Endocannabinoid system

CB1
CB2

Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells.

In each tissue, the cannabinoid system performs different tasks, but the goal is always the same: homeostasis, the maintenance of a stable internal environment despite fluctuations in the external environment(1).

CB1 Receptors are abundant in the central nervous system particularly in the cortex, basal ganglia, hippocampus and cerebellum’(2) however are sparse within the brainstem(3). CB2 Receptors are abundant throughout the body however are present in much lower levels compared to CB1 receptors in the brain(2). Other potential receptors are under investigation such as GPR55 which is found in particular areas of the brain, spleen and adipose tissue however its function is only speculated(4) as too is that of CB3 receptors(5).

References
References
  1. Sulak, D., 2015, The Endocannabinoid System, Healer.com, viewed 2 April 2016 http://healer.com/the-endocannabinoid-system/.
  2. Lu, H.C, Mackie, K., 2016, An introduction to the Endogenous Cannabinoid System, Biological Psychiatry, Vol. 79, p. 517.
  3. Backes, M., 2014, Cannabis Pharmacy: The Practical Guide to Medical Marijuana, Black Dog & Leventhal Publishers, New York, p.41.
  4. Baker, D., Pryce, G., Davies, W.L., Hiley, C.R., 2006 In silico patent searching reveals a new cannabinoid receptor, Trends in Pharmacological sciences, Vol. 27, No. 1, p.p. 1-4.
  5. Fride, E., Foox, A., Rosenburg, E., Faigenbolm, M., Cohen, V., Barda, L., Blau, H., Mechoulam, R., 2003, Milk intake and survival in newborn cannabinoid CB1 receptor knockout mideL evidence for a “CB3” receptor, European Journal of Pharmacology, Vol. 461, No. 1, p.p. 27-34.
  6. Cannabis: The Evidence for Medical Use May 2016 Professor Michael P Barnes MD FRCP, Honorary Professor of Neurological Rehabilitation, Newcastle University. Dr Jennifer C Barnes DPsychol, Clinical Psychologist, Northumberland, Tyne & Wear NHS Foundation Trust https://www.drugsandalcohol.ie/26086/1/Cannabis_medical_use_evidence.pdf

What’s in a Cannabis plant?

100%

Two main cannabinoids

THC

Medical benefits
Medical benefits
  • Relieves pain
  • Helps with relaxation
  • Suppresses pain from nerve damage
  • Stimulates appetite
  • Reduces nausea and vomiting
  • Reduces risk of nerve damage
  • Suppresses muscle spasms and convulsions

CBD

Medical benefits
Medical benefits
  • Anti-inflammatory properties
  • Reduces seizures and convulsions
  • Stimulates bone growth
  • Anti-oxidant properties
  • Anti-psychotic properties
  • Moderates THC side effects
  • Anti-bacterial
  • Relieves pain

Compounds effecting wellness

Terpenes

Terpenes: More than 200 in Cannabis

A-Pinene

  • Anti-inflammatory
  • Bronchodilator
  • Aids memory
  • Anti-bacterial

Also found in pine needles

Linalool

  • Anesthetic
  • Anti-convulsant
  • Analgesic
  • Anti-anxiety

Also found in lavender

Beta Caryophyllene

  • Anti-inflammatory
  • Analgesic
  • Protects cells lining the digestive tract

Also found in black pepper

Myrcene

  • Contributes to sedative effect of strong indicas
  • Sleep aid
  • Muscle relaxant

Also found in hops

Limonene

  • Treats acid reflux
  • Anti-anxiety
  • Anti-depressant

Also found in citrus

Understanding Medical Cannabis

Medical Cannabis dosing regulations

Start Low, Go
Slow, Stay Low

Dosing Considerations
Key principles
Routes of administration
Adult THC Dosing: Start Low, Go Slow, Stay Low
Adult CBD Dosing: Start Low, Go Slow, Stay Low
Chronic Conditions
Inhalation
Tolerance
Cease Cannabis
References
Dosing Considerations
  • Is the patient cannabis naïve? Slow upward dose titration for tolerance to THC psychoactive effects
  • Most adverse effects due to the THC component
  • Daytime verses nighttime dosing
  • Use oral oils as base of therapy with vaporised products for rescue/breakthrough
  • Full spectrum (extracts) vs isolates
  • Indica vs sativa profile. What strain—indica/sativa/indica-sativa hybrid?
  • Terpene profile—which effects are complimentary for therapeutic goal?
  • Does exceeding 20–30mg/day THC may increase ADE or induce tolerance without improving efficiacy
Key principles
  • Start Low, Go Slow, Stay Low
  • For Cannabis naïve:
    —Start with CBD and add in THC at night only initially
  • Non Cannabis naïve:
    —Can start with CBD and THC mix
  • CBD should always be given with THC as can balance out side effects
  • Aim for higher CBD and low THC
  • Very personalised response—significant variability
  • Full extract (spectrum) products need much lower dosing than isolates
  • Use oral oils as base of therapy with vaporised products for rescue/breakthrough
Routes of administration
Route Smoking Inhalation Oral Oral-Mucosal Topical
Onset 5-10mins 5-10mins 1-3 hours 15-45 mins Variable
Duration 2-4 hours 2-4 hours 6-8 hours 6-8 hours Variable
Bioavailability 2-56% 40% 6-20% (due to 1st pass Metabolism) 20% 5% systemic

Recommended that a symptom chart is kept to record dosing and symptom control. Genetic variation regarding effect and DNA profiling is useful to identify optimal treatment.

Adult THC Dosing: Start Low, Go Slow, Stay Low
  • Start at 1–2.5mg THC daily (bedtime to limit ADE)
  • Increase slowly (every 3 days) in 1–2mg increments and increase as needed and as tolerated to 10mg THC 2-3 times daily

NB: Professor Barnes recommended 15–20mg maximum daily dose.1

Recommended maximum total daily dose equivalent of THC is 30mg/day2

Doses exceeding 20–30 mg/day may increase adverse events or induce tolerance without improving efficacy.

THC-mediated side effects such as fatigue, tachycardia and dizziness are avoidable when starting dose is low and titration is slow.

Slow upward dose titration promotes tolerance to psychoactive sequelae of THC, which is especially important for naive users.

Most of the adverse effects are due to the THC component.

Adult CBD Dosing: Start Low, Go Slow, Stay Low
  • Start with 5 to 10mg in divided doses (2-3 times daily)
  • Increase by 5–15mg every 3–5 days up to 100/200mg daily in divided doses
  • Try to take consistently with/without food

Exceptions to max dose:

  • Psychosis: Max daily CBD dose is 800mg
  • Seizure disorders: CBD 20–50mg/kg (or 2500mg max daily dose)

PAEDIATRIC CBD DOSING:

  • Start with 1mg/kg per day
  • Increase in 5 mg/kg increments
  • Up to a maximum of 25mg/kg daily

CBD can balance THC side effects, especially in daytime use, or when driving is required.

Higher doses of CBD may be required for adjunctive effect in the treatment of pain/inflammation and to alleviate anxiety/tachycardia effects of THC.

Aim for the higher levels of CBD with small amounts of THC to achieve best improvement in symptom control, function, and quality of life, with the fewest adverse events.

Chronic Conditions

For chronic conditions and symptoms, long acting oral preparations are the mainstay of treatment. Vaporisation can be utilised as an add-on as required technique for episodic exacerbations of symptoms.

Inhalation

For cannabis inhalation, patients should start with 1 inhalation and wait 15min. Then, they may increase by 1 inhalation every 15–30 min until desired symptom control has been achieved.

Higher THC concentrations of herbal cannabis may allow utilisation of lower amounts. Patients should titrate accordingly to avoid adverse events.

Tolerance

If tolerance occurs (often happens at 10–12 months) then:

  • Try increasing dose
  • Try reducing dose (biphasic effect-identify the optimal dose)
  • Drug holiday
  • Strain swop
  • Try THCA or CBDA (raw acid forms)
Cease Cannabis

Cease medical cannabis if the desired effect is not apparent after 4–12 weeks or if the side effects become prohibitive.

References

1Barnes, M. Barnes, J. Cannabis : The evidence for medical use May 2016 https://www.drugsandalcohol.ie/26086/1/Cannabis_medical_use_evidence.pdf

2MacCallum, C. Russo, E. Practical Considerations in Medical Cannabis Administration 0953-6205/ © 2018 European Federation of Internal Medicine.

Adverse effects and drug interactions

There are a number of potential drug-drug interactions with cannabis-based medicinal products and other medications or substances.

CONTRAINDICATIONS Cannabis is to be avoided in the following:
DRUG INTERACTIONS Pharmacodynamic Interactions
Cytochrome P-450 isoenzymes
1A2 inducement could result in decreased levels of:
2D6 Inhibition causes potential increased levels of:
3A4 Inhibition could result in increased levels of:
Cautions: Two drugs require extra monitoring
References
CONTRAINDICATIONS Cannabis is to be avoided in the following:
  • Children except for CBD/low THC products for intractable epilepsy
  • Adolescents (<20 years female and <25 in young males)
  • Pregnancy and breast-feeding Mothers
  • Those with unstable psychiatric conditions or at high risk of psychosis or schizophrenia (including family history)
  • History of suicide attempt or suicide ideation
  • Severe cardiovascular disease (arrhythmia/post MI)
  • Post stroke
  • Immunological conditions (especially liver related)
  • Cirrhosis-Hep C related
  • Kidney Disease
  • Cannabis Use Disorder (THC)
DRUG INTERACTIONS Pharmacodynamic Interactions
  • Additive sedation effect with alcohol, barbiturates, benzodiazepines and
    possibly opioids
  • Drugs with sympathomimetic activity (tachycardia, hypertension)
  • CNS depressants (drowsiness, ataxia)
  • Drugs with anticholinergic effects (tachycardia, drowsiness)
Cytochrome P-450 isoenzymes

There are a number of potential drug-drug interactions with cannabis-based medicinal products and other medications or substances. Data suggests that CBD and THC act as enzyme inhibitors of cytochrome P-450 isoenzymes. Therefore caution should be taken when cannabis-based medicines are co-administered with any medications that are CYP inhibitors or inducers.

  • THC is metabolised by CYP-2C9 and CYP-3A4—watch patients who are poor metabolisers of CYP2C9 – can lead to higher blood levels (x3)
  • Inhibitors of CYP-2C9—will result in increased THC levels
  • THC induces CYP-1A2 and can reduce levels of drugs metabolized by CYP-1A2
  • Ketoconazole (inhibitor of CYP-3A4) shown to increase THC levels by 1.2–1.8 (as likely with other 3A4 inhibitors)
  • Rifampicin (a CYP-3A4 inducer) reduce THC levels by 20–40%
  • CBD is a potent inhibitor of CYP-2D6 and CYP-3A4 (25% of all medicines) thus can increase levels of drugs metbolised by these isoenzymes1.
  • CBD is a Substrate of CYP-3A4 and CYP-2C19
  • Ketoconazole shown to increase CBD levels by about 2-fold
  • Rifampicin reduces CBD levels by 50–60%
  • Other CYP3A4/CYP 2C19 inhibitors and inducers could effect CBD levels
1A2 inducement could result in decreased levels of:
  • Clozapine
  • Duloxetine
  • Naproxen
  • Olanzapine
  • Haloperidol
  • Chlorpromazine2
2D6 Inhibition causes potential increased levels of:
  • Many of the antidepressants
    —TCA: Including amitriptyline
    —SSRI: Including Fluoxetine
  • Antipyscotics
  • Beta blockers
  • Opioids (including codeine and oxycodone)
3A4 Inhibition could result in increased levels of:
  • Erythromycin (macrolides)
  • Antihistamines
  • Haloperidol
  • Quinidine
  • Benzodiazepines
  • Cyclosporine
  • Calcium Channel Blockers
  • Some statins: Atorvastatin and Simvastatin, but not Pravastatin or Rosuvastatin
  • Estrogen/testosterone
  • Sildenafil (and other PDE inhibitors)
  • Antiretrovirals

Clinically significant drug interactions are rare and there is no drug that cannot be given with cannabis if necessary3. Existing studies have not demonstrated toxicity/loss of effect of concomitant medications, but still theoretically possible4

Cautions: Two drugs require extra monitoring

High dose CBD with clobazam, where high levels of a sedating metabolite, N-desmethyl clobazam will require a dose reduction for that drug5

Warfarin: THC and CBD increase warfarin levels6.

In patients taking warfarin, INR monitoring is suggested during initiation and up-titration of cannabinoids7.

References
  1. https://doh.dc.gov/sites/default/files/dc/sites/doh/publication/attachments/Medical%20Cannabis%20Adverse%20Effects%20and%20Drug%20Interactions_0.pdf
  2. Flockhart 2007, Watanabe et al 2007
  3. Russo EB. Current therapeutic cannabis controversies and clinical trial design issues. Front Pharmacol 2016;7:309.
  4. Ujvary I, Hanus L. Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res 2016;1:90–101.
  5. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017;376:2011–20.
  6. Yamaori et al 2012
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789126/

Health effects

The health effects of Cannabis and Cannabinoids

In the report The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research, an expert, ad hoc committee of the National Academies of Sciences, Engineering, and Medicine presents nearly 100 conclusions related to the health effects of cannabis and cannabinoid use.

Additional resources

References for Medical Cannabis: Evidence and Safety/Risk Profiles
TGA Medicinal Cannabis Guidance Documents

Mike Selvey, re: Martin Crowe

The apparently hale nature of his condition was a camouflage. When he was awake, he said, he did indeed feel good, but rather than undergoing yet more chemotherapy he was by then self-medicating with liquid marijuana and sleeping 15 hours a day. Happy hours, though.

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