Safety & Adverse Effects

12 of 13 included studies reported gastrointestinal symptoms in cannabis users, including nausea, vomiting, diarrhea, abdominal pain and adult intussusception.

Systematic review on cannabis-induced gastrointestinal symptoms in adults; k=13 studies (2 SR, 1 retrospective cohort, 1 chart review, 2 cross-sectional, 1 survey, 6 case reports), n=79.779 participants; 12/13 studies report GI symptoms (nausea, vomiting, diarrhea, abdominal pain); limitations: small sample sizes, heterogeneous designs, data gaps for geriatric users.

THC-containing cannabinoid medicines show increased rates of adverse events (in particular dry mouth, dizziness, balance disorders, perception problems and drowsiness) in a dose-dependent manner, while serious adverse effects, discontinuations and deaths are not significantly increased.

Systematic review + meta-analysis across k=58 RCTs (n=6.611, age ≥50 years, 50% male, n=3.450 received cannabis products). Incidence Rate Difference (IRD) for all adverse events with THC-containing products: THC alone IRD=18,83 (95% CI 1,47–55,79), THC:CBD combination IRD=19,37 (95% CI 4,24–45,47). IRD for serious adverse effects, discontinuations, deaths not significantly increased. THC dose-dependent: dry mouth, dizziness, coordination difficulties, somnolence. Weekly THC:CBD dose interaction relevant for neurological, psychiatric, cardiac adverse effects.

THC-containing cannabinoids significantly increase the rate of adverse events in older adults, but are not more dangerous than controls with regard to serious AEs and deaths; CBD alone appears safe.

SR+MA, k=46 RCTs, n=6.216 adults ≥50 years; THC-containing CBMs significantly increased all AEs: THC alone IRR 1,42 [95% CI 1,12–1,78]; THC:CBD combination IRR 1,58 [95% CI 1,26–1,98]; THC:CBD increased discontinuation rate due to AEs (RR 1,40 [95% CI 1,08–1,80]); no significantly increased risk for serious AEs or deaths; CBD alone: IRR 1,02 [95% CI 0,90–1,16], no increased AE risk.

Unlike with alcohol and opioids, no significant difference in striatal dopamine receptor availability was found in cannabis users.

Meta-analysis of in-vivo neuroimaging studies on the striatal dopamine system in users of alcohol, opioids and cannabis (n=723 substance users, 752 healthy controls). Cannabis users showed NO significant reduction in striatal D2/D3 receptor availability compared with controls — in contrast to alcohol (g=0,46) and opioid users (g=1,17). Too few cannabis studies available to evaluate dopamine transporter or synthesis capacity.

CBD was associated with an increased likelihood of study discontinuation, serious adverse events (especially in childhood epilepsy), diarrhoea, somnolence and sedation compared to placebo.

Systematic review + meta-analysis on CBD safety across k=12 double-blind RCTs (n=803). CBD vs. placebo: increased risk for study discontinuation (OR 2.61, 95% CI 1.38-4.96), serious adverse events (OR 2.30, 95% CI 1.18-4.48), abnormal liver values (OR 11.19, 95% CI 2.09-60.02), pneumonia (OR 5.37, 95% CI 1.17-24.65), decreased appetite (OR 3.56, 95% CI 1.94-6.53), diarrhoea (OR 2.61, 95% CI 1.46-4.67), somnolence (OR 2.23, 95% CI 1.07-4.64). Liver value abnormalities, somnolence, sedation and pneumonia limited to childhood epilepsy studies (possible interaction with clobazam/valproate). After exclusion of childhood epilepsy: only diarrhoea associated (OR 5.03, 95% CI 1.44-17.61).

Regular cannabis use was associated with mild cognitive impairments as well as structural and functional brain changes, although the study evidence was heterogeneous.

Systematic review (k=56 studies, PubMed/LILACS/SciELO, 2010–2016) on the effects of regular cannabis use on neurocognition, brain structure and function in adults; subtle cognitive deficits demonstrated ≥7 days after intensive use. Growing evidence for volume reduction in the hippocampus and reduced gray matter density compared to non-users; morphological changes in other brain regions controversial.

CBD shows good tolerability with predominantly mild to moderate side effects, but few serious adverse events were reported, especially in combinations with other medications.

Systematic review on CBD toxicity and side effects (k=51 studies, Feb 2019–Sep 2022); primarily treatment-resistant epilepsies examined. Most common side effects: diarrhoea, somnolence, sedation, respiratory tract infections (mostly mild/moderate). CBD well tolerated at therapeutic doses (children & adults); few serious side effects, mainly with co-medication with clobazam/valproate.

Meta-analysis shows increased prevalence of cannabis use disorders in ADHD (lifetime 26,9%, current 19,2%) and increased risk (2,85- to 2,91-fold) compared to the general population.

Systematic review and meta-analysis on the prevalence of cannabis use disorder (CUD) in ADHD; k=14 studies. Lifetime prevalence of CUD in ADHD 26,9% (prediction interval 12,4–48,8%), current prevalence 19,2% (prediction interval 5,5–39,1%). Risk ratio: ADHD patients have a 2,85-fold increased risk for lifetime CUD and a 2,91-fold increased risk for current CUD compared to the general population.

Systematic review + meta-analysis on cannabis advertising and cannabis use (k=21 studies, of which 10 poolable in meta-analysis). Cross-sectional meta-analysis: cannabis advertising exposure vs. no contact associated with cannabis use (aOR=1.77, 95% CI [1.32, 2.30], p<0.05); general-advertising subgroup aOR=1.67 [1.27, 2.21]. Moderate heterogeneity I²=42.3% (Q=22.73, p<0.05). 18/21 studies cross-sectional, 3 longitudinal; setting USA/Canada, age 11–65+ years.

Cannabinoid therapies are associated with a broad spectrum of side effects, particularly gastrointestinal, neurological and psychiatric disorders, while possibly offering symptomatic relief.

Systematic review of k=14 RCTs on side effects of cannabinoid therapies in adult cancer patients (n=12–399 per study, intervention duration 48h–12 months). Most common side effects: gastrointestinal (nausea, dry mouth), neurological (dizziness, somnolence) and psychiatric (anxiety, hallucinations). 1–>12 different side effects reported per study. 10 studies with 'some concerns', 2 with 'high risk' in the bias assessment.

Serious adverse effects of CBD are rare, but include increased transaminases, seizures, sedation, lethargy and upper respiratory tract infections, partly related to drug interactions.

Systematic analysis of serious adverse events (SAEs) in RCTs with oral CBD (≥1 week). SAEs rare; include increased transaminases (interaction with valproate), convulsions, sedation, lethargy, respiratory tract infections (interaction with clobazam). Monitoring recommended with co-medication with antiepileptics.

CBD was well tolerated at all doses without serious AEs, but showed gastrointestinal side effects and a strongly food-dependent bioavailability.

Phase I safety study in healthy subjects, CBD oral 1500–6000 mg (SAD), 750/1500 mg 2x daily (MD); CBD well tolerated, all AEs mild to moderate, no severe/serious events, no study discontinuations; most common AEs: diarrhoea, nausea, headache, somnolence; high-fat meal increased CBD exposure (Cmax and AUCt) by 4,85-fold and 4,2-fold respectively; terminal t½ ~60 h after multiple dosing.

CBD 600 mg significantly inhibited THC-induced paranoia and hippocampus-dependent memory impairment compared with placebo.

n=48 healthy subjects, RCT: CBD 600 mg oral before IV THC 1,5 mg. THC-induced paranoia (SSPS) significantly reduced by CBD pretreatment (t=2,28, p<0,05); memory impairment (HVLT-R -10,6% placebo vs. -0,4% CBD, t=2,39, p<0,05). Demonstrates cannabis THC as a risk factor for acute psychiatric adverse drug reactions; CBD co-administration as a protective factor.

Add-on CBD reduced motor seizures in LGS/DS consistently by median 50% over the long term with an acceptable safety profile.

n=607 patients (multi-center EAP), CBD (Epidiolex) long-term follow-up up to 144 weeks. Most common AEs: somnolence 30%, diarrhoea 24%. Discontinuation rate LGS/DS 28%, of which 20% due to lack of efficacy, 4 due to AEs. Acceptable safety profile with long-term use.

Highly purified CBD significantly and sustainably reduces seizure frequency and severity in treatment-refractory epilepsy over 2 years.

n=169 TRE patients (children + adults), CBD up to 50 mg/kg/day over up to 2 years. Most common AEs: diarrhea, sedation, decreased appetite. Adverse Events Profile (AEP) showed significant improvement versus baseline at several time points (p<0,0001); mean AEP scores consistently <baseline throughout study duration. Proportion with AE-related treatment discontinuation was a minority — CBD well tolerated with long-term use up to 2 years.

CBD significantly reduced emotional exhaustion symptoms, but caused serious adverse effects (hepatotoxicity, pharmacodermia) exclusively in the verum arm.

RCT (n=120), CBD 300 mg/d vs. standard care over 28 days in frontline healthcare personnel; 5 serious adverse reactions in the CBD arm: 4 liver value elevations (1 critical, 3 mild), 1 severe pharmacodermia; treatment discontinuation in 2 participants (n=2/61, ~3,3%). Primary efficacy outcome (burnout scale) showed improvement (day difference day 28: 4,01 points, 95%-CI 0,43–7,59), but liver toxicity as a relevant safety signal for CBD.

The 1:1 ratio of medical cannabis significantly improved sleep, physical and functional capacity without serious adverse effects.

Phase 2 RCT n=88 glioma patients; no serious adverse events; frequent mild adverse events: dry mouth, nighttime fatigue, dizziness, drowsiness; well tolerated single nightly dose of THC-containing medical cannabis (no SAE signal).

Transdermal CBD gel was safe and was associated with a relevant reduction in seizure frequency as well as improvements in quality of life.

Safety profile of transdermal CBD gel (n=48 children, DEEs): 60% ≥1 treatment-related AE; 96% of AEs mild/moderate; most common AEs application site dryness, pain and somnolence (each 8%); no gastrointestinal AE except diarrhoea in 1 patient; no serious treatment-related AEs documented.

CBD significantly reduced seizure frequency and major seizures and increased seizure-free days compared to baseline.

n=45 children with TRE, CBD up to 50 mg/kg/day over up to 36 months; 100% of patients experienced ≥1 adverse event (AE); 12 children reported 20 serious AEs, none classified as CBD-related; high-dose group showed more AEs before dose increase, but significantly lower AE rate after switching to >25 mg/kg/day (p=0,004); treatment up to 50 mg/kg/day overall well tolerated.

Nabilone improved chorea and neuropsychiatric symptoms, but not the total motor score, compared with placebo.

n=44 Huntington's disease patients (nabilone 1–2 mg vs. placebo, cross-over); nabilone safe and well tolerated, no psychotic episodes; treatment difference in UHDRS total motor score 0,86 (95% CI: −1,8 to 3,52); chorea score difference 1,68 (95% CI: 0,44 to 2,92). No serious adverse event documented.

Therapeutic CBD (750 mg) shows no relevant abuse potential; higher doses produce small but significantly lower subjective effects than the positive controls alprazolam and dronabinol.

n=43 healthy recreational drug users, randomised crossover RCT; CBD 750 mg showed no significantly higher abuse potential vs. placebo (Drug-Liking E_max p=0.51); CBD 1500 mg and 4500 mg statistically different from placebo (p=0.04 and p=0.002, respectively), but mean difference <10 VAS points vs. >18 points for positive controls (alprazolam, dronabinol); no serious adverse events.

Renal impairment has no influence on the pharmacokinetics of CBD; no dose adjustment required.

Phase I safety study (n=32; n=8 each for mild/moderate/severe renal impairment and normal function); single dose 200 mg oral CBD (Epidiolex). No statistically significant difference in Cmax, AUCt or AUC∞ between renal impairment groups and normal function (Cmax ratio GMR 0,68–1,35). 5 AEs in total, all mild; no serious AEs or discontinuations. CBD well tolerated across varying renal function; no need for dose adjustment.

Abrupt discontinuation of CBD did not lead to a clinically measurable withdrawal syndrome in healthy volunteers.

n=30 healthy volunteers: CBD 750 mg twice daily (Epidiolex) over 4 weeks, then abrupt discontinuation vs. placebo. No withdrawal syndrome detectable; CWS scores 0–4/190 (Arm 1) vs. 0–0,5/190 (Arm 2); PWC-20 median scores 0/60 in both arms. 97% of volunteers in Part 1 reported AEs; most common: diarrhea (63%). 9 study discontinuations due to AEs in Part 1; no serious AEs.

Δ9-THC did not significantly reduce chronic abdominal pain in pancreatitis compared to active placebo.

n=24 patients (chronic pancreatitis), Δ9-THC 8 mg oral vs. diazepam; feeling of anxiety and heart rate significantly increased after THC (p significant); most common adverse events: somnolence, dry mouth, dizziness, euphoric mood. THC overall well tolerated; no serious adverse events with single dose.

CBD was well tolerated at all dose levels, without clinically relevant safety signals and with dose-proportional plasma exposure.

Phase 1 dose-escalation RCT (n=24 healthy subjects), oral CBD formulation 5/10/20 mg/kg vs. placebo; no serious adverse events (SAEs), no clinically relevant laboratory abnormalities or ECG changes. Most common TEAEs: headache (17%) and diarrhea (8%). CBD well tolerated with dose-linear plasma exposure (Cmax and AUC proportional) and half-life ~70 h.

CBD showed no DDI with clobazam itself, but significantly increased the exposure of the metabolite N-desmethylclobazam by 2- to 2,6-fold.

Phase 2 RCT (n=20) on pharmacokinetic interaction of CBD (Epidiolex) with clobazam in epilepsy patients: no DDI between CBD and CLB (GMR Cmax=1,0; AUCtau=1,1; 90%CI 0,8–1,2 and 0,9–1,2 respectively), but significant DDI with N-desmethylclobazam (GMR Cmax=2,2, AUCtau=2,6; 90%CI 1,4–3,5 and 2,0–3,6 respectively). AEs predominantly mild to moderate; 1 serious AE (seizure cluster) led to CBD discontinuation.

CBD markedly reduced seizure frequency in TSC patients, with consistent responder rates of 38,9–50% over 12 months.

n=18 children/adolescents with TSC-associated refractory epilepsy under CBD: adverse event rate 66,7% (12/18 patients). Most common adverse events: somnolence 44,4% (8/18), ataxia 27,8% (5/18), diarrhea 22,2% (4/18). All adverse events classified as possibly CBD-related. No treatment discontinuation due to adverse events reported. Safety profile consistent with other CBD expanded access studies in refractory epilepsy.

CBD leads to a clinically relevant drug interaction with clobazam (strongly increased norclobazam levels), but enables a >50% seizure reduction in 70% of patients.

n=13 children with refractory epilepsy: CBD-clobazam interaction with clinical safety relevance. CLB levels +60±80% (95% CI –2 to +91%), N-desmethylclobazam (nCLB) +500±300% (95% CI +90 to +610%) after 4 weeks. Adverse drug reactions in 77% of patients (10/13); resolved through CLB dose reduction in 77% (10/13). Safety-relevant finding: CYP2C19 inhibition by CBD → nCLB accumulation; monitoring mandatory.

The study protocol was fully feasible and acceptable; a preliminary efficacy signal favoring cannabidiol was observed, without significant adverse events.

Pilot RCT (n=8 children with intellectual disability and severe behavioral problems, 8–16 years); CBD 20 mg/kg/day (max. 500 mg 2×/day) vs. placebo over 8 weeks; 0 serious adverse events, 0 study dropouts; medication adherence 100%; blood tests 92%; parental acceptance high; efficacy signal favoring CBD.

CBD markedly increased N-desmethylclobazam exposure (3,4-fold) and moderately affected stiripentol, while valproate and CBD showed no clinically relevant mutual interaction.

Phase 1 DDI study (healthy subjects): CBD (GW formulation, Epidiolex) inhibits CYP3A4/2C19 — N-desmethylclobazam exposure increased 3,4-fold with concomitant clobazam; stiripentol AUC increased 1,6-fold; no clinically relevant effect on valproate. Stiripentol decreased 7-OH-CBD exposure by 29%. No deaths, no serious adverse reactions; CBD moderately tolerable with all comedications.

Oral CBD was well tolerated short-term in pediatric epilepsy patients, but showed relevant pharmacokinetic interactions with clobazam and interindividual exposure variability.

n=61 pediatric patients (1–17 years) with treatment-resistant epilepsy; most common ADRs under CBD solution: somnolence 21,3%, anemia 18,0%, diarrhea 16,4%; relevant bidirectional drug interaction with clobazam (2,5-fold increased CBD exposure at 40 mg/kg/day); short-term use generally well tolerated.

CBD treatment led to no cognitive deterioration and significantly improved selective attention as well as behavior.

Open-label study (n=39 epilepsy patients), CBD over 3 months: no adverse cognitive group effects; >89% of all test results stable or improved; no significant relationship between CBD dose and cognitive changes. CBD shows a favorable side effect profile from a cognitive and behavioral perspective.

CBD was dose-proportionally bioavailable and generally tolerated in children with Dravet syndrome, but showed interactions with the clobazam metabolite and transient transaminase elevations under valproate.

n=34 children with Dravet syndrome (4–10 years), CBD 5/10/20 mg/kg/d vs. placebo. Completion rate 94% (32/34). CBD caused more adverse events than placebo (Class I evidence): most common AEs fever, somnolence, loss of appetite, sedation, vomiting, ataxia, abnormal behavior. 6 of 34 patients (17,6%) developed elevated transaminases (all recovered); interaction with N-desmethylclobazam (nCLB levels increased). Overall well tolerated at therapeutic doses.

Artisanal CBD reduced seizure frequency by at least 50% in just under 38% of children, but the majority showed no benefit.

n=29 pediatric DEE patients, CBD oil up to 25 mg/kg/day for ≥6 months; adverse events in 7/29 (24,1%) — most common: somnolence, decreased appetite, diarrhoea; all mild and transient, no dose adjustment of CBD or comedication required; no patient reported worsening of seizure frequency as an adverse effect; safety profile of artisanal CBD preparation (98–99% pure) acceptable.

Nabiximols was safe and tolerable; 1-year survival was numerically higher than under placebo, however progression-free rate at 6 months was identical.

Phase 1b safety data for nabiximols + temozolomide in glioblastoma (n=21); most common AEs: vomiting, dizziness, fatigue, nausea, headache (predominantly grade 2-3 CTCAE); no drug-drug interaction with TMZ; acceptable safety and tolerability profile with individualized dosing.

Cannabinoids (CBD/THC) were predominantly well tolerated and led to a relevant symptom reduction in 43% of palliative patients, however without a control group and with a high dropout rate by day 28.

Pilot trial n=21 cancer patients in palliative care (CBD n=16, THC n=5); median maximum tolerated dose CBD 300 mg/day, THC 10 mg/day; drowsiness as most common adverse event; 43% response rate; no life-threatening adverse events reported; 86% study completion rate by day 14 — feasibility and safety data for an escalating CBD/THC dosing regimen.

ZYN002 significantly reduced anxiety and behavioral symptoms and was well tolerated, without serious adverse events.

Phase 1/2 safety study (n=20 pediatric patients) with transdermal CBD gel (ZYN002) over 12 weeks: 85% of participants reported treatment-emergent AEs, of which 70% were mild — no serious adverse reactions. Diarrhea, fatigue and somnolence documented as common adverse effects. CBD well tolerated at doses of 50–250 mg/day.

CBD wafer and oil solution were well tolerated and showed comparable bioavailability to nabiximols, with mild to moderate adverse events such as somnolence and mood changes.

Phase I safety study (n=12 healthy volunteers): CBD as sublingual wafer (25/50 mg) or oil solution (50 mg) vs. nabiximols spray. Adverse events: mild to moderate somnolence, sedation and mood changes; no serious events. Relative bioavailability wafer vs. oil: 90% CI 83–131% (equivalent). Maximum CBD plasma concentration: 9,4 ng/mL (oil) vs. 11,9 ng/mL (wafer); half-life approx. 6 hours. No statistically significant difference in AUC compared to nabiximols.

High-fat meals increase CBD bioavailability the most (3,8-fold AUC, 5,2-fold Cmax), followed by low-fat meals, whole milk, and alcohol.

Phase 1 RCT (n=29 fasted reference group) on CBD 750 mg (Epidiolex) and the effect of food on exposure: AUC 3,8-fold higher with high-fat meal (vs. fasted), Cmax increased 5,2-fold; low-fat meal +2,7-fold AUC; whole milk +2,4-fold AUC; alcohol +1,6-fold AUC. No serious adverse events.

CBD was neither symptomatically effective nor toxic compared to placebo in Huntington's patients.

Double-blind randomized cross-over trial n=15 HD patients; oral CBD ~700 mg/day for 6 weeks vs. placebo; no significant difference (p>0,05) in chorea severity, clinical laboratory values or Cannabis Side Effects Inventory; CBD safe and non-toxic at high dosage over 6 weeks.

CBD as add-on therapy achieved high responder rates and EEG improvements in refractory epileptic spasms in childhood.

Safety data from open-label study (n=9 children with refractory epileptic spasms): adverse event rate 89% (n=8), primarily somnolence; no serious adverse reactions reported that led to discontinuation. CBD expanded-access dosing up to 25 mg/kg/day as add-on therapy well tolerated.

Regular cannabis use prospectively increases the risk of specific psychiatric disorders and reduces mental quality of life.

NESARC longitudinal study (Wave 1 N=43.093, Wave 2 N=34.653); regular cannabis use (weekly) prospectively predicted the occurrence of panic disorder with agoraphobia and social phobia; cannabis use correlated cross-sectionally with higher rates of psychiatric disorders; no significant effect on physical health.

Adolescent cannabis use is associated with a significantly increased risk of depression and anxiety disorders in adulthood.

Northern Finland Birth Cohort 1986 (n=6.325, follow-up up to 33 years); adolescent cannabis use (5-16 years) associated with increased risk of anxiety disorder (HR 2.01, 95% CI 1.15–3.82 for ≥5× use) and increased risk of depression (HR 1.93, 95% CI 1.30–2.87 for one-time use) after adjustment for parental psychiatric history, substance use and baseline behavior.

Early onset and frequent cannabis use are associated, independently of other influencing factors, with a significantly increased risk of anxiety and depression in young adulthood.

Prospective cohort n=3.239; early cannabis use before age 15 with frequent use at age 21 associated with OR=3,4 (95% CI 1,9–6,1) for anxiety and depression symptoms in young adulthood, independent of use of other illegal drugs.

High subjective effectiveness across a broad spectrum of indications, but frequent side effects and, in 17 % of users, a moderate/severe cannabis use disorder.

Australian cross-sectional survey of medical cannabis users (n=1.748); frequent side effects: drowsiness, eye irritation, lethargy, memory impairment; 17% met DSM-5 criteria for moderate or severe cannabis use disorder. 83.4% inhaled. Convenience sample — no control group; real-world safety profile from patient report.

Adolescent cannabis use significantly increases the risk of depression and suicidality in adulthood, but not the risk of anxiety disorders.

30-year cohort study (n=591). Cannabis use in adolescence showed no significant association with anxiety disorders in adulthood (aOR=1.10, 95%-CI=0.82-1.48). Negative finding with precise OR estimates; no increased risk of anxiety disorders from adolescent cannabis use in this long-term cohort study.

Oral CBD achieved a clinically relevant seizure reduction in a subset of pediatric LGS and DS patients with a tolerable side effect profile.

Retrospective safety evaluation of CBD in pediatric epilepsy (LGS/DS), n=44 children; adverse events in 36,3% of patients, predominantly gastrointestinal; no life-threatening adverse drug reactions in either group over the observation period.

Cannabidiol showed a manageable side-effect profile with subjective benefit in a proportion of children, but also relevant adverse events such as somnolence and elevated liver values.

n=40 children with severe pharmacoresistant epilepsy (NSW Compassionate Access Scheme), add-on CBD up to 25 mg/kg/day; 39/40 patients reported ≥1 adverse event; most common treatment-related ADR: somnolence (n=15, particularly with higher clobazam dose, spontaneous resolution in 10/15), gastrointestinal effects (7–9 patients each); 4 study discontinuations (including 1 elevated transaminases); caregiver global impression markedly/very markedly improved in 12/40 patients.

Nabiximols worsened postural control in MS patients, especially under dual-task conditions.

n=22 MS patients; nabiximols (cannabis extract) significantly worsened postural control in treatment continuers after 12 months: single task F=3,07, p=0,044; dual task F=4,90, p=0,005; Stroop dual task F=3,17, p=0,038. Safety signal: nabiximols impairs balance >especially< in multi-tasking situations.

CBD significantly increases the trough levels of everolimus and sirolimus and can thereby lead to clinically relevant mTOR inhibitor toxicity.

Retrospective case series (n=25 TSC patients under mTOR inhibitor + CBD): 76% showed significantly increased mTOR inhibitor levels after CBD initiation (p=0,0003); median level increase +9,8 ng/mL (everolimus) and +5,1 ng/mL (sirolimus). Adverse events in 40% (most common: diarrhoea). Clinically relevant drug interaction — CBD inhibits mTOR inhibitor metabolism.

After discontinuation of cannabidiol, the methadone serum level decreased from 271 to 125 ng/mL, which correlated with improvement of somnolence and fatigue.

Single case report of a 13-year-old patient with metastatic cancer and chronic pain; CBD-methadone interaction led to an increased methadone serum level (271 ng/mL, reduction to 125 ng/mL after CBD discontinuation) with sedation/fatigue. Mechanism: CBD inhibits CYP3A4/CYP2C19.

Narrative overview of pharmacokinetic and pharmacodynamic interactions of medical cannabinoids; bidirectional effects via P-glycoprotein, BCRP, MRP and CYP450/UGT enzymes. Particular caution recommended in elderly patients and persons with renal/hepatic disease.