]

PTSD:

• There are high concentrations of endocannabinoid receptors in the prefrontal cortex, amygdala, PAG, and hippocampus, thus having a role in fear acquisition and extinction. [Sarris et al., 2020]

A small retrospective study of 80 patients analysing PTSD symptoms identified a greater than 75% reduction in Clinician-Administered Posttraumatic Scale for DSM-IV (CAPS) symptom scores when patients with PTSD were using cannabis compared to when they were not. Further studies are ongoing. [Greer et al., 2014]

Nabilone was effective in reducing nightmares in PTSD but recurrence occurred post cessation. [El-Solh, 2018]

• Dose in PTSD: 5 mg 1 hour prior to bedtime and titrated up to 4.0 mg.
• Tolerability has been mixed.
• Longer-term safety has not been established
• Caution in patients with psychosis or BPAD.

Depression: 

• Potential antidepressant effects are mediated by modulation of the endocannabinoid system and the 5HT1A receptor.
• Results of the use of cannabinoids in depression are mixed.
• One study involving cancer patients using nabiximols showed a significant reduction in mood for those who used the highest dose (11–16 sprays per day) compared to the placebo. [Portenoy et al., 2012]
• Due to a causal relationship between cannabis and depression, higher dose THC should be avoided in people with major depressive disorder (MDD) or low mood. [Lev-Ran et al., 2014]
• Despite the potential harm, a cross-sectional survey of medicinal cannabis users (1429 users) showed that approx 50% used it for depression and 58% for anxiety with perceived efficacy and as a substitute for pharmaceutical prescriptions. [Sexton et al., 2016]

Insomnia: 

• Only one RCT has been carried out in chronic insomnia. The study showed that two weeks of nightly sublingual administration of a cannabinoid extract (ZTL-101) was well tolerated and improved insomnia symptoms and sleep quality in individuals with chronic insomnia symptoms. [Walsh et al., 2021]
• Cannabinoids show secondary beneficial effects on sleep in patients with pain, anxiety, and PTSD, but the evidence is weak.

Psychosis and Schizophrenia: 

• THC, the psychoactive component and CB1 receptor agonist, is strongly associated with psychosis, and data suggest a causal relationship.
• Data from 11 sites across Europe and Brazil involving patients with first-episode psychosis showed that daily cannabis use was associated with increased odds of a psychotic disorder compared with never-users, with nearly five-times increased odds for daily use of high-potency THC types of cannabis. [Di Forti et al., 2019]
• Exposure to THC increases extracellular dopamine and glutamate and decreases GABA concentrations in the prefrontal cortex with striatal glutamate increases linked to acute cannabis-induced psychosis.

Read more on Cannabis and Mental Health.

• Cannabidiol (CBD), on the other hand, does not strongly activate the CB1 receptor contributing to its minimal adverse psychomimetic effects.
• CBD indirectly enhances endogenous anandamide signalling by inhibiting the intracellular degradation of anandamide catalysed by the enzyme fatty acid amide hydrolase (FAAH), which contributes to antipsychotic effects.
• Alternative mechanisms to FAAH inhibition contributing to antipsychotic effects include interactions with serotonin 5HT_1A receptors, GPR55 receptors, and transient receptor potential vanilloid-1 receptors. [Leweke et al., 2012]
• CBD has shown to be beneficial in positive psychotic symptoms and treatment-resistant schizophrenia between doses of 600-1500 mg/day. Studies have prescribed CBD as an adjunct and compared it on its own to antipsychotics. CBD was well tolerated in studies. In addition, an increase in anandamide levels by CBD was associated with clinical improvement.
• A recent single-dose RCT found that 600 mg CBD temporarily normalised aberrant brain activity in the parahippocampal, striatal, and midbrain areas, which is associated with increased psychosis risk, offering potential as a protective agent in young patients with clinical high risk (CHR) for psychosis.  [Bhattacharyya et al., 2018]
• An ongoing clinical trial in the UK is assessing the efficacy of 600 mg of CBD per day for reducing symptoms of psychosis in young people at clinical high-risk for psychosis.

Bipolar Disorder: 

• Cannabis use can increase the risk of mania and bipolar disorder, although the evidence is not as strong as with psychosis.
• Case reports on the use of CBD are mixed.
• There is a postulated role for CB2 receptor agonists in mood stabilisation. [Arjmand et al., 2019]

ADHD:

• A qualitative analysis of online forum discussions on cannabis use and ADHD showed that a quarter found cannabis therapeutic in ADHD.
• Adults with ADHD may represent a subgroup of individuals who experience a reduction of symptoms and no cognitive impairments following cannabinoid use, as shown in a pilot RCT using nabiximol (cannabinoid/terpene combination) oromucosal spray in 30 adults with ADHD for 6 weeks. [Cooper et al., 2017]

OTHER POTENTIAL THERAPEUTIC TARGETS

Pain

• Endocannabinoids inhibit the CB1 receptor-dependent release of neurotransmitters that control nociceptive inputs, particularly in regions known to be involved in the transmission and modulation of pain signals (e.g. sensory terminals, skin, and dorsal root ganglia).
• A systematic review of RCTs examined exogenous cannabinoids in treating chronic non-cancer pain and pain conditions such as neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain states [Lynch and Campbell, 2011]. This study demonstrated a significant analgesic effect of cannabinoids compared to placebo for smoked cannabis, nabilone, and dronabinol.
• Their use was generally well-tolerated, and adverse effects had mild-to-moderate severity. Overall, evidence suggests that cannabinoids are safe and moderately effective in neuropathic pain, with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis in particular.
• Moreover, a recent review of 38 published RCTs analysed cannabinoids in the treatment of headaches.  71% of trials that studied cannabinoid treatment had statistically significant pain-relieving effects for migraine. [Aggarwal, 2013]

Multiple Sclerosis

• In multiple sclerosis (MS), pain is a frequent and debilitating feature, with current estimates suggesting that almost 50% of patients live with refractory pain. [Foley P et al., 2013], [O’Connor A et al.,2008] MS-associated central pain states include issues such as trigeminal neuralgia and chronic upper motor neuron syndrome.

The American Academy of Neurology issued a Summary of Systematic Reviews for Clinicians that indicates [American Academy of Neurology, 2014]:

• Strong evidence – For patients with MS with central pain or painful spasms, oral cannabis extract effectively reduces central pain.
• Moderate evidence – THC and nabiximols are probably effective for treating MS-related pain or painful spasms.
• Insufficient evidence – Smoked marijuana is of unclear efficacy for reducing pain.

Epilepsy

• Treatment-refractory epilepsy involves poorly controlled homeostasis of excitatory and inhibitory synaptic transmission in the brain. With the legalisation of medicinal marijuana, its role in activating the endocannabinoid system—which confers protection against convulsive activity—is generating considerable interest.
• Cannabis has a long history of use in the treatment of convulsions, with both Δ9 –THC and CBD suggested to act in synergy to suppress seizures.
• The specialised strain of cannabis known as Charlotte’s Web has become a popular treatment for refractory childhood epilepsy. This strain has been specifically bred to have high-CBD and low-THC content, thus avoiding unwanted psychotropic effects.

CONTRAINDICATIONS AND ADVERSE EFFECTS

Drug interactions: 

While few clinical studies have specifically evaluated cannabis-drug interactions, most studies have investigated the effects of cannabis (e.g. smoked, vapourised, or orally ingested) and cannabinoid-based medicines (e.g. dronabinol, nabilone, nabiximols) in patients that were concomitantly taking other medications.

For example, the presence of NSAIDs, opioids, antidepressants, and anticonvulsants did not appear to cause a significant increase in adverse effects associated with the combination of cannabis or cannabinoids with these medications.

Δ9-THC: 

Δ9-THC is metabolised in the liver by cytochrome P450 (CYP) oxidases (CYP2C9, 2C19, and 3A) while also modulating the expression level of other types of CYP enzymes.

Δ9-THC inhibits the activity of the CYP1A1, 1A2, and 1B1 enzymes, while poly-aromatic hydrocarbons (found in tobacco and cannabis smoke) induce the expression of CYP1A2.

This is important because it affects the metabolism of other drugs. Examples include:

• Theophylline
• Clozapine and olanzapine
• Amitriptyline
• Fentanyl and related opioids
• Anti-retroviral medications

CBD:

• CBD is an inhibitor of cytochrome P450 (CYP450) enzymes such as CYP3A4 and CYP2C19. High doses of CBD used to treat childhood epilepsies increase plasma concentrations of anticonvulsant medications, particularly clobazam, leading to increased sedation.
• Strong inducers of CYP3A4, such as carbamazepine, enzalutamide, mitotane, St. John’s wort, and/or strong inducers of CYP2C19, such as rifampin, administered concomitantly with CBD may decrease the plasma concentrations of cannabidiol and decrease the effectiveness of CBD.
• Concomitant use of CBD and valproate increases the incidence of transaminase enzyme elevations.
• CBD has pharmacokinetic interactions with warfarin, tacrolimus and methadone, requiring close monitoring with careful uptitration of CBD.

Contraindications: 

• Cannabis containing THC can cause tachycardia, and there are reports of cannabis-induced myocardial infarction. Hence recommendations are to avoid using medicinal cannabis containing THC in patients with angina or a history of myocardial infarction.
• Pregnancy and breastfeeding
• Avoid prescribing medicinal cannabis with THC content to patients with a known sensitivity to cannabis or those who have a personal or family history of schizophrenia or psychotic disorders.

Adverse effects

Most information regarding adverse effects reported with cannabis use comes from reports that evaluate recreational users rather than subjects in controlled clinical studies.

Therefore, these reported adverse side effects should not be assumed to be universal cannabis side effects:

• Sedative – Somnolence and amotivational syndrome
• Psychological – Euphoria and dysphoria; anxiety and panic attacks; aggravation of psychosis
• Perception – Synesthesia and hallucinations
• Motor function – Ataxia, weakness, and dysarthria
• Cognitive function – Impaired memory and mental clarity
• Dependence – Physical and psychological dependence is associated with heavy cannabis use
• Cerebrovascular – Limited data, but cases of stroke have been connected
• Cardiovascular – Vasodilation, postural and supine hypotension, tachycardia, ventricular arrhythmia, and atrial fibrillation

THC related adverse effects: [Arnold, 2021]

• When intoxicated, patients may experience euphoria and anxiolysis as well as enhanced sensory perceptions. 
• Higher doses of THC are associated with anxiety, panic, and disorientation in some individuals.
• Subtle cognitive deficits such as impaired attention and short-term memory impairment may be experienced.
• THC-containing cannabis may impair driving performance

CBD associated adverse effects: 

• Diarrhoea

When validating the toxicology of cannabis, epidemiological and social science-based drug ranking approaches have shown that alcohol has the highest mortality rating, followed by heroin, cocaine, tobacco, ecstasy, methamphetamine, and lastly, cannabis. [Lachenmeier and Rehm, 2015] This comparative risk assessment study also suggested that cannabis was approximately 114 times less lethal than alcohol.

Dependence: 

• While recreational cannabis use is associated with dependence, the use of medicinal cannabis is less likely to be habit-forming.
• CBT does not have habit-forming properties
• In individuals with cannabis dependence, Cannabis withdrawal promotes symptoms of insomnia, depression, anxiety, and gastrointestinal disturbance that may last 48–72 hours.

Cannabis Hyperemesis Syndrome:

• Heavy recreational cannabis use is associated with severe nausea and vomiting, known as the cannabis hyperemesis syndrome.
• The syndrome is associated with compulsive bathing behaviour and resolves on cessation of cannabis use. Cannabis hyperemesis syndrome appears to be mediated by THC, and there is no evidence of CBD causing the syndrome.
• Medicinal cannabis is associated with this syndrome. [Suarez et al., 2018]

SUMMARY

Medicinal cannabis is an umbrella term for a range of cannabinoids that have health benefits.

In Australia, only Nabiximol (Sativex) and CBD (Epidyolex) are approved. Clinicians need to carefully consider the ∆9-tetrahydrocannabinol (THC)  and/or cannabidiol (CBD) content.

In the US, Dronabinol and Nabilone are additionally approved.

THC is the primary psychoactive component. CBD is not psychoactive and has fewer safety concerns than THC. When commencing a new medicinal cannabis product, the recommendation is to prescribe relatively low doses and slowly up-titrate the dose: this minimizes dose-related toxicities and the potential for drug-drug interactions with concomitant medications.

As policy evolves and medicinal marijuana becomes more readily available, primary research and clinical outcome studies must be carried out. Unfortunately, there is a dearth of evidence, and we must understand the efficacy, safety, and risk-benefit analyses of medicinal cannabis before use for different health conditions.

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