Safety Considerations in Cannabinoid-Based Medicine

Figures & data

Figure 1 Types of cannabinoids.⁸,9

Table 1 Safety Data from Phase 3 Randomized Controlled Trials in Registered, Approved Cannabinoid-Based Medicines

NCT Number and Citation	Product	Indication	Patient Population^a	Dosing	Proportion of Patients with AEs and Serious AEs	Other Safety Observations	Comments
NCT02224690 Thiele EA et al 2018^Citation12	Epidiolex (oral)	Lennox-Gastaut syndrome	Children and adults (2–55 years) (n=171)	20 mg/kg/day	AEs reported in 86% (all-cause, any severity) with epidiolex vs 69% with PBO 78% vs 97% of AEs were mild or moderate with epidiolex vs PBO	Common AEs (>10%) with epidiolex: diarrhea, somnolence, pyrexia, decreased appetite, vomiting Common AEs (>10%) with PBO: vomiting Most common related serious AEs with epidiolex: increased ALT, increased AST, increased GGT	Double-blind, PBO controlled
NCT02224560 Devinsky et al 2018^Citation44	Epidiolex (oral)	Lennox-Gastaut syndrome	Children and adults (2–55 years) (n=225)	10 mg/kg/day or 20 mg/kg/day	AEs reported in 94% in 20 mg epidiolex group vs 84% in 10 mg epidiolex vs 72% in PBO group 89% of AEs (overall) considered mild or moderate	Common AEs (>10%) with epidiolex: somnolence, decreased appetite, diarrhea, upper respiratory tract infection, pyrexia, nasopharyngitis, vomiting, status epilepticus Common AEs (>10%) with PBO: upper respiratory tract infection, pyrexia, vomiting Related serious AEs with epidiolex: elevated AST, elevated ALT, elevated GGT, somnolence, increased seizures, non-convulsive status epilepticus, lethargy, constipation, worsening chronic cholecystitis	Double-blind, PBO controlled
NCT01610700 Wade et al 2004^Citation13	Sativex (oromucosal spray)	MS	Adults (≥18 years) (n=160)	Max. dose in 24 h: 130 mg THC/120 mg CBD	Not available	Common AEs (>10%) with Sativex: dizziness, fatigue, application site discomfort	Double-blind, PBO controlled Very limited safety information reported
NCT01610687 Wade et al 2006^Citation48 (safety extension of study NCT01610700)	Sativex (oromucosal spray)	MS	Adults (≥18 years) (n=137)	Max. dose in 24 h: 130 mg THC/120 mg CBD	Not available	Most common possibly, probably, or definitely related AEs (>10%): oral pain, dizziness, diarrhea, nausea Related serious AEs: seizures, vomiting, impaired balance, diarrhea	No PBO arm (open-label extension)
NCT01610713 Wade et al 2004^Citation13 (open-label extension of study NCT01610700, results of both studies reported in same article)	Sativex (oromucosal spray)	MS	Adults (≥18 years) (n=160)	Max. dose in 24 h: 130 mg THC/120 mg CBD	As per NCT01610700	As per NCT01610700	As per NCT01610700
NCT01606137 Serpell et al 2013^Citation47,b	Sativex (oromucosal spray)	MS: spasticity/pain	Adults (≥18 years) (n=146)	Max. dose per day: 130 mg THC/120 mg CBD	AEs reported in 95% (all-cause) Majority of AEs considered mild or moderate	Common AEs (>10%): dizziness, MS aggravated, headache, nausea, vomiting, diarrhea, fatigue, urinary tract infection, nasopharyngitis, muscle spasms Related serious AEs: aspiration pneumonia, abnormal liver function test, convulsions, dizziness, paresthesia, tremor, nausea, delusion perception, and paranoia	No PBO arm (open-label extension)
NCT01599234 Collin et al 2010^Citation43	Sativex (oromucosal spray)	MS: spasticity	Adults (≥18 years) (n=337)	Max. dose in 24 h: 65 mg THC/60 mg CBD	AEs reported in 93% in Sativex group vs 78% in PBO group Most AEs considered mild or moderate	Common AEs (≥10%) with Sativex: dizziness, somnolence, muscle spasticity, fatigue, asthenia, nausea, dry mouth, urinary tract infection, vertigo Common AEs with PBO (≥10%): dizziness, fatigue, nausea, urinary tract infection Related serious AEs with Sativex: psychiatric disorders, urinary tract infection	Double-blind, PBO controlled
NCT00702468 Notcutt et al 2012^Citation45	Sativex (oromucosal spray)	MS: spasticity	Adults (≥18 years) (n=36)	THC 27 mg/mL/CBD 25 mg/mL at current effective dose	AEs reported in 83% in Sativex group vs 78% in PBO group Most AEs considered mild or moderate	Common AEs (>10%) with Sativex: fatigue, pain, muscle spasticity, muscle spasms, back pain, musculoskeletal stiffness, urinary tract infection, diarrhea Common AEs (>10%) with PBO: pain, muscle spasticity, trigeminal neuralgia, muscle spasms, depressed mood Serious AEs with Sativex: pain in hip/thigh, lumbar spine stenosis (unrelated to treatment)	PBO controlled, parallel group Randomized withdrawal study design
NCT00681538 Novotna et al 2011^Citation46	Sativex (oromucosal spray)	MS: spasticity	Adults (≥18 years) (n=241)	Max. dose in 24 h: 32.4 mg THC/30 mg CBD	AEs reported in 53% in Sativex group vs 49% in PBO group	Common AEs (≥5%) with Sativex: vertigo, fatigue, urinary tract infection, muscle spasms Common AEs (≥5%) with PBO: diarrhea, urinary tract infection, muscle spasms	Patients entered 4-week single-blind treatment phase prior to double-blind phase Limited safety information
NCT00711646 Collin et al 2007^Citation42	Sativex (oromucosal spray)	MS: spasticity	Adults (≥18 years) (n=189)	Max. dose in 24 h: 129.6 mg THC/120 mg CBD	AEs reported in 82% in Sativex group vs 71% in PBO group Most AEs considered mild or moderate	Common AEs (>10%) with Sativex: dizziness, fatigue, urinary tract infection Common AEs (>10%) with PBO: dizziness, oral pain Serious AEs (possibly related) with Sativex: vomiting	Double-blind, PBO controlled

Notes: Search strategy: ClinicalTrials.gov search for: Epidiolex (synonyms: cannabidiol); dronabinol (synonyms: Marinol, Syndros, tetrahydrocannabinol, delta-9-THC); nabilone (synonyms: Cesamet); Sativex (synonyms: marijuana, cannabis). Note that synonyms were generated automatically by ClinicalTrials.gov. Inclusion criteria: interventional studies; Phase 3 studies; studies in approved product indications^c; adult or mixed pediatric and adult populations; studies with published data. Exclusion criteria: observational, registry and expanded access studies; early Phase 1 and 2, Phase 4, and Phase N/A studies; studies in other indications; studies in pediatric-only populations; studies without a published manuscript. Search date: November 7, 2019. ^aAccording to inclusion criteria, not analysis set; ^bSafety listed as primary outcome measure in ClinicalTrials.gov entry; ^cEpidiolex: Lennox-Gastaut and Dravet syndromes; dronabinol: anorexia associated with AIDS or cancer; nabilone: anti-emetic or analgesic for neuropathic pain; Sativex: spasticity associated with MS.

Abbreviations: AE, adverse event; ALT, alanine transaminase; AST, aspartate aminotransferase; CBD, cannabidiol; GGT, gamma-glutamyl transferase; Max., maximum; MS, multiple sclerosis; PBO, placebo; THC, Δ⁹-tetrahydrocannabinol.

Figure 2 Patient-reported primary indications for cannabinoid-based medicine uptake in Canada. Adapted under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) from Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain. 2018;19(1):37.⁶⁶

Table 2 Common Adverse Effects of Treatment Options^a for Neuropathic Pain

Treatment	Common Adverse Effects
Tricyclic antidepressants (amitriptyline, nortriptyline, desipramine)	Drowsiness, confusion, orthostatic hypotension, dry mouth, constipation, urinary retention, weight gain, arrhythmia
Serotonin–noradrenaline reuptake inhibitors (venlafaxine, duloxetine)	Venlafaxine: nausea, dizziness, drowsiness, hyperhidrosis, hypertension Duloxetine: sedation, nausea, constipation, ataxia, dry mouth
Anticonvulsants (gabapentin, pregabalin, carbamazepine)	Gabapentin and pregabalin: drowsiness, dizziness, peripheral edema, blurred vision Carbamazepine: drowsiness, dizziness, blurred vision, ataxia, headache, nausea, rash
Controlled-release opioid analgesics (morphine, oxycodone, fentanyl, hydromorphone)	Nausea, vomiting, sedation, dizziness, urinary retention, constipation
Tramadol	Ataxia, sedation, constipation, seizures, orthostatic hypotension
Lidocaine (topical)	Virtually no systemic side effects
Nabiximols (~1:1 THC:CBD oromucosal spray)	Dizziness, fatigue, nausea, euphoria
Nabilone (synthetic THC analog)	Dizziness, drowsiness, dry mouth

Notes: ^aTreatments included according to the Canadian Pain Society consensus statement on the pharmacologic management of chronic neuropathic pain. Adapted under the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) from Moulin DE, Boulanger A, Clark AJ et al, Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6): 328–335.⁴

Abbreviations: CBD, cannabidiol; THC, Δ⁹-tetrahydrocannabinol.

Table 3 Current Monitoring Recommendations for Concomitant Medicationsa,^73,77,78

Medication Class	Theoretical Effect	Clinical Recommendation
Anticholinergics, eg, amitriptyline	Additive tachycardia and/or hypertension	Monitor
CNS depressants, eg, alcohol, barbiturates, benzodiazepines, opioids	Additive effects including cognitive impairment BUT may be used in combination with opioids or benzodiazepines with the aim of reducing reliance on these medications	Monitor
CYP1A2 substrates, eg, acetaminophen, duloxetine, estrogen	Increased serum concentration of substrates	Monitor
CYP3A4 inducers/inhibitors, eg, St. John’s Wort, erythromycin	Reduces/increases (respectively) serum concentration of cannabinoids	Monitor
CYP2C9 inhibitors, eg, fluconazole	Increases serum concentration of cannabinoids	Monitor
Disulfiram	Enhances adverse-effect profile (data from 2 case reports only)	Monitor
Nicotine	Additive tachycardia and stimulant effects	Monitor
Some anti-cancer therapies, eg, PD-1/PD-L1 inhibitors	Reduces response to treatment	Generally avoid

Notes: ^aMany data supporting these recommendations are in studies of recreational cannabis use and should be interpreted with caution. Individual interactions of THC and CBD may differ and this list is not exhaustive.

Abbreviations: CBD, cannabidiol; CNS, central nervous system; PD-1/PD-L1, programmed death-1/programmed death ligand-1; THC, Δ⁹-tetrahydrocannabinol.

Table 4 Recommended Contraindications for Cannabinoid-Based Medicines Based on the Current State of Evidence^a,35,73

Contraindication	THC or CBD^b	Reason
Known sensitivity	THC/CBD	Existing sensitivity to cannabinoids
Aged <25 years^c	THC	Increased risk of addiction or schizophrenia
Hepatitis C	THC/CBD	Linked to progression of fibrosis/steatosis
Pregnant/breastfeeding	THC/CBD	Various serious/long-term adverse effects on offspring
Personal or family history of psychosis or schizophrenia	THC^d	Increased risk of earlier onset of psychosis in those already at risk of developing schizophrenia
Previous substance-abuse disorder	THC/CBD	Increased risk of developing cannabis-use disorder

Notes: ^aTable relates to cannabinoid-based medicines that are not licensed for a specific indication. Products approved and licensed for specific indications by national regulatory bodies have clearly defined contraindications and physicians should check the latest prescribing information to ensure compliance; ^bNot necessarily known which cannabinoid is contraindicated; ^cIn some cases of strong clinical need, it may be appropriate to prescribe products containing THC for patients aged <25 years if the benefits outweigh the risks; ^dSome preliminary research shows that CBD may be beneficial in treating schizophrenia.

Abbreviations: CBD, cannabidiol; THC, Δ⁹-tetrahydrocannabinol.

Figure 3 Number of deaths related to selected drugs, where the drug name was listed on the death certificate, England and Wales, 2018. ^aData from the Office for National Statistics, accessed February 20, 2020: all deaths relating to drug poisoning in England and Wales registered in 2018, where a drug was mentioned on the death certificate. Any opiate includes unspecified opiates and excludes paracetamol compounds. Codeine and dihydrocodeine not from compound formulations (eg, co-codamol). Paracetamol includes paracetamol compounds. Office for National Statistics. Deaths related to drug poisoning, England and Wales. 2019. Available from: (https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/datasets/deathsrelatedtodrugpoisoningenglandandwalesreferencetable). Public sector information licensed under the Open Government Licence v3.0 (http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3/).⁷⁰

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