Table 1.
Study characteristics
| Author and year | Country and setting | Population | Sample size (n) | Mean age and sex | Treatment period | Design | Cannabis delivery | Cannabis content | Tests | Outcome | Findings | Possible affected cognitive functions | EPHPP |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sativex spraya | |||||||||||||
| Alessandria, 2020 [9] | Italy. University of Genoa | MS | 20 |
Age: 50.2 ± 11.4 Female/male: 11/9 |
12 months (including titration) | Pre-post study | Sativex spray |
THC, 27 mg/mL CBD, 25 mg/mL Self-titration over 2 weeks. Average = 5/day range 2–9 Max dose 12 sprays/day. |
The Italian version of the International Cognitive Assessment for Multiple Sclerosis (BICAMS): Symbol Digit Modalities Test (SDMT) California Verbal Learning Test (2. Version) (CVLT) The Brief Visuospatial Memory Test (BVMT-R) PASAT The Free and Cued Selective Remind Test (FCSRT) |
Cognition |
Improvement Improvement 6-MO: SDMT: 2.5, p < .001. CVLT: 5.7, p < .0001 Improvement 12-MO: SDMT: 2.0, p = .020. CVLT: 7.0, p < .0001 Corrected for multiple testing |
Visual scanning, mental flexibility, sustained attention, psychomotor speed, and speed of information processing Learning and memory, semantic clustering, intrusions, interference, and recognition |
Weak |
| Aragona, 2009 [22] |
Italy. MS Outpatient Clinic |
MS | 17 |
Age: 49.8 ± 6.64 Female/male: 11/6 |
3 weeks (including titration) with 2 weeks washout between active periods | Randomised, double-blind, placebo-controlled, crossover | Sativex spray |
Mean puffs/day: Active group: 8.20, SD = 3.15 Placebo group: 15.16, SD = 4.51 |
Paced Auditory Serial Additional Test (PASAT) | Fatigue, disability, cognitive functioning and quality of life | N.S. | Strong | |
| Cooper, 2017 [23] |
UK. King's College London |
ADHD | 30 |
Active group (n = 15): Age: 36.91 ± 11.70. Female/males: 6/9 Placebo group (n=15): Age: 38.90 ± 11.54 Females/males: 5/10 |
42 days (excluding 2 weeks titration) | Two-group, randomised, double-blind, placebo-controlled | Sativex spray |
Maximum 14 sprays/day. Mean number of active sprays/day = 4.7, SD = 3.3 |
Quantitative Behavioural Test (QbTest) (Sustained attention and response inhibition, as well as motor restlessness) The Sustained Attention to Response Task (SART) |
Cognitive performance and activity level (head movements) measured using the QbTest | N.S. | Moderate | |
| Rog, 2005 [14] |
UK. Walton Centre Clinical Trials Unit |
MS + neuropatic pain |
66 34 active group |
Active group (n = 34): Age: 50.3 ± 6.7 Female/male: 28/6 Placebo group (n = 32): Age: 48.1 ± 9.7 Female/male: 24/8 |
5 weeks, 4 visits (including titration) | Two-group randomised, double-blind, placebo-controlled | Sativex spray |
Maximum 48 sprays/day. Mean number of sprays/day: Active group = 9.6. SD = 6.0 Placebo group = 19.1 SD = 12.9 |
Spatial Recall Test Symbol Digit Modalities Test Paced Auditory Serial Addition Test Word Generation List Selective Reminding Test |
Primary: pain Secondary: sleep disturbance, neuropsychological outcomes, anxiety, depression and disability. |
N.S. | Strong | |
| Vachová, 2014 [15] |
Czech Republic. Six centres |
MS + spasticity |
121 61 active group |
Age: 48.6 ± 9.64 Female/male = 76/45 |
48 weeks (excluding 2 weeks titration) |
Two-group randomised, double-blind, placebo-controlled | Sativex spray |
Maximum 12 sprays/day. Mean number of sprays 6–8 in active group |
PASAT |
Primary: Cognition Secondary: subject-, physician- and caregiver global impression of change |
N.S. | Strong | |
| Wade, 2004 [24] |
UK. Three clinical centres |
MS | 160 |
Active group (n = 80) Age: 51.0 ± 9.4 Female/male: 47/33 Placebo group: (n = 80) Age: 50.4 ± 9.3. Female/male: 52/28 |
6 weeks | Two-group randomised, double-blind, placebo-controlled | Sativex spray | Maximum of 120 mg THC and 120 mg CBD per day and < 20 mg of each in any 3-h period. |
Short Orientation- Memory-Concentration Test Adapted Adult Memory and Information Processing Battery Test of Attention. |
Primary: symptoms in multiple sclerosis Secondary: Other symptoms, disability, cognition, mood, sleep and fatigue |
N.S. | Strong | |
| Russo, 2016 [25] |
Italy. IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina |
MS + spasticity | 61 |
Age: 43 ± 9 Female/male: not reported |
6 months | Pre-post | Sativex spray | The number of sprays was gradually augmented within 10 days up to 8–9 puffs | Montreal Cognitive Assessment (MoCA), The Attentive Matrices (AM), The Trail Making Test (TMT-A, B, BA), The Babcock Story Recall Test (BSRT), RT Hand Motor Task | Spasticity and cognition | N.S. | Moderate | |
| Castelli, 2018 [26] |
Italy. Setting not reported |
MS |
22 Continuers = 11 Quitters = 11 |
Age: 49.7 ± 8.3 Female/male: 13/9 |
1 year | Case-control, groups are studied retrospective, continuers vs. quitters | Sativex spray | Median sprays/day in both groups = 6 | The Stroop Color-Word Test |
Primary: postural sway with and without dual task (Stroop) |
Impairment Dual task condition F[1.9, 37.4] = 1.19, p = 0.312, η2 = 0.06 |
Ability to inhibit cognitive interference, attention, processing speed, cognitive flexibility, and executive function | Weak |
| Epidiolexb | |||||||||||||
| Martin, 2019 [17] | USA. University of Alabama | Treatment resistant epilepsy. | 27 |
Age: 34 ± 14 Female/male: 14/13 |
1 year (including titration) | Pre-post | Epidiolex (highly purified CBD) Oral solution 100 mg/ml |
Start dose: 5 mg/kg/day (divided between morning and evening). Maximum dose: 50 mg/kg/day. Mean dose: 36.5 mg/kg/day |
NIH Toolbox: Dimensional Change Card Sort (DCCS), Flanker Inhibitory Control and Attention Test, Picture Sequence Memory Test, Pattern Comparison Processing Speed Test, List Sorting Working Memory Test, Oral Reading Recognition Test, The Picture Vocabulary Test |
Primary: Cognitive functioning |
N.S. Bonferroni’s corrected for multiple testing |
Weak | |
| Metternich, 2020 [27] | Germany. University of Freiburg | Pharma-coresistant epilepsy | 13 (Adults completers) |
Age: range 18–59 years Female/male: not reported |
Three months (including titration) | Pre-post | Epidyolex/Epidiolex (N = 10) or Pharmaceutical formulation of synthetic CBD in a 100 mg per ml MCT-oil-based oral solution (N = 38) |
Epidyolex: 100 mg CBD per 1 ml 2–5 mg/kg/day divided into two daily doses and triated up to 18–20 mg/kg/day over 14–21 days |
Verbal Learning and Memory Test (VLMT) Digit Span Semantic verbal fluency Five point test Trail Making Test (TMT A & B) D2 The Epitrack ®: TMT-A, TMT-B, a maze task, a phonemic verbal fluency task and a measure of digit span backwards (Incl. parallel version) semantic verbal fluency (animals or food) Design fluency (the five-point-test) Auditory Verbal Learning Test |
Primary: Cognitive and behavioral |
N. S. | Moderate | |
| Other spray | |||||||||||||
| Almog, 2020 [28] |
Israel. Pain Research Unit of Rambam Health Care Campus, Haifa |
Chronic pain | 27 (ITT = 25) |
Age: 48.3 ± 11.9 Female/male: 8/19 |
3 doses on 3 separate days (3×3) | Three-group randomised, double-blind, placebo-controlled, crossover |
Aerosolize doses Syqe Inhaler, software controlled thermal selective-dose inhalation medical device. |
Aerosolised doses of granulated raw plants 22% THC, < 0.1% cannabidiol (CBD), < 0.2% cannabinol (CBN) or a matched placebo 0.50 mg session: THC: 0.537 ± 0.052 mg 1.00 mg session: THC: 1.083 ± 0.076 mg |
Cambridge Neuropsychological Test Automated Battery (CANTAB): Reaction Time Test, (RTI) Paired Associates Learning Task, (PAL) Spatial Working Memory Test, (SWM) Rapid Visual Information Processing Test, (RVP). |
Primary: Analgesic efficacy Secondary: Safety and tolerability Cognitive |
N. S. | Strong | |
| Wade, 2003 [29] | UK. Outpatient clinics |
MS (14) Spinal cord injury (4) Brachial plexus damage (1) Limb amputation due to neuro-fibromatosis (1) |
20 |
Age: 48 Female/male: 10/10 |
2 weeks (including titration) | Randomised, double-blind, placebo-controlled, crossover | Spray (pump-action sublingual spray that delivered 2.5 mg THC and/or CBD at each actuation.) |
Three types of concentrations: THC-rich CBD-rich 1/1 (THC/CBD) Max dose 120 mg/24 h |
Short Orientation-Memory-Concentration Test | Intractable neurogenic symptoms, i.e. pain, spasticity. |
Impairment THC-group: short orientation-memory-concentration test: 25.7, SD 3.4, p < 0.05. |
Orientation, memory, and concentration | Moderate |
| Gelatin capsules | |||||||||||||
| Müller-Vahl, 2001 [30] | Germany. Outpatient clinic | Tourette syndrome patients | 12 |
Age: 34 ± 13 Female/male: 1/11 |
Single dose Separated by 4 weeks washout period |
Randomised, double-blind, placebo-controlled, crossover |
Gelatin capsules 2.5 and 5.0 mg THC |
Dose according to body weight, sex, and prior use of marijuana. A single dose of 5, 7, 5 and 10 mg. | Auditory Verbal Learning Test (VLMT), Digit Span, Multiple Choice Vocabulary test, Benton Visual Retention Test, Signal Detection, Vienna Reaction Time, Sustained Attention, Divided Attention. | Neuropsychological performance | N.S. | Moderate | |
| Müller-Vahl, 2003 [31] | Germany. Outpatient clinic | Tourette syndrome patients |
24 9 active group |
Age: 33 ± 11 Female/male: 5/19 |
6 weeks (including titration) | Randomised, double-blind, placebo-controlled |
Gelatin capsules 2.5 mg and 5.0 mg THC |
n = 6, 10 mg n = 2, 7, 5 mg n = 1, 2, 5 mg |
Auditory Verbal Learning Test Benton Visual Retention-Test Divided Attention (TAP) Multiple Choice Vocabulary Test |
Neuropsychological performance | N.S. | Moderate | |
| Vaney, 2004 [16] | Switzerland. In-patient rehabilitation centre | MS + spasticity |
57 50 Intention-to-treat analysis |
Age: 54.9 ± 10 Female/male: 29/28 |
14 days (excluding titration) | Randomised, double-blind, placebo-controlled, crossover | Gelatin capsule whole plant extract |
Capsule: THC: 2.5 mg, CBD: 0.9 mg Maximum of 30 mg THC/day |
Paced Auditory Serial Addition Test (PASAT) Digit span (WAIS R) |
Primary: efficacy, safety and tolerability in the treatment of spasticity Secondary: daily activities cognitive functions |
N.S. | Strong | |
| Smocked or vaped | |||||||||||||
| Corey-Bloom, 2012 [11] |
USA. MS clinic |
MS + spasticity | 30 |
Age: 51 ± 8 Female/male: 19/11 |
3 days | Randomised, double-blind, placebo-controlled, crossover | Smoked | 4 puffs of pre-rolled cannabis cigarettes contained about 4% THC by weight | Paced Auditory Serial Addition Test (PASAT) |
Primary: change in spasticity Secondary: pain, physical performance, cognitive function |
Impairment PASAT: Reduction of 8.67 points (95% bootstrap CI 4.10 to 14.31) more than placebo (p = 0.003) |
Attention, sustained attention, working memory, and processing speed | Moderate |
| Wallace, 2015 [12] |
USA California Outpatient clinic |
Painful diabetic peripheral neuropathy | 16 |
Age 56.9 ± 8.2 Female/male: 7/9 |
3 h Separated by 2 weeks washout periods |
Randomised, double-blind, placebo-controlled, crossover |
Cannabis cigarette Aerosolized Volcano system vaporizer |
Three types of concentrations: 1% THC 4% THC 7% THC CBD concentration was < 1%. 0, 4, 16, or 28 mg THC per dosing session. |
Trail Making Test A and B, Paced Auditory Serial Attention Test (PASAT). |
Pain, evoked pain, and cognitive |
Impairment PASAT: medium dose at 15 min: d = 1.03, p = .024) high dose at 15 min: d = − 1.14, p = .008 Trail making part B: high dose at 120 min: d = − 1.15, p = .009 Adjusted for multiple comparisons using the Dunnett method |
Attention, sustained attention, working Memory, and processing speed | Strong |
| Wilsey, 2008 [13] |
USA California Davus/Sacramento VA medical Center |
Neuropathic Pain patients | 38 |
Median age: 46 Range 21–71 Female/male: 18/20 |
Three 6-h sessions Separated by 3 days washout periods |
Randomised, double-blinded, placebo controlled, crossover | Smoked cannabis cigarettes |
Cannabis ranging in strength from 3 to 7% THC THC 19 mg low dose THC 34 mg high dose |
Wechsler Adult Intelligence Scale (WAIS-III), Digit Symbol Test, The Hopkins Verbal Learning Test Revised (HVLT), The Grooved Pegboard Test |
Primary: pain intensity Secondary: neuropsychological performance |
Impairment Mean Difference: pegboard dominant hand: 7% vs placebo: 1.14, p = .007 pegboard non-dominant hand: 7% vs placebo: 1.34, p < .001 3.5% vs placebo: 1.01, p < .01 Last point vs linear trend: 3.19, p < .01 Digit symbol test: last point vs linear trend: 1.30, p = .001 HVLT–learning: 7% vs placebo: 1.31, p = .02 Last point vs linear trend: 6.19, p < .001 HVLT–recall: 7% vs placebo: 1.30, p = .03 Last point vs linear trend: 6.16, p < .000 Not corrected for multiple testing |
Visual scanning, mental flexibility, sustained attention, psychomotor speed, and speed of information processing, verbal learning and memory, psychomotor speed, fine motor control, and rapid Visual-motor coordination | Strong |
| Wilsey, 2013 [32] |
USA California Pain clinics |
Neuropathic pain patients | 39 |
Age: 50 ± 11 Female/male: not reported |
Three 6-h sessions, separated by 3 days washout periods. | Randomised, double-blind, placebo-controlled, crossover |
Vaporised Volcano vaporiser |
Cannabis ranging in strength from 1.29 to 7% THC Medium-dose (3.53% THC), 19 mg Low-dose (1.29% THC), ca. 9.5 mg |
Wechsler Adult Intelligence Scale (WAIS-III), Digit Symbol Test, The Hopkins Verbal Learning Test Revised (HVLT), The Grooved Pegboard Test |
Primary: spontaneous pain relief Secondary: neurocognitive |
Impairment Significance levels: pegboard dominant hand: 60 min: p = .0007, 240 min: p = .0023 Pegboard non-dominant hand: 120 min: p = .0035, 180 min: p = .0325 WAIS III digit symbol: 60 min: p = .0415, 180 min: p = .0006 HVLT sum of all trials: 60 min: p = .0256, 180 min: p < .0001, 240 min: p = .0002 HVLT delay: 120 min: p = .0273, 180 min: p = .0013, 240 min: p = .0060 Not corrected for multiple testing (Only significance levels are reported) |
Visual scanning, mental flexibility, sustained attention, psychomotor speed, and speed of information processing, verbal learning and memory, psychomotor speed, fine Motor control, and rapid visual-motor coordination | Strong |
| Abdallah, 2018 [33] | Canada. McGill University | Global Initiative for Obstructive Lung disease | 16 |
Age: 65.4 ± 7.7 Female/male: 6/10 |
Single dose | Randomised, double-blind, placebo-controlled, crossover | Vaped |
THC 35 mg, 18.2% CBD < 0.1% |
Mini-Mental Status Examination (MMSE) |
Primary: breathlessness intensity ratings during exercise exercise endurance time |
N.S. | Moderate | |
| Other | |||||||||||||
| Bar-Sela, 2019 [34] |
Israel. Day Care Clinic |
Advanced cancer patients | 34 |
Active group (n = 17): Age: 63, range 35–85 Female/male: 10/7 Control group (n = 17): Age: 63, range 40–85 Female/male: 7/10 |
3 months | Case-control | Own choice: smoking, inhalation or oil. |
Three types of concentrations (THC/CBD): 1/1, n = 1 2/1, n = 4 3/1, n = 12 |
The Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Digit-Finger Tapping Test |
Primary: cognitive function secondary: symptom relief and QOL |
N.S. | Weak | |
| Gustavsen, 2021 [35] | Denmark. University Hospital, Copenhagen | MS | 28 |
Age: 50 (range 27–74) Female/male 21/7 |
Four weeks (including titration) | Pre-post | Three full spectrum oils from the company STENOCARE, Denmark |
Full-spectrum cannabis extracts: THC DROPS (25 mg THC, < 2 mg CBD/mL) CBD DROPS (25 mg CBD, 2 mg THC/mL) 1:1 DROPS (12.5 mg THC and CBD/mL) + due to production stop Broad spectrum cannabis product: THC/CBD 1:2.5.c |
9-Hole Peg Test (9-HPT) Symbol Digit Modalities Test (SDMT) |
Primary: adverse events changes in neurological examination Secondary: treatment effectiveness |
N.S. | Moderate | |
| Withdrawal | |||||||||||||
| Feinstein, 2019 [10] |
Canada Sclerosis clinic |
MS |
39 Cannabis continuation (CC) = 20 Cannabis withdrawal (CW) = 19 |
CC group: Age: 39.3 ± 8.47 Female/male: 9/11 CW group: Age: 36.26 ± 11.69 Female/male: 11/8 |
28 days withdrawal CW mean = 5.62 years (SD = 5.10) versus CC mean = 9.61 years (SD = 5.67), t = 2.31; P = 0.03]. |
Randomized, controlled MS patients and cannabis users were divided by odd-even number selection into two groups: cannabis continuation and cannabis withdrawal. Controlled by urine test. |
– |
From urine tests: THC/creatinine ratio CC = 165.65 day 28. |
Brief Repeatable Neuropsychological Battery (BRNB) for Multiple Sclerosis Functional: The Selective Reminding Test, the 10/36 Test, Paced Auditory Serial Addition Test (PASAT), Symbol Digit, Modalities Test (SDMT), Controlled Oral Word Association Test (COWAT) |
Primary: cognition |
Improvement with withdrawal PASAT 3”: t = − 7.85, p < .000 PASAT 2”: t =− 7.48, p < .000 SDMT: t = − 5.10, p < .000 COWAT: t = − 4.22, p < .000 Controlled for multiple comparisons |
Attention, sustained attention, working memory, processing speed, visual scanning, mental flexibility, psychomotor Speed, speed of information processing, and verbal fluency | Weak |
Abbreviations: MS multiple sclerose, ADHD attention deficit and hyperactivity disorders, ITT intention to treat
aSativex spray: Each actuation delivers 100 μL of spray, containing THC 2.7 mg and CBD 2.5 mg
bEpidiolex: Oral solution containing 100 mg cannabidiol
cUnfortunately, 6 months after study initiation the supplier of the three full-spectrum oils, CannTrust, Canada, was involved in a case with the Canadian authorities for using unapproved cultivating grow rooms. As a result, STENOCARE immediately stopped the import and distribution of their products. Subsequently, one pharma-grade broad-spectrum cannabis product (THC/CBD, 1:2.5) was available, which contained active pharmaceutical Ingredients (API) of both THC and CBD. The API of THC and other organic compounds were extracted from dried cannabis flowers, Bedrocan (high THC, low CBD) by solvent extraction