Medicinal Cannabis

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There is no good evidence to support the use of medicinal cannabis in Musculoskeletal Medicine. See Cogan for a recent cutting open access review on the controversies of this area.

Indications and Efficacy

The literature on medicinal cannabis is rife with misrepresentation and overestimation of low level scientific findings, as well as an abundance of hypothetical propositions that are then prematurely translated into clinical practice. Further research should of course occur, but we must be cautious in our interpretation of results from low quality evidence, and not conflate hypothesis with fact. The only FDA-approved products are for childhood epilepsy. Advocates of medicinal cannabis claim discrimination, however this is refuted by showing the speed at which the FDA has approved products for paediatric epilepsy following the publication of large RCTs showing positive results. The fact that there are no approved products for other conditions is simply because the evidence does not exist.

In musculoskeletal medicine, the question of analgesic efficacy is most pertinent. The IASP in 2021 reviewed 36 randomised controlled trials with 7217 participants. All trials had unclear or a high risk of bias. The evidence was low or very low quality for the use of cannabinoids in any type of pain. The evidence to date neither supports nor refutes the use of cannabinoids or cannabis for pain. The IASP does not currently endorse the use of cannabis and cannabinoids for pain relief. The risk benefit trade off for pain is generally poor.

Stockings et al published a systematic review in 2018 of 47 RCTs and 57 observational studies. It is important to note that 48 of the studies were in neuropathic pain, and 7 were in fibromyalgia. The NNT for a 30% pain reduction is 24 (29% vs 26% for placebo). There was no difference between placebo for a 50% pain reduction. The standardised mean difference in pain is equivalent to a 3mm reduction on a 100mm visual analogue scale greater than placebo. The highest quality evidence is for neuropathic pain and multiple sclerosis related pain. There is low quality evidence for improved sleep, and patient global impression of change. There is no significant effect on physical functioning or emotional functioning.

With respect to pure CBD products, only 21 RCTs have been published without a single study on pain. There is zero evidence to support the use of CBD for pain. There is some evidence for its use in rare childhood epileptic seizure disorders (Dravet syndrome, Lennox-Gastaut syndrome, and tuberous slerosis complex). The FDA has been very rapid with approving CBD when evidence has been published in these conditions, refuting conspiracy thinking around FDA approvals.

Adverse Effects

In population studies, nonmedical cannabis is associated with psychosis, cognitive effects in adolescents and young adults, motor vehicle accidents, respiratory problems, and low birth weight in infants of cannabis exposed mothers. In RCTs for pain, common side effects are dizziness, sedation, and fatigue. The review by Stockings et al found that side effects were extremely common, occurring in 81%, compared to 66% compared to placebo, equating to a NNH of 6 (note comparison of NNT above of 24). There is also financial harm due to the very high costs of medicinal cannabis products in New Zealand.

Adverse effects of CBD include liver injury, drug interactions, changes in alertness (somnolence or insomnia), gastrointestinal (diarrhoea &/or decreased appetite, abdominal pain, upset stomach), changes in mood (irritability & agitation).

Pharmacology

There are various compounds in the cannabis plant.

• THC - euphoric and hypothetical therapeutic effects
• Cannabinoids - There are over 140 phytocannabinoids in the cannabis plant, with most being non-psychoactive. Each cannabinoid has a unique pharmacological action. CBD does not have euphoric effects, but has hypothetical therapeutic effects.
• Terpenes - individual mix of oils which provide a particular aroma and have their own unique pharmacology
• Other components - hydrocarbons, sugars, alkaloids, flavonoid-glycosides, phenols, ketones, aldehydes, steroids, alcohols, pigments.

The endocannabinoid system is involved in neuroimmune homeostasis signalling and uses retrograde neurotransmission. This system is present in all vertebrates, and cannabinoid receptors are found throughout the body. CBD1 receptors are found in the nervous system, gastrointestinal tract, and respiratory tract. CBD2 receptors are found in the immune system. CB3 and other receptors are under investigation. It is thought that the retrograde neurotransmission has an inhibitory effect.

Postulated Mechanisms of Action

A buzz word used commonly by those promoting medicinal cannabis is the "entourage effect." This is a vague proposition that the sum is greater than the parts of the cannabis plant for therapeutic effects. This proposition is something that cannot be falsified. For whenever there is a negative trial the answer can always be that the trial didn't use the correct combination of compounds. When you dig deeper into this claim, there is no answer to what combination exactly is required for a postulated therapeutic outcome.

“pointing to the concept of cannabis polypharmacy and suggesting that an entourage is needed to render maximum benefit is no more informative than pointing to the concept of pharmacology and suggesting that chemicals are needed to treat disease. In either instance, we are left with an unavoidable question: which ones?”

—Cogan 2020

Promotional material tries to impress the reader with all the different compounds and about the endocannabinoid system in the body. These are two undisputed material facts, yet there is an illogical leap to the conclusion that therefore exogenous use is supposed to lead to therapeutic benefit. That conclusion does not necessarily follow from those two premises. A simple analogy of where this reasoning fails is that we have an endogenous opioid system, yet exogenous opioids do not work for chronic pain.

Clinical endocannabinoid deficiency is a putative phenomenon purported to be a cause of various functional disorders. Proponents claim that because of said deficiency, supplementation with exogenous cannabinoids should therefore be used. This theory falls down in several material and logical avenues. Firstly endocannabinoids are elevated in fibromyalgia, and heavy cannabis use correlates with hospitilisation for irritable bowel syndrome. Furthermore, let's consider retrograde neurotransmission, i.e. where neuron B releases endocannabinoids to neuron A to inhibit further anterograde neurotransmission. Low levels of endocannabinoids could simply reflect reduced primary neurotransmitter activity, and so the lower levels of endogenous cannabinoids may be simply a flow on effect from that (i.e. simply a proxy marker of disease). Supplementing with exogenous cannabinoids could then result in even lower levels of primary neurotransmitters. The history of medicine is littered with getting overly excited about proxy markers and making premature therapeutic recommendations. Using the endogenous opioid system analogy again, no one is proposing using P. somniferum to treat "opioid deficiencies."

Products

Definitions

• Recreational - High in THC and low in CBD.
• Therapeutic - What people are procuring or growing themselves that is used for therapeutic reasons
• Medicinal - Standardised preparations with a spectrum of from THC, combined products, and CBD. Not usually smoked, but rather taken orally as a spray, drops, lozenges, or capsules. It can also be vaped or applied as a topical balm.

Availability in New Zealand

Generally, medicinal cannabis products are only available, on prescription, if they have:

• been assessed by the Medicinal Cannabis Agency as meeting the minimum quality standard under the Misuse of Drugs (Medicinal Cannabis) Regulations 2019
  • These are unapproved medicines meeting minimum quality standards but no assessment as to their safety and efficacy
• obtained consent for distribution under the Medicines Act 1981 (approved and provisionally approved medicines)
  • Assessed by medsafe meeting standards of quality, safety, and efficacy.

See here for a list of which products fall under which category. Any practitioner (not only non-GP specialists) is able to prescribe specific THC products that have been individually approved by the Medicinal Cannabis agency - this only includes Tilray products at the time of writing. Pricing varies greatly, a (may not be up to date) pricing guide can be found here.

Contraindications and Concerns

Psychosis/Schizophrenia - There is unlikely to be a problem with CBD only or low THC products

Substance Use Disorders - Addiction is unlikely with CBD products.

Children - THC isn't generally recommended in children, but CBD is likely safe. The most common reason for prescribing in children is for certain epilepsy disorders.

Patterns of Use

Globally and in Australasia the prevalence rate of cannabis substance use disorders is 290 per 100,000. This compares to an opioid use disorder prevalence of 353 per 100,000 globally, 415 per 100,000 in Australasia; and alcohol use disorder prevalence of 1321 per 100,000 globally, and 1305 per 100,000 in Australasia.

See Also

• BPAC article 2018
• Pharmac youtube lecture series 2019 - part 2a and part 2b and slides