Cannabis contains about 500 molecules, in 18 chemical classes, including about 100 plant-derived cannabis compounds (phytocannabinoids), terpenes and flavonoids. The most characterized phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).
The major cannabinoid is delta-9-tetrahydrocannabinol (Δ9-THC), which is widely known for its psychoactive effects. Cannabis plants with high Δ9-THC content are called marijuana, while cannabis plants with high cannabidiol (CBD) and little or no Δ9-THC content are known as hemp. CBD has less potent psychotropic effects.
Other cannabinoids include ∆9-tetrahydrocannabinol and other less-studied cannabinoids including cannabinol (CBD) and ∆8-tetrahydrocannabivarin.
Endocannabinoid system
The endocannabinoid system is a widespread lipid signaling system with a wide range of regulatory functions in the body.
The system consists of cannabinoid receptors 1 (CB1) and 2 (CB2) as well as the endogenous signaling ligands, N-arachidonyl-ethanolamide (AEA) and sn-2-arachidonoyl-glycerol (2-AG).
CB1 receptor
Endocannabinoid system
The endocannabinoid system is a widespread lipid signaling system with a wide range of regulatory functions in the body.
The system consists of cannabinoid receptors 1 (CB1) and 2 (CB2) as well as the endogenous signaling ligands, N-arachidonyl-ethanolamide (AEA) and sn-2-arachidonoyl-glycerol (2-AG).
CB1 receptor
- The most common G-protein coupled receptor in the brain is located mainly in axons and presynaptic nerve endings.
- The receptor is particularly abundant in the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem.
- Also present at some non-CNS sites
CB2 receptor
- They are mainly found in the periphery, where they influence cytokines and cell migration.
- In the CNS, CB2 receptor expression is associated with inflammation and localized mainly in microglia.
Activation of CB1 receptors in the presynaptic nerve terminal results in:
- Activation of potassium channels and closure of voltage-dependent calcium channels;
- Hyperpolarisation of the presynaptic terminal (known as depolarisation-induced suppression of inhibition (DSI))
- Hyperpolarisation directly inhibits the release of inhibitory and excitatory neurotransmitters such as glutamate, acetylcholine, and dopamine.
- Indirect suppression of other neurotransmitters, including serotonin, N-methyl-D-aspartate (NMDA), opiate, and γ-aminobutyric acid (GABA).
- 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:
Appetite and digestiont:
Appetite and digestiont:
- 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):
Δ9-THC:
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):
Δ9-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: the primary active metabolite of THC and, in part, responsible for the psychoactive effects of THC.
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.
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.
- 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):
- 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:
- 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):
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:
- 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.
Cannabis use in mental illness
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.
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.
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.
Nabilone was effective in reducing nightmares in PTSD but recurrence occurred post cessation.
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.
Nabilone was effective in reducing nightmares in PTSD but recurrence occurred post cessation.
- 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 5-HT1A 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.
- 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.
- 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.
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.
- 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.
- 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.
- 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 5-HT1A receptors, GPR55 receptors, and transient receptor potential vanilloid-1 receptors.
- 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.
- 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.
- DHD
- 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.