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Table 2 Studies of the use of CBD and CBD-containing compounds such as nabiximols in the treatment of cannabis-related disorders and levels of evidence (1–5)

From: The therapeutic role of Cannabidiol in mental health: a systematic review

AuthorDiagnosisStudy designPharmacological agentStrength of evidence*Group (n)DurationAge range (years)Dose range (mg)Scales to measure the clinical outcomeClinical outcomeCommon side effectsReference number
Allsop et al., 2014Cannabis withdrawalRCTNabiximolsLevel 2Nabiximols = 27
Placebo = 24
6 days of nabiximols or placebo treatment, 3 days of washout, and 28-day follow-up period
Total duration = 37 days
18–65Starting dose = 8 sprays, total dose of 21.6 mg THC and 20 mg CBD at 4 PM and 10 PM
Maximum dose = 8 sprays 4 times a day
CWS- Nabiximols reduced CWS scores by 66% compared to 52% with placebo for duration for treatment (P = .01).
- It resulted in a decrease in appetite loss, decrease in cravings (p = 0.4), irritability and aggression (p = .o1).
- The time duration for cannabis withdrawal was 3.10 days with Nabiximols compared to 4.9 days with placebo (p = .04)
- The retention rate was 85% with medications compared to 50% with placebo.
Decreased appetite.
The number and severity of adverse events did not differ significantly between groups.
31
Trigo et al., 2016Cannabis moderate-severe use and withdrawalRCTNabiximolsLevel 2168 weeks18–50Nabiximols = 108 mg THC/100 mg CBD
Fixed dose = 4 sprays of medications every hour
Self-titrated dose: Patients were allowed to use 4 sprays as needed every hour. The maximum dose was 40 sprays/day.
MCQ, CWS,
SMHSQ,
DEQ,
ARCI, MNWS
- Medication intake was higher on fixed regimen as compared to self-titration conditions. There was significant differences between conditions (F(3,24) = 8.561, p < 0.001).
- Mean time for having feeling of “high” was clearly higher during SAU (6.6–7.3 h) compared with Sativex (2.4–3.3 h) or placebo (0.1–0.3 h), as self-reported by participants in their smoking diary (Fig. 1c)
- There were lesser withdrawal during self-titrated and fixed Sativex as compared to the corresponding placebo conditions (F(7,56) = 3.860, p < 0.01).
No significant difference in side effects was observed between the experimental and placebo group.28
Trigo et al., 2018Cannabis moderate to severe useRCTNabiximolsLevel 2Nabiximols and weekly MET/CBT = 20
Placebo = 20
12 weeks18–65Nabiximols = 113.4 mg THC/105 mg CBDBPRS, SAFTEE, HAM-A, HDRS, TLFB for cannabis, tobacco, caffeine
and alcohol, FTND, ASI, BDI, DEQ, Profile of Mood States, MWC, MCQ-SF, SMHSQ
- Nabiximols was well-tolerated with a dose range of 4.1 to 12.8 sprays/day.
- There was reduction in cannabis use in the nabiximols (70.5%) and placebo groups (42.6%).
- Five participants in the placebo group and four participants in the nabiximols group used other recreational drugs.
- High medication sub-group suggested a significant effect of time (F12,90.1 = 10.386, p < .001), no effects of treatment (F1,8.1 = 1.200, p = .305) but a significant time x treatment interaction.
No serious adverse events were observed.29
Pokorski et al., 2017Cannabis withdrawalOpen-label pilot studyCBDLevel 387 days21–62
Mean age = 40 years
CBD = 600–1200 mg/day in divided dosesCWS, daily urine sample and blood samples on day 1, 3, and 7, THC COOH and CBD quantification- For 600 mg/day of CBD: 2 out of 5 participants completed the 7-day inpatient treatment. These 2 participants reported abstinence at follow-up (day 28) and the 3 remaining participants reported decreased cannabis use, confirmed by blood and urine analysis.
- For 600 mg twice a day: of 3 participants, 2 reported abstinence and the 1 remaining one had decreased use of cannabis, confirmed by blood and urine analysis.
- All participants reported a decrease in CWS score.
The participants did not report any unwanted or adverse effects of the CBD.32
Solowij et al., 2018Impaired cognition and elevated psychological symptoms in patients with chronic cannabis useOpen-label trialCBDLevel 32010 weeksMedian age = 25.1 yearsCBD = 200 mg in divided dosesBDI, STAI-I, STAI-II, GAF, SOFAS, CAPE, RAVLT, AST- There was an improvement in severity of depression (p = 0.017), verbal learning, memory performance, and frequency of positive psychotic-like symptoms (p = 0.025) with decreased level of distress from baseline to endpoint.
- The state anxiety increased with no change in trait anxiety, functional impairment, and accuracy on cognitive tests.
No side effects were reported.19
Trigo et al., 2016Cannabis moderate to severe useCase seriesNabiximolsLevel 4412-week follow-up phase with 4 weekly visits and 2 subsequent monthly visits24–43 Mean age = 35 yearsSelf-titrated nabiximols = 77.5–113.4 mg THC
71.5–105 mg CBD
CWC, CCQ, TLFB for cannabis, tobacco, caffeine and alcohol- Reduction in cannabis intake from baseline to endpoint with no compensatory increase in use of other substances (F(18,54) = 4.663, p < 0.001).
- The craving scores increased initially during the first 2 weeks with a subsequent reduction in craving from week 9 (F(18,54) = 7.091, p < 0.001) .
- No significant difference in withdrawal scores for the duration of study (F(18,54) = 0.805, p value = non-significant)
No side effects were reported.30
Crippa et al., 2013Cannabis withdrawal syndromeCase reportCBDLevel 4110 days19The dose of CBD was 300 mg on day 1 and 600 mg on days 2–10.
600 mg was administered in divided doses.
MWC, WDS- CBD resulted in faster, progressive relief from withdrawal, anxiety, and dissociative symptoms.
- Marijuana withdrawal symptom checklist had drop of baseline score of 12 to zero, from 5 to zero for Withdrawal discomfort scale.
- The scores for Beck Anxiety Inventory decreased from 6 to zero and 10 to zero for Beck Depression Inventory.
- At 6 month follow-up, return to cannabis use but at a lower rate.
No side effects were reported.27
Shannon & Lehman, 2015Cannabis moderate to severe useCase reportCBDLevel 41Follow-up for 129 days27Initial regimen: 24 mg CBD (6 sprays as needed during the day and 2 sprays at night).
The dose was decreased to 18 mg with 6 spray at night only.
Self-reported cannabis use, PSQI, HAM-A- Patient was able to maintain abstinence from cannabis.
- Improvement in HAM-A score from 16 to 8 was reported, indicating mild anxiety.
- Patient had a regular sleep schedule and scores of 7 to eight were reported.
No side effects were reported.33
  1. ARCI: Addiction Research Center Inventory, ASI: Addiction Severity Index, AST: Attention Switching Task, BDI: Beck Depression Inventory, BPRS: Brief Psychiatric Rating Scale, CAPE: Community Assessment of Psychic Experiences-Positive Scale, CBD: cannabidiol, CBT: cognitive–behavioral therapy, CCQ: Cannabis Craving Questionnaire, CWS: Cannabis Withdrawal Scale, DEQ: Drug Effects Questionnaire, FTND: Fagerstrom Test for Nicotine Dependence, GAF: Global Assessment of Functioning, HAM-A: Hamilton Anxiety Rating Scale, HDRS: Hamilton Rating Scale for Depression, MCQ: Marijuana Craving Questionnaire, MCQ-SF: Marijuana Craving Questionnaire-Short Form, MET: motivational enhancement therapy, MNWS: Minnesota Nicotine Withdrawal Scale, MWC: Marijuana Withdrawal Symptom Checklist, PSQI: Pittsburgh Sleep Quality Index, RAVLT: Rey Auditory Verbal Learning Test, SAFTEE: Systematic Assessment for Treatment Emergent Events, SOFAS: Social and Occupational Functioning Assessment Scale, SMHSQ: St Mary’s Hospital Sleep Questionnaire, STAI: Spielberger State-Trait Anxiety Inventory, TLFB: Timeline Follow-Back, WDS: Withdrawal Discomfort Score, THCCOOH: 11-nor-9-carboxy-Δ9-tetrahydrocannnabinol, Δ9-THC: Δ9-tetrahydrocannabinol
  2. “The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence was used to grade the quality of evidence (OCEBM, 2019). Level 1 evidence is for systematic review of RCTs or individual RCT of narrow confidence interval, Level 2 for cohort studies or systematic review of cohort studies, Level 3 for case-control studies or systematic review of case-control studies, and Level 4 for case-series for studies focused on therapy, prevention, etiology and harm (OCEBM, 2019)