Cannabinoids for Medical Use: a Systematic Review

Supplementary Online Content

Whiting PF, Wolff RF, Deshpande S, et a. Cannabinoids for medical use: a systematic review

and meta-analysis. JAMA. doi: 10.1001/jama.2015.6358

This supplementary material has been provided by the authors to give readers additional

information about their work.

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table of Contents eAppendix 1. Review Protocol ...... 4 eAppendix 2. Search Strategy ...... 5 DATABASES SEARCHED: ...... 5 EMBASE SEARCH STRATEGY ...... 6 eAppendix 3. Nausea and Vomiting Due to Chemotherapy ...... 7 A. STUDY CHARACTERISTICS...... 7 B. DICHOTOMOUS OUTCOME RESULTS ...... 11 C. CONTINUOUS OUTCOME RESULTS ...... 12 D. CATEGORICAL OUTCOME RESULTS ...... 15 E. CROSS-OVER TRIALS THAT COMPARED TREATMENTS WITHIN PATIENTS ...... 17 eAppendix 4. Appetite Stimulation in HIV/AIDS ...... 18 A. STUDY CHARACTERISTICS ...... 18 B. DICHOTOMOUS OUTCOME RESULTS ...... 19 C. CONTINUOUS OUTCOME RESULTS ...... 19 eAppendix 5. Chronic Pain ...... 20 A: STUDY CHARACTERISTICS ...... 20 B. DICHOTOMOUS OUTCOME RESULTS ...... 25 C. CONTINUOUS OUTCOME RESULTS ...... 26 eAppendix 6. Spasticity in MS and Paraplegia ...... 36 A. STUDY CHARACTERISTICS...... 36 B. DICHOTOMOUS OUTCOMES RESULTS ...... 38 C. CONTINUOUS OUTCOME RESULTS ...... 38 eAppendix 7. Depression ...... 43 A. CONTINUOUS OUTCOME MEASURES ...... 43 eAppendix 8. Anxiety Disorder ...... 44 A. STUDY CHARACTERISTICS...... 44 B. CONTINUOUS OUTCOME RESULTS ...... 45 eAppendix 9. Sleep Disorder ...... 46 A. STUDY CHARACTERISTICS...... 46 B. DICHOTOMOUS OUTCOMES RESULTS ...... 47 C. CONTINUOUS OUTCOMES RESULTS ...... 47 eAppendix 10. Psychosis ...... 50 A. STUDY CHARACTERISTICS...... 50 B. CONTINUOUS OUTCOMES RESULTS ...... 51 eAppendix 11. Glaucoma ...... 52 A. STUDY CHARACTERISTICS...... 52 B. CONTINUOUS OUTCOMES RESULTS ...... 53

Downloaded From: https://jamanetwork.com/ on 09/29/2021 eAppendix 12. Tourette Syndrome ...... 54 A. STUDY CHARACTERISTICS ...... 54 B. CONTINUOUS OUTCOMES RESULTS ...... 55 eAppendices 13. Risk of Bias in Each Included Study, Grouped by Indication ...... 56 eReferences...... 59

Downloaded From: https://jamanetwork.com/ on 09/29/2021 eAppendix 1. Review Protocol See separate pdf document

Downloaded From: https://jamanetwork.com/ on 09/29/2021 eAppendix 2. Search Strategy

Databases searched:

• Cochrane Database of Systematic Reviews (CDSR) (Wiley): Issue 4/12, April 2015 • Database of Abstracts of Reviews of Effects (DARE) (Wiley): Issue 1/4, January 2015 • Health Technology Assessment Database (HTA) (Wiley): Issue 1/4, January 2015 • NHS Economic Evaluation Database (NHS EED) (Wiley): Issue 1/4, January 2015 • International Network of Agencies for Health Technology Assessment (INAHTA) (Internet): up to 2015/4/9 • National Institute for Health Research (NIHR) Project Portfolio (Internet): up to 2015/4/9 • International Guidelines Library (GIN) (Internet): 2000-2015/4/9 • National Guidelines Clearinghouse (NGC) (Internet): up to 2015/4/9 • National Institute for Health and Care Excellence (NICE) Guidance (Internet): up to 2015/4/9 • Turning Evidence into Practice (TRIP) database (Internet): up to 2015/4/9 • Canadian Agency for Drugs and Technologies in Health (CADTH) (Internet): up to 2015/4/9 • PROSPERO (Internet): up to 9/4/2015 • International Information Network on New and Emerging Health Technologies (EuroScan) (Internet): up to 2015/4/9 • Embase (OvidSP): 1974-2015/wk 14 • Medline (OvidSP): 1946-2015/Mar wk 5 • Medline In-Process & Daily Update (OvidSP): up to 7 April 2015 • PubMed (https://www.ncbi.nlm.nih.gov/pubmed): up to 8.4.2015 • PsycINFO (OvidSP): 1806-2015/Mar wk 5 • BIOSIS Citation Index (Web of Knowledge): 1926-2015/04/07 • CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCO): 1981-2015/04/03 • Science Citation Index (Web of Knowledge): 1900-2015/04/08 • Allied and Complimentary Medicine Database (AMED) (ProQuest): 1985-2015 (Current) • Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley): Issue 3/12, March 2015 • International Association of Cannabis Medicines (IACM) (Internet): up to 2015/04/09 • IACM Database of Clinical Studies and Case Reports (Internet): up to 2015/04/09 • National Institutes of Health (NIH) Clinicaltrials.gov (Internet): up to 2015/4/9 • metaRegister of Controlled Trials (mRCT) (Internet): up to 2014/4/7 • World Health Organization (WHO) International Clinical Trials Register Portfolio (ICTRP) (Internet): up to 9/04/15

Databases highlighted in grey are grey literature sources

Downloaded From: https://jamanetwork.com/ on 09/29/2021 EMBASE search strategy

Embase (OvidSP): 1974-2015/wk 14; Searched 8.4.15

1 Cannabaceae/ (57) 2 exp cannabinoid/ (46319) 3 (marijuana or marihuana or cannabis or canabis).ti,ab,ot,hw. (34580) 4 (Hashish or hash or bhang or ganja or ganjah or hemp or charas).ti,ab,ot,hw. (1814) 5 (cannador or eucannabinolide or 8001-45-4 or 8063-14-7 or 38458-58-1).ti,ab,ot,hw,rn. (22203) 6 (9tetrahydrocannabinol$ or delta3-thc or sp-104 or sp104 or 1972-08-3).ti,ab,ot,hw,rn. (4927) 7 (Dronabinol or Marinol or dronabinolum or deltanyne or ea-1477 or ea1477 or tetranabinex or qcd-84924 or qcd84924 or 7663-50-5).ti,ab,ot,hw,rn. (5801) 8 (delta-9-THC or 5957-75-5 or 1972-08-3).ti,ab,ot,hw,rn. (5302) 9 delta9?11?tetrahydrocannabinol.ti,ab,ot,hw. (0) 10 (THC or CBD or AEA).ti,ab,ot. (14442) 11 (nabidiolex or 13956-29-1).ti,ab,ot,hw,rn. (2003) 12 (dexanabinol or Hu-210 or Hu-211 or hu210 or hu211 or 112924-45-5).ti,ab,ot,hw,rn. (1126) 13 (Cannabichromene or 521-35-7).ti,ab,ot,hw,rn. (983) 14 (Nabilone or Cesamet or cesametic or cpd109514 or cpd-109514 or lilly-109514 or lilly109514 or 51022-71- 0).ti,ab,ot,hw,rn. (1012) 15 (Nabiximols or Sativex or Gw-1000 or gw1000 or sab-378 or sab378 or 56575-23-6).ti,ab,ot,hw,rn. (329) 16 (Anandamide or N-arachidonoylethanolamine).ti,ab,ot,hw. (5277) 17 (canabinoid$ or canabidiol$ or cannabinoid$ or Tetrahydrocannabinol$ or tetra-hydrocannabinol$ or endocannabinoid$ or Cannabidiol or cannabinol).ti,ab,ot. (22843) 18 (nantradol or cp-44001 or cp44001 or cp-44001-1 or cp 440011 or cp440011 or cp44001-1 or 72028-54- 7).ti,ab,ot,hw,rn. (99) 19 or/1-18 (65861) 20 Random$.tw. or clinical trial$.mp. or exp health care quality/ (3478722) 21 animal/ (1640271) 22 animal experiment/ (1838682) 23 (rat or rats or mouse or mice or murine or rodent or rodents or hamster or hamsters or pig or pigs or porcine or rabbit or rabbits or animal or animals or dogs or dog or cats or cow or bovine or sheep or ovine or monkey or monkeys).ti,ab,ot,hw. (5875314) 24 or/21-23 (5875314) 25 exp human/ (15736600) 26 human experiment/ (335349) 27 or/25-26 (15738041) 28 24 not (24 and 27) (4667131) 29 20 not 28 (3310584) 30 19 and 29 (9519)

Trials filter: Wong SS, Wilczynski NL, Haynes RB. Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. J Med Libr Assoc 2006;94(1):41-7.

Downloaded From: https://jamanetwork.com/ on 09/29/2021 eAppendix 3. Nausea and Vomiting Due to Chemotherapy A. STUDY CHARACTERISTICS

Study Country RCT N Duration Patient details Intervention Intervention Intervention Comparator Risk Details Design 1 2 3 of Bias Ahmedzai UK Cross- 34 4 days (4 Small cell bronchial carcinoma; eligible for Nabilone Proclor-  45 (1983) over day chemotherapy (Cesamet); perazine; washout) Max dose Max dose

4mg/day 30mg/day Broder USA Cross- 44 1 Cancer type not specified; failed prior anti- THC; Hydroxizine; ? (1982)15 over chemo- emetic therapy. 10mg/m2 50mg every 4-

therapy every 4-6 6 hours cycle hours Chan Canada Cross- 40 1 Peadiatric malignancies; Repeated courses Nabilone Prochlor-  28,52 (1987) over chemo- of CTx with severe drug-induced nausea (Cesamet); perazine; therapy and vomiting. max dose wieght cycle 9mg/day dependent (weight dependent) Dalzell UK Cross- 23 1 Peadiatric malignancies; scheduled to Nabilone Domperidone  30 (1986) over chemo- receive two identical (courses of (Cesamet); oromucosal therapy emetogenic chemotherapy max dose spray; max cycle 3mg/day dose 15mg 3x/day Duran Spain Parallel 16 5 Days Breast, Ovary, Lung cancer; chemotherapy- Nabiximols Placebo  24 (2010) group induced nausea and vomiting > 24 h (Sativex); despite prophylaxis with standard anti- max 8 emetic treatment after moderately sprays in emetogenic chemotherapy any 4h period every 24h Einhorn USA Cross- 100 1 Sarcoma, Hodgkin's disease, lymphoma, Nabilone Prochlor-  40 (1981) over chemo- bladder, testicular; (Cesamet); perazine; max therapy max 8mg/24 40mg/24h Combination chemotherapy with drug cycle h regimens that produce severe nausea and vomiting. Frytak USA Parallel 117 4 Days Gastro-intestinal cancers; THC; max Prochlor- Placebo  (1979)44,54 group 45mg/24h perazine; Initial chemotherapy with specified agents max © 2015 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 09/29/2021 30mg/24h George France Cross- 20 1 Gyn-aecological cancer (advanced); Nabilone Chlor- ? (1983)35 over chemo- receiving identical courses of (Cesamet); promazine;

therapy chemotherapy. max max cycle 3mg/24h 37.5mg/24h Heim Germany Cross- 57 1 lung, lymphona, soft-tissue sarcoma, Levon- Meto-  33 (1984) over chemo- breast, testis, melanoma, ovarary, antradol clopramide therapy osteosarcoma, prostate cancer, and head (IM); 0.5mg (IM); 10mg x 3 cycle and neck cancer; x 3 Receiving chemotherapy with high emetic potential. Herman USA Cross- 152 1 Testicular carcinoma, non-Hodgkin's Nabilone Prochlor-  57 (1979) over chemo- lymphoma, Hodgkin's disease; (Cesamet); perazine; max therapy max 40mg/day Repeated courses of chemotherapy, all had cycle 8mg/day experienced drug indeced nausea and vomiting. Hutcheon UK Parallel 108 24 Hours NR; First course of potentially high Levon- Levon- Levon- Chlor- ? (1983)34 group antiemetic cytotoxic chemotherapy. antradol antradol antradol promazine

(IM): (IM): (IM): 2mg/day 3mg/day 4mg/day Johansson Finland Cross- 27 1 Cervix, fallopian tubes, ovary, testis, head Nabilone Prochlor-  38 (1982) over chemo- and neck, bronchus, histiocytoma, (Cesamet); perazine; max therapy fibrosarcoma, oligoden-drioma lymphoma; max dose dose cycle Same chemotherapy as previous cycles; 4mg/24h 20mg/24h uncontrolled nausea and vomiting despite use of standard antiemetic drugs. Jones USA Cross- 54 1 Breast, lymphoma, ovary, lung, melanoma, Nabilone Placebo  36 (1982) over chemo- testes, miscellaneous; (Cesamet); therapy max dose Adults with cancer receiving chemotherapy cycle 4mg/24h regimens likely to produce nausea and vomiting; likely to receive at least 2 identical courses of chemotherapy. Lane USA Parallel 62 6 Days Breast, colon, lung, lymphoma, Dronabinol Proclor-  26,50 (1991) group miscellaneous; chemotherapy not (Marinol); perazine; max reported max dose dose 40mg/24h 40mg/24h Levitt ( Canada Cross- 58 1 Lung cancer, ovarian cancer, breast cancer, Nabilone Placebo  51 1982) over chemo- other; chemotherapy not reported (Cesamet); therapy max dose

Downloaded From: https://jamanetwork.com/ on 09/29/2021 cycle 4mg/24h Long USA Cross- 42 1 Cancer type not reported; Levon- Prochlor-  (1982)16 over chemo- antradol perazine; max strongly emetic chemotherapy therapy (oral); max dose cycle dose 40mg/24h 4mg/24h McCabe USA Cross- 36 1 Breast, haematologic, sarcomas, gastro- THC (oral); Prochlor-  27,56 2 (1988) over chemo- intestinal, melanoma, ovarian, testicular; 14mg/m perazine; max therapy every 4h dose Experiencing severe nausea and vomiting cycle 40mg/24h refractory to standard anti-emetics. Meiri USA Parallel 64 5 days Breast cancer, non-small cell lung cancer, Dronabinol Dronabinol Ondansetron; Placebo  25,53,55 (2007) group colon, rectal, or gastric cancer, lung cancer, (Marinol); + max others; max dose ondansetron 16mg/day 10mg/day Moderately to highly emetogenic regimen

Melhem- USA Parallel 62 5 Days Breast cancer, lymphoma; Dronabinol Placebo ? Bertrandt group 2 (Marinol); ≤cyclophosphamide 1500 mg/m and/or (2014)48, max dose doxorubicin ≥40 mg/m2. #10222,58 15mg/day Niederle Germany Cross- 20 1 Testicular cancer; chemotherapy regimen Nabilone Alizapride;  31 (1986) over chemo- not reported (Cesamet); max dose therapy max dose 450mg/day cycle 4mg/day Niiranen Finland Cross- 32 1 Lung cancer; scheduled to receive at least Nabilone Prochlor-  32 (1985) over chemo- two identical consecutive cycles of (Cesamet); perazine; max therapy chemotherapy max dose dose cycle 2mg/day 15mg/day Orr USA Cross- 79 1 Variety of neoplasms; previously THC (oral); Prochlor- Placebo  39,41 2 (1980) over chemo- demonstrated repeated vomiting from 7mg/m x 4 perazine; therapy anti-cancer agents known to induce doses 7mg/m2 x 4 cycle emesis; failed standeard antiemetic doses therapy Pomeroy Eire Parallel 38 2 Ovary, testis, bronchus, non-Hodgkin's Nabilone Domperidone;  29 (1986) (Ireland) group chemo- lymphoma, Hodgkin's disease, sarcoma, (Cesamet); max dose therapy breast, melanoma, nephro-blastoma; max dose 60mg/day cycles 3mg/day Highly emetogenic chemotherapy regimens

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Sallan USA Cross- 84 1 Cancer type not reported; THC (oal); Prochlor-  (1980)43 over chemo- 10mg/m2 x 3 perazine; max Nausea and vomiting inadequately therapy doses dose controlled by conventional anti-emetics. cycle 30mg/24h Sheidler USA Cross- 20 NR Small cell lung cancer, multiple myeloma, Levon- Prochlor-  47 (1984) over ovarian, adeno-carcinoma of the lung, antradol perazine; max breast cancer, diffuse histocytic lymphom, (IM); max dose rhabdomyosarcoma; dose 40mg/24h 4mg/24h Inpatient chemotherapy Steele USA Cross- 55 1 NR Nabilone Prochlor-  42 (1980) over chemo- (Cesamet); perazine; max therapy max dose dose cycle 10mg/24h 50mg/24h Ungerleider USA Cross- 214 1 Carcinoma, sarcoma, lymphoma/ THC (oral); Prochlor- ? (1982)46 over chemo- Hodgkins, and leukemia; previous max dose perazine; max therapy 50mg/24h dose chemotherapy associated with nausea and cycle (dependent 40mg/24h vomiting, or be on the first course of on size) chemotherapy of a drug with a high emetic potential

Wada USA Cross- 114 1 Lung, breast, ovarian, lymphoma, colonic, Nabilone Placebo  (1982)37 over chemo- prostatitc, adeno-carcinoma, bladder, (Cesamet); therapy melanoma, pancreatic, oesophagus, max dose cycle stomach, sarcoma, testis, other; 4mg/day chemotherapy regimens likely to produce nausea and vomiting; likely to receive at least 2 identical courses of chemotherapy. IM: intramuscular; NR: not reported; RCT: randomised controlled trial; THC: tetrahydrocannabinol  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

Downloaded From: https://jamanetwork.com/ on 09/29/2021 B. DICHOTOMOUS OUTCOME RESULTS

Study Details Intervention Comparator Outcome Intervention Placebo OR (95% CI) Events/ n Events/n

Appetitie & Weight Einhorn Nabilone Prochlorpera “Depressed appetite 64/80 72/80 0·46 (0·19, 1·12) (1981)40 (Cesamet) zine and reduced food intake”

Nausea & vomiting: Lane (1991)26 Dronabinol Proclor- Complete response 7/17 6/20 1·5 (0·42, 5·94) (Marinol) perazine McCabe THC Proclor- Complete response 9/36 0/36 25·2 (1·40, (1988)27 perazine 452·22)

Meiri (2007)25 Dronabinol Placebo Complete response 8/14 3/13 3·9 (0·80, 19·10) (no vomiting, nausea Dronabinol + 7/14 3/13 3·0 (0·61, 14·52) < 5 mm on a 100-mm ondansetron VASP) Melhem- Dronabinol Placebo Complete response 11/30 5/29 2·6 (0·80, 8·52) Bertrandt (2014)58

Duran Nabiximols Placebo Complete response 5/7 2/9 6·6 (0·83, 52·29) (2010)24 (no vomiting and a mean nausea VAS score of ≤10mm) Melhem- Dronabinol Placebo Complete response 14/30 9/29 1·8 (0·66, 5·38) Bertrandt (No vomiting, nausea (2014)58 intensity NRS >3) Duran Nabiximols Placebo Partial response 1/7 5/9 0·1 (0·02, 1·65) (2010)24 (vomiting on average 1-4x daily and a mean nausea VAS score of ≤25mm ) Lane (1991)26 Dronabinol Proclor- Partial response (≤2 12/17 9/20 2·7 (0·73, 10·30) (Marinol) perazine episodes of nausea or vomiting) Long (1982)16 Levonan- Proclor- Partial response 13/34 3/34 5·6 (1·54, 20·67) tradol perazine ('Significantly less nausea and vomiting') McCabe THC Proclor- Partial response 14/36 1/36 15·2 (2·61, (1988)27 perazine (≥50% decrease in 88·83)

frequency and intensity) Nausea Meiri (2007)25 Dronabinol Placebo Complete response 10/14 2/13 10·7 (1·85, 62·25)

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Dronabinol + Complete response 7/14 2/13 4·6 (0·83, 25·21) ondansetron Ahmedzai Nabilone Proclor- Complete response 21/26 10/30 7·6 (2·30, 25·23) (1983)45 perazine

Melhem- Dronabinol Placebo Complete response 11/30 5/29 2·6 (0·80, 8·52) Bertrandt (2014)58 Melhem- Dronabinol Placebo No significant 15/30 10/29 1·8 (0·66, 5·19) Bertrandt nausea(NRS >3) (2014)58 Lane (1991)26 Dronabinol Proclor- Anticipatory nausea 6/20 0/20 18·3 (0·95, (Marinol) perazine 352·58) Retching Ahmedzai Nabilone Proclor- Retching: Complete 22/26 13/30 6·4 (1·88, 22·31) (1983)45 perazine response (No retching) Vomiting & retching Chan (1987)28 Nabilone Proclor- Vomiting and 3/30 3/30 1·0 (0·20, 4·82) perazine retching: Complete response

Chan (1987)28 Nabilone Proclor- Vomiting and 21/30 9/30 5·1 (1·73, 15·08) perazine retching: Partial response ("Overall improvement ") Chan (1987)28 Nabilone Proclor- Vomiting and 18/30 6/30 5·5 (1·81, 17·16) perazine retching: Partial response ("Less retching and vomiting") Vomiting Melhem- Dronabinol Placebo Vomiting: 15/30 12/29 1·4 (0·50, 3·84) Bertrandt Complete response (2014)58 Ahmedzai Nabilone Proclor- Vomiting: Complete 26/26 22/30 20·0 (1·09, (1983)45 perazine response 366·45) Heim (1984)33 Levon- Metoclo- Vomiting: Episodes of 140/45 301/45 NA antradol pramide vomiting Melhem- Dronabinol Placebo Vomiting: Episodes of 19/30 19/29 NA Bertrandt vomiting (2014)58 NRS: numerical rating scale; THC: tetrahydrocannabinol; VAS: visual analogue scale

C. CONTINUOUS OUTCOME RESULTS

Study Details Inter- Comparator Outcome MD at p- Analysis Details vention follow-up: values

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Appetite & weight: Broder THC Hydroxizine Anorexia Favoured p<0·05 McNemar’s Test (1982)15 THC Ungerleider THC Prochlor- Appetite 0·08 NR NR (1982)46 perazine Single day regimen Ungerleider THC Prochlor- Appetite 0·11 NR NR (1982)46 perazine Multiple day regimen Levitt (1982)51 Nabilone Placebo Food intake ( 0 (no 0·78 0·001 NR food intake) - 3 (more than usual)) Broder THC Hydroxizine Food intake Favoured p<0·05 McNemar’s Test (1982)15 THC Ungerleide THC Prochlor- Food intake -0·02 NR NR r(1982)46 perazine Single day regimen Pomeroy Nabilone Domperidone Food intake 0·34 NR Kolmagorov-Smirnov (1986)29 test Ungerleider THC Prochlor- Food intake 0·08 NR NR (1982)46 perazine Multiple day regimen Broder THC Hydroxizine Fluid intake Favoured p<0·05 McNemar’s Test (1982)15 THC Nausea Broder THC Hydroxizine Severity/intensity Favoured p<0·05 McNemar’s Test (1982)15 THC Dalzell Nabilone Domperidone Severity/intensity -1·0 <0·01 Wilcoxen signed rank (1986)30 Pomeroy Nabilone Domperidone Severity/intensity -0·5 ≥0·05 Kolmagorov-Smirnov (1986)29 test

Einhorn Nabilone Prochlor- Severity/intensity NR 0·003 ANOVA (1981)40 perazine Jones (1982)36 Nabilone Placebo Severity/intensity -0·8 <0·001 NR Ahmedzai Nabilone Proclor- Severity/intensity -0·5 ≤0·05 Mann- Whitney/ (1983)45 perazine Wilcoxon test Levitt (1982)51 Nabilone Placebo Severity/intensity -1·22 ≤0·001 NR Meiri (2007)25 Drona- Placebo Severity/intensity -38·3 <0·05 Wilcoxon rank sum test binol Drona- -38·3 <0·05 binol + ondansetron Wada (1982)37 Nabilone Placebo Severity/intensity -0·74 ≤0·001 “Non-parametric test on ranks” Melhem-Bertr Drona- Placebo Average nausea -0·24 0·033 Mann-Whitney/ andt (2014)58 binol episodes/day) Wilcoxon test Steele Nabilone Prochlor- Duration (days) Medians 0·7 NR NR (1980)42 perazine vs 1·0 Melhem-Bertr Drona- Placebo Duration (days) -1·24 0·027 Mann-Whitney/ andt (2014)58 binol Wilcoxon test Niederle Nabilone Alizapride Duration (hours) -3·8 <0·01 Wilcoxen signed rank (1986)31

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Lane (1991)26 Drona- Proclor- Duration (mins) -5 0·09 Mann-Whitney/ binol perazine Wilcoxon test Retching Ahmedzai Nabilone Proclor- Severity -0·4 ≥0·05 Mann- Whitney/ (1983)45 perazine Wilcoxon test Vomiting Broder THC Hydroxizine Number of Favoured <0·01 McNemar’s Test (1982)15 episodes THC

Dalzell Nabilone Domperidone Number of -10·78 <0·01 Wilcoxen signed rank (1986)30 episodes Einhorn Nabilone Prochlor- Number of NR 0·003 ANOVA (1981)40 perazine episodes George Nabilone Chlor- Number of -1·9 NR NR (1983)35 promazine episodes Johansson Nabilone Prochlor- Number of -20·3 ≤0·001 ANOVA (1982)38 perazine episodes Jones (1982)36 Nabilone Placebo Number of -11·6 <0·001 NR episodes Levitt (1982)51 Nabilone Placebo Number of -4·5 ≤0·001 NR episodes Meiri (2007)25 Drona- Placebo Number of -1·1 NR NR binol episodes Meiri (2007)25 Drona- Placebo Number of -1·1 NR NR binol + episodes ondansetron Niiranen Nabilone Prochlor- Number of -4·5 p<0·05 Hills and Armitage (1985)32 perazine episodes Pomeroy Nabilone Domperidone Number of -6·28 ≤0·01 t-test (1986)29 episodes Wada (1982)37 Nabilone Placebo Number of -2·89 ≤0·001 NR episodes Ahmedzai Nabilone Proclor- Severity/intensity -0·6 ≤0·001 Mann- Whitney/ (1983)45 perazine Wilcoxon test Lane (1991)26 Drona- Proclor- Duration (mins) -2 NR Mann-Whitney/ binol perazine Wilcoxon test Steele Nabilone Prochlor- Duration (hours) Medians 3·2 NR NR (1980)42 perazine vs 5·2 Steele Nabilone Prochlor- Severity/intensity Medians 1·5 NR NR (1980)42 perazine vs 1·9 Steele Nabilone Prochlor- (Frequency Medians 6 NR NR (1980)42 perazine (hours)) vs 11·5 Nausea & vomiting: Lane (1991)26 Drona- Proclor- Duration of 0 NR Mann-Whitney/ binol perazine nausea/vomiting Wilcoxon test (mins) Ungerleider THC Prochlor- Severity/intensity 0·23 NR NR (1982)46 perazine Single day regimen Ungerleider THC Prochlor- Severity/intensity -0·11 NR NR (1982)46 perazine Multiple day regimen

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Global impression Meiri (2007)25 Drona- Placebo ECOG assessment -0·02 0·036 ANOVA binol Drona- Placebo -0·02 0·036 ANOVA binol + ondansetron Johansson Nabilone Prochlor- Physician global -1·2 ≤0·001 ANOVA (1982)38 perazine impression (1 to 5 (scale meaning unclear - 1 appears best)) ANOVA: analysis of variance; NR: not reported; THC: tetrahydrocannabinol Quantitative data reported based on information available in primary studies

D. CATEGORICAL OUTCOME RESULTS

Study Intervention Comparator Outcome Categories Inter- Compa P-value vention rator events event Frytak THC Placebo Nausea & None 16 7 0·053 (1979)44 vomiting Nausea only 2 6 Nausea and vomiting 20 24 THC Prochlor- None 16 17 0·768 perazine Nausea only 2 1 Nausea and vomiting 20 24 Herman Nabilone Prochlor- Nausea & Complete response 9 0 <0·01 (1979)57 perazine vomiting Partial response 81 36 No response 23 77 Hutcheon Levonan- Chlorpro- Appetite Good 2 4 0·132 (1983)34 tradol (2mg) mazine Normal 14 6 Fair 6 7 Poor 5 10 Nausea None 14 9 0·140 severity/inte Mild 6 13 nsity Moderate 7 4 Severe 0 1 Number of 0 20 11 0·016 vomiting 1-4 3 9 episodes 5-10 2 7 10 2 0 Levonan- Appetite Good 3 4 0·270 tradol (3mg) Normal 2 6 Fair 13 7 Poor 10 10 Nausea None 8 9 0·979 severity/inte Mild 14 13 nsity Moderate 5 4 Severe 1 1 Number of 0 11 11 0·679

Downloaded From: https://jamanetwork.com/ on 09/29/2021 vomiting 1-4 11 9 episodes 5-10 5 7 10 1 0 Levonan- Appetite Good 1 4 0·483 tradol (4mg) Normal 9 6 Fair 6 7 Poor 9 10

Nausea None 13 9 0·076 severity/ Mild 4 13 intensity Moderate 6 4 Severe 3 1

Number of 0 14 11 0·312 vomiting 1-4 4 9 episodes 5-10 8 7 10 0 0

Johansson Nabilone Prochlor- Nausea None 3 0 0·027 (1982)38 perazine severity/inte Mild 6 3 nsity Moderate 7 11 Severe 2 4 Number of 0 3 0 0·281 vomiting 1-5 3 2 episodes 6-10 5 2 11-20 4 5 >20 3 9 Niederle Nabilone Alizapride Nausea None 12 7 0·281 (1986)31 severity/ Mild 4 6 intensity Moderate 4 5 Severe 0 2 Niiranen Nabilone Prochlor- Appetite Not diminished 8 5 0·498 (1985)32 perazine Moderately 14 15 diminished 2 4 Markedly dimished 0 0 Response Very good (no N or V) 3 5 0·059 Good 9 3 Fair 5 6 Poor 6 3 very poor (>15 1 7 episodes of vomitting or severe nausea) Nausea None 1 4 0·432 severity/ Mild 7 4 intensity Moderate 9 10 Severe 7 6 Orr(1980)41 THC Prochlor- Nausea None 40 5 <0·01 perazine severity/ Mild 7 8 intensity Severe 5 13 Emesis 3 29 THC Placebo None 40 8 <0·01 Mild 7 11

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Severe 5 18 Emesis 3 18 Sallan THC Prochlor- Nausea and Complete response 36 16 0·004 (1980)43 perazine vomiting Partial response 10 15 response No response 33 47 Sheidler Levonan- Prochlor- Nausea Complete response 1 2 0·61 (1984)47 tradol perazine Partial response 9 9 No response 6 5 THC: tetrahydrocannabinol

E. CROSS-OVER TRIALS THAT COMPARED TREATMENTS WITHIN PATIENTS

Study Intervention Comparator Outcome No. patients reporting that p-value intervention was associated with best outcomes CBM No Comparator difference Heim (1984)33 Dronabinol Meto- Nausea 28 12 5 <0·05 clopramide Vomiting 25 12 8 <0·05 Appetite 22 21 2 <0·05 Johansson (1982)38 Nabilone Prochlor- Nausea 9 8 1 NR perazine Jones (1982)36 Nabilone Placebo Nausea 15 8 1 <0·001 Vomiting 19 2 3 <0·001 Levitt (1982)51 Nabilone Placebo Nausea 26 8 2 <0·001 Vomiting 29 3 4 <0·001 Wada (1982)37 Nabilone Placebo Nausea 56 27 9 NR Vomiting 53 18 21 NR NR: not reported

Downloaded From: https://jamanetwork.com/ on 09/29/2021 eAppendix 4. Appetite Stimulation in HIV/AIDS A. STUDY CHARACTERISTICS

Study Details Country RCT Design N Duration Patient details Intervention 1 Intervention 2 Comparator Risk of Bias Abrams (2003)59 USA Parallel 67 3 Stable antiretroviral regimen Marijuana (smoked); Dronabinol (max Placebo  group for ≥ 8 weeks; stable viral load (max 3 7.5mg/day)

for 16 weeks cigarettes/day, 4% THC) Beal (1995)62 USA Parallel 139 6 ≥1 AIDS defining event; loss Dronabinol Placebo  group ≥2.3 kg normal body (5mg/day) bodyweight Struwe (1993)61 USA Cross-over 12 5 weeks loss of ≥2.25 kg normal body Dronabinol (max Placebo  (2 week weight but were at least 70% 10mg/day) washout) of ideal body weight Timpone (1997)60 USA Parallel 37 12 >10% weight loss or BMI that Dronabinol Dronabinol megestrol  group was low; stable antiretroviral (5mg/day) (5mg/day) + acetate regimen for ≥ 4 weeks megestrol acetate (750mg/day) (750mg/day) RCT: randomised controlled trial  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

Downloaded From: https://jamanetwork.com/ on 09/29/2021 B. DICHOTOMOUS OUTCOME RESULTS

Study Details Intervention Outcome Intervention Placebo OR (95% CI) Events/ n Events/n

Beal (1995)62 Dronabinol Number of patients 11/50 4/38 2·2 (0·68, 7·27) (Marinol) who gained ≥2kg

C. CONTINUOUS OUTCOME RESULTS

Study Intervention Outcome MD change from p-value Analysis Details Details baseline:

Appetite & weight: Abrams Dronabinol Weight (kg) Only medians 0·004 Mann-Whitney (2003)59 reported Marijuana 0·021

Beal Dronabinol Weight (kg) 0·50 0·14 ANOVA (1995)62 Struwe Dronabinol Weight (kg) 1·0* 0·13 Wilcoxen signed (1993)61 rank

Timpone Dronabinol Weight (kg) -8·5 (-9·18, -7·82) NR NR (1997)60 Dronabinol + -0·5 (-1·10, 0·10) NR megestrol acetate Beal Dronabinol Appetite (VAS scale; %) 20 0·05 ANOVA (1995)62 Struwe Dronabinol Appetite (Score 0 (extremely -19·5 0·14 Wilcoxen signed (1993)61 hungry) - 100 (not hungry)) rank

Struwe Dronabinol Caloric/food intake (kcal/kg/24h) 4·2 0·50 Wilcoxen signed (1993)61 rank

Struwe Dronabinol Body fat (%) 0·76 0·04 Wilcoxen signed (1993)61 rank

Nausea & Vomiting: Beal Dronabinol Nausea severity/intensity (VAS -18 0·26 ANOVA (1995)62 scale; %) Global impression: Beal Dronabinol Karnofsky performance status 0·70 0·07 ANOVA (1995)62 Struwe Dronabinol Symptoms/functional limitations -33·5 0·04 Wilcoxen signed (1993)61 (out of 340)) rank

ANOVA: analysis of variance; NR: not reported Quantitative data reported based on information available in primary studies

Downloaded From: https://jamanetwork.com/ on 09/29/2021 eAppendix 5. Chronic Pain A: STUDY CHARACTERISTICS

Study Details Country RCT N Duration Patient details Intervention Intervention 2 Intervention Intervention Comparator Risk Design (weeks) 1 3 4 of Bias c. Chronic pain Abrams USA Parallel 55 12 days HIV-associated THC (4%; Placebo  (2007)77,97,103 group sensory neuropathy; smoked); cigarette

average daily pain One score ≥ 30 on 100 cigarette mm VAS (0.9g) daily Berman (2007)19,87 Romania, Parallel 117 3 Central neuropathic Nabiximols Placebo  UK group pain (non-acute (Sativex); spinal cord injury); max 48 average daily pain sprays/24 h score ≥4 on NRS Berman (2004)81,99 UK Cross- 48 2 (no Central neuropathic Nabiximols THC oromucosal Placebo  over washout) pain (brachial plexus (Sativex); spray

avulsion); average max 48

daily pain score ≥4 on sprays/24 h NRS Blake (2006)79 UK Parallel 58 5 Pain caused by Nabiximols Placebo ? group rheumatoid arthritis (Sativex);

max 48

sprays/24 h Ellis (2009)71,101 USA Cross- 34 5 days (2 HIV-associated THC Placebo  over week sensory neuropathy; (smoked);

washout) average score ≥5 on dose started

the pain intensity at 4% and sub-scale of the adjusted as Descriptor necessary. Differential Scale Four daily (DDS) smoking sessions. Frank (2008)75,116 UK Cross- 96 6 (2 Mixed neuropathic Nabilone Dihydrocodeine; Placebo  over washout) pain; (Cesamet); max 8 capsules max 8 (30mg each) Average pain score > capsules 40 on 0-100 mm VAS. (240ug each) © 2015 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 09/29/2021 GW Pharma Ltd Czech Parallel 297 14 Diabetic peripheral Nabiximols Placebo  (2005)22,108 Republic, group neuropathy (DPN); (Sativex); Romania, last 6 daily NRS pain max 24 UK scores ≥ 24; sprays/24 h GW Pharma Ltd UK Parallel 70 3 Chronic refractory Nabiximols Placebo  (2012)23 group pain due to MS or (Sativex); other defects of max 48 neurological origin; sprays/24 h average score >4 on Box-Scale 11 on 4 consecutive days Johnson Belgium; Parallel 177 2 Cancer-related pain; Nabiximols THC oromucosal Placebo  (2010)69,105 Romania; group pain severity score ≥4 (Sativex); spray UK on 0-10 NRS max 8 sprays/24 h Karst (2003)83,93 Germany Cross- 21 1 (1 Chronic neuropathic CT3 Placebo  over week pain capsules; washout) max 8 capsules (10mg each) Langford UK, Parallel 339 14 Central neuropathic Nabiximols Placebo ? (2013)65,91 Czech group pain (CNP) due to (Sativex); Republic, MS; sum score of max 12 Canada, ≥24 on a pain 0–10 sprays/24 h Spain point NRS on the last 6 days Lynch (2014)85,110 Canada Cross- 18 4 (2 Chemotherapy Nabiximols Placebo  over weeks) induced pain; (Sativex); max 12 average 7 day pain sprays/24 h intensity ≥4 on 11- point NRS Narang (2008)73,111 USA Cross- 30 8 hours Chronic non cancer Dronabinol Dronabinol; 10 Placebo  over (72 hour pain; (Marinol); mg daily washout) 20mg daily Pain > 4 NRS (0-10). Noyes (1975)84 USA Cross- 10 1 day Cancer-related pain; THC THC Capsules; THC THC Placebo ? over (none) Capsules; 10mg Capsules; Capsules; “continuous 5mg 15mg 20mg moderate pain” Nurmikko Belgium, Parallel 125 5 Neuropathic pain Nabiximols Placebo  characterised by (Sativex); © 2015 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 09/29/2021 (2007)76,95,106,109,113 UK group allodynia; max 48 sprays/24 h pain ≥4 NRS for 4- 7 days Pinsger (2006)78,94 Austria Cross- 30 4 (5 Chronic refractory Nabilone Placebo ? over washout) pain due to problems (Cesamet); of the max 4 musculoskeletal capsules system; (0.25mg each) VAS>5 Portenoy Belgium, Parallel 360 9 Cancer pain; Score 4- Nabiximols Nabiximols Nabiximols Placebo ? (2012)67,104 Canada, group 8 on NRS pain scale, (Sativex); (Sativex); 6-10 (Sativex); Chile, not changed by ≥2 max 4 sprays sprays per day 11-16 sprays Czech points over 3 per day per day Republic, consecutive days in Finland, 14 days France, Germany, India, Italy, Mexico, Poland, Romania, South Africa, Spain, UK, USA Rog UK Parallel 66 5 Central neuropathic Nabiximols Placebo ? (2005)80,98,107,118 group pain syndromes due (Sativex); to MS; max 48

sprays/24 h Not specified Selvarajah UK Parallel 30 12 Diabetic peripheral Nabiximols Placebo ? (2010)63,70,117 group neuropathy (Sativex); max unclear Serpell (2014)88,115 Belgium, Parallel 246 15 Peripheral Nabiximols Placebo ? Canada, group neuropathic pain (Sativex); Czech (PNP) associated with max 24 Republic, allodynia; sprays/24 h Romania, ≥24 on pain 0–10 UK NRS for ≥ 6

Downloaded From: https://jamanetwork.com/ on 09/29/2021 days during baseline Skrabek Canada Parallel 40 4 Fibromylagia; pain Nabilone Placebo  (2008)74,112 group despite the use of (Cesamet); other oral max 4 medications. capsules (0.5mg each) Svendsen Denmark Cross- 24 3 (3 Central pain in MS Dronabinol Placebo ? (2004)82,92 over washout) patients; (Marinol); max dose Central pain at the 10mg/day maximal pain site with a pain intensity score ≥ 3 on a 0-10 NRS Turcotte (2015)121 Canada Paralell 15 9 Relapsing remitting Gabapentin + Gabapentin + group MS; MS-induced nabilone placebo neuropathic pain; (target 2mg) inadequate pain relief from gabapentin (VAS≥50) Wallace (2015) USA Cross- 16 4 hours Painful diabetic THC (7%) THC (4%) THC (1%) Placebo  20,86,120 over (2 peripheral oromucosal oromucosal oromucosal weeks) neuropathy; spray spray spray > 4 on 11 point NPS Ware Canada Cross- 32 2 (2 Chronic pain Nabilone Amitriptyline:  (2010)63,64,89,90 over washout) conditions (Cesamet); 10mg/day (fibromyalgia) 0.5mg/day Ware (2010)68,114 Canada Cross- 23 5 days (9 Neuropathic pain; THC (2.5%) THC (6%) THC (9.4%) Placebo  over days smoked smoked smoked Average weekly pain washout) intensity score ≥ 4 on a 10-cm VAS Wilsey (2013)66,102 USA Cross- 39 6 hours Peripheral Cannabis Cannabis Placebo  over (washout neuropathic pain; (3·53%) (1·29%) 3-7 days) vaporised; 4 vaporised 4 VAS > 3/10 puffs 1 hour ;puffs 1 hour from from baseline, baseline, 4-8 4-8 puffs 3 puffs 3 hours hours Wilsey(2011)72,100 USA Cross- 38 6 hours Neuropathic pain; THC (3·5%) THC (7%) Placebo  over (3-21 smoked: 9 smoked: 9 puffs

Downloaded From: https://jamanetwork.com/ on 09/29/2021 day VAS > 3/10 puffs following washout) following standard standard procedure procedure CBD: cannabidiol; DSM: diagnostic and statistical manual of mental disorders; IM: intramuscular; MS: multiple sclerosis; NR: not reported; RCT: randomised controlled trial; THC: tetrahydrocannabinol  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

Downloaded From: https://jamanetwork.com/ on 09/29/2021 B. DICHOTOMOUS OUTCOME RESULTS

Study Details Intervention Outcome Intervention Placebo OR (95% CI) Events/ n Events/n

Abrams (2007)77 THC Neuropathic pain scale 13/25 6/25 3·2 (1·00, 10·48) (VAS) (>30% reduction) GW Pharma Ltd Nabiximols NRS (≥30% reduction) 54/149 59/148 0·8 (0·53, 1·36) 22 (2005)

Johnson (2010)69 Nabiximols Pain relief (NRS) (≥30% 23/53 12/56 2·7 (1·20, 6·26) THC reduction) 12/52 12/56 1·0 (0·45, 2·68)

Karst (2003)83 CT3 Neuropathic pain scale 9/19 3/19 4·27 (1·00, (≥30% reduction) 18·17) Langford (2013)65 Nabiximols NRS (≥30% reduction) 84/167 77/172 1·2 (0·81, 1·90)

Nurmikko (2007)76 Nabiximols NRS (≥30% reduction) 16/63 9/62 1·9 (0·80, 4·75) (Sativex)

Portenoy (2012)67 Nabiximols (1-4 NRS (≥30% reduction) 30/91 24/91 1·37 (0·72, 2·58) sprays) (6-10 sprays) 26/87 24/91 1·19 (0·62, 2·27) (11-14 sprays) 22/90 24/91 0·90 (0·47, 1·76) Selvarajah (2010)70 Nabiximols Neuropathic pain 8/15 9/14 0·6 (0·15, 2·76) scale(VAS) (≥30% reduction) Serpell (2014)88 Nabiximols NRS (≥30% reduction) 34/123 19/117 1·9 (1·04, 3·63)

Wilsey (2013)66 Cannabis (1·29%) VAS score (≥30% 21/37 10/38 3·5 (1·36, 9·19) Cannabis (3·53%) reduction) 22/36 10/38 4·2 (1·60, 11·08) Wilsey (2011)72 THC (3·5%) VAS score (≥30% 4/36 2/33 1·74 (0·34, 8·83) THC (7%) reduction) 0/34 2/33 0·18 (0·01, 3·95) Karst (2003)83 CT3 Neuropathic pain scale 2/19 0/19 5·5 (0·24, (≥50% reduction) 124·20) Nurmikko (2007)76 Nabiximols NRS (>50% reduction) 13/63 5/62 2·7 (0·96, 8·07) (Sativex)

Svendsen (2004)82 Dronabinol NRS (50% pain relief) 11/24 4/24 3·8 (1·07, 14·07)

Serpell (2014)88 Nabiximols NRS (≥50% improvement) NR/123 NR/117 1·70 (0·65, 4·48) p-value=0·280 Wallace (2013)20,86,120 THC (1%) Spontaneous pain (≥30% 10/16 10/16 1.00 (0.24, 4.18) THC (4%) reduction) 12/16 1.80 (0.39, 8.22) THC (7%) 13/16 2.60 (0.52, 13.0) Portenoy (2012)67 Nabiximols (1-4 Composite outcome: NR/91 NR/91 1·87 sprays) change in NRS and change p-value=0·038 Nabiximols (6-10 in opioid consumption; NR/87 NR/91 NR

Downloaded From: https://jamanetwork.com/ on 09/29/2021 sprays) positive response Nabiximols (11-16 improvement in one and NR/90 NR/91 1·16 sprays) other stable or improved p-value=0·622 Johnson (2010)69 Nabiximols Breakthrough analgesia NR NR 0·96 use (Number of days p-value=0·697 THC breakthrough medication NR NR 1·20 used) p-value=0·555 Berman (2007)87 Nabiximols Patient global impression 30/56 12/60 4·47 (1·98, (number of participants 10·05) reporting improvement) GW Pharma Ltd Nabiximols Patient global impression 9/36 9/34 0·9 (0·32, 2·64) 23 (2012)

GW Pharma Ltd Nabiximols Patient global impression NR NR 1·3 (0·86, 1·98) (2005)22

Langford (2013)65 Nabiximols Patient global impression NR NR 1·47 (0·99, 2·18)

Rog (2005)80 Nabiximols Patient global impression 24/34 10/32 5·0 (1·79, 13·99) (number of participants reporting improvement) Turcotte (2015)121 Nabilone Patient global impression 8/8 3/7 21.9 (0.91, (PGIC) 523.4)

C. CONTINUOUS OUTCOME RESULTS

Study Details Intervention Outcome MD at follow- MD change p-value Analysis Details up from baseline:

Pain Serpell (2014)88 Nabiximols (Peripheral NR -0·34 (-0·79, 0·139 ANCOVA neuropathic pain 0·11) 0-10 NRS) Svendsen Dronabinol (Radiating pain -0·6 (-1·3, 0·0) NR 0·039 NR (2004)82 (NRS 0-10))

Wilsey (2013)66 Cannabis (Unpleasantness) NR NR <0·001 Repeated (3·53%) measures model

GW Pharma Ltd Nabiximols Breakthrough NR -0·17(-0·59, 0·410 ANCOVA (2005)22 analgesia use 0·24) (daily number of paracetamol tablets) GW Pharma Ltd Nabiximols BPI-SF (severity -1·66 (-4·42, NR 0·233 ANCOVA (2012)23 scomposite score) 1·10)

Langford Nabiximols BPI-SF (no further NR -0·12 0·564 NR (2013)65 details)

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Serpell (2014)88 Nabiximols BPI-SF (Average NR -0·34 (-0·71, 0·148 ANCOVA pain) 0·12)

Johnson Nabiximols BPI- NR -1·04 (-5·23, 0·619 ANCOVA (2010)69 SF(Interference 3·15) composite score) THC BPI- NR -4·07 0·048 ANCOVA SF(Interference (-8·10, -0·05) composite score) Portenoy Nabiximols BPI-SF NR NR 0·871 NR (2012)67 (1-4 sprays) (Interference Nabiximols (6- composite score) NR NR 0·088 NR 10 sprays) Nabiximols NR NR 0·956 NR (11-16 sprays) Serpell (2014)88 Nabiximols BPI-SF NR -0·32 (-0·80, 0·183 ANCOVA (Interference 0·15) composite score) GW Pharma Ltd Nabiximols BPI-SF (Severity NR -0·05 (-0·51, 0·841 ANCOVA (2005)22 Composite Score) 0·42)

Serpell (2014)88 Nabiximols BPI-SF (Severity NR -0·25 (-0·72, 0·288 ANCOVA composite score) 0·21)

Portenoy Nabiximols BPI-SF(Severity NR NR 0·236 NR (2012)67 (1-4 sprays) composite score) Nabiximols (6- NR NR 0·119 NR 10 sprays) Nabiximols NR NR 0·861 NR (11-16 sprays) Serpell (2014)88 Nabiximols BPI-SF(worst pain) NR -0·30 (-0·82, 0·255 ANCOVA 0·22)

Selvarajah Nabiximols Deep pain NR 10·50(-12·20, Linear (2010)70 (100mm VAS 30·80) 0·38 regression scale) Ellis (2009)71 THC Descriptor NR 3·30 0·016 Wilcoxon's Differential Scale signed rank test Wilsey (2011)72 THC 3·5% Descriptor 0·12 (0·065, NR <0·01 Linear mixed Differential Scale 0·18) model (Global THC 7% impression of 0·12 (0·064, NR <0·01 NR change (pain 0·18) relief)) Berman (2007)87 Nabiximols Descriptor 0·79 NR 0·007 NR Differential Scale (least pain in the last 24h (points)) Berman (2007)87 Nabiximols Descriptor 0·46 NR 0·04 NR Differential Scale (mean BPI

Downloaded From: https://jamanetwork.com/ on 09/29/2021 (points)) Wilsey (2011)72 THC 3·5% Descriptor -0·21 NR ≤0·01 NR Differential Scale (-0·33, -0·09) (Pain THC 7% unpleasantness -0·21 NR ≤0·01 NR (measure of the (-0·33, -0·09) emotional dimension of pain by VAS) Berman (2007)87 Nabiximols Descriptor -1·93 NR 0·032 ANCOVA Differential Scale (-3·69, -0·16) (Total BPI (points)) Frank (2008)75 Nabilone Descriptor 6·0 (1·40, 10·50) NR 0·01 NR Differential Scale (VAS (0-100mm))

Skrabek Nabilone Descriptor -0·79 NR ≤0·02 NR (2008)74 Differential Scale (VAS (0-100mm)) Wilsey (2011)72 THC 3·5% Descriptor -0·0036 NR 0·03 NR Differential Scale (-0·0069, (VAS (0-100mm)) 0·0003) THC 7% -0·0035 NR 0·04 NR (-0·0068, -0·000 2) GW Pharma Ltd Nabiximols Diabetic NR -0·12 (-0·60, 0·634 ANCOVA (2005)22 Neuropathy Pain 0·36) (0-10 NRS) Selvarajah Nabiximols McGill Pain rating NR -1·3(-3·0, 2·4) 0·81 Linear (2010)70 (Affective scale) regression

Ware (2010)64 Nabilone McGill Pain rating NR 1·4 (-4·3, 7·20) NR NR vs (Present pain Amitriptyline intensity)

Selvarajah Nabiximols McGill Pain rating NR 0·53(-0·79, 0·57 Linear (2010)70 (Present pain 1·40) regression intensity) Nabiximols NR 3·30(-5·39, 0·65 Linear 8·44) regression

Blake (2006)79 Nabiximols McGill Pain rating NR 3(-3, 9) 0·302 Mann-Whitney/ ((SF-MPQ): total Wilcoxon test; intensity of pain Berman (2004)81 Nabiximols McGill Pain rating -1·7 (-3·64, NR 0·146 ANCOVA (SF-MPQ Pain 0·55) Rating Index (total THC score=45)) -2·1 (-4·29, -0·1) NR 0·04 NR

Berman (2004)81 Nabiximols McGill Pain rating -7·8 NR 0·092 ANCOVA (SF-MPQ VAS) (-15·78, -1·21)

Downloaded From: https://jamanetwork.com/ on 09/29/2021 THC -9·3 NR 0·0037 NR (-17·41, -0·57) Blake (2006)79 Nabiximols McGill Pain rating NR -3(-18, 9) 0·574 Mann-Whitney/ (SF-MPQ VAS) Wilcoxon test; Blake (2006)79 Nabiximols McGill Pain rating NR -0·72 0·016 Mann-Whitney/ (SF-MPQ VAS) (-1·30, -0·14) Wilcoxon test;

Ware (2010)68 THC (2·5%) McGill Pain rating 1·30 (-9·19, NR NR NR (Total score) 11·79) THC (6%) -3·30 (-12·86, NR NR NR 6·26) THC (9·4%) -4·30 (-13·82, NR NR NR 5·22) Selvarajah Nabiximols McGill Pain rating NR 1·0(-0·91, 0·24 Linear (2010)70 (VAS) 3·40) regression

Blake (2006)79 Nabiximols Morning pain on NR -0·95(-1·83, -0· 0·044 ANCOVA movement (0-10 02) NRS) Blake (2006)79 Nabiximols Morning pain at NR -1·04(-1·90, -0· 0·018 Mann-Whitney/ rest (0-10 NRS) 18) Wilcoxon test;

Selvarajah Nabiximols Muscular pain NR 10·3 (-9·15, 0·26 Linear (2010)70 (100mm VAS 33·00) regression scale) Langford Nabiximols Neuropathic pain NR 1·83 0·310 NR 65 (2013) scale (0-100)

Selvarajah Nabiximols Neuropathic pain NR -7·80(-20·10, 0·62 Linear (2010)70 scale (0-100) 12·10) regression

Serpell (2014)88 Nabiximols Neuropathic pain NR -2·86 (-7·22, 0·198 ANCOVA scale (0-100) 1·50)

Abrams (2007)77 THC Neuropathic pain NR 18 0·03 Mann-Whitney/ scale (% median Wilcoxon test reduction in chronic neuropathic pain (VAS)) Abrams (2007)77 THC Neuropathic pain NR NR ≤0·001 Mann-Whitney/ scale (% reduction Wilcoxon test chronic pain ratings (AUC)) Rog (2005)80 Nabiximols Neuropathic pain NR -6·58(-12·97, - 0·044 ANCOVA scale (0-100) 0·19)

GW Pharma Ltd Nabiximols Neuropathic pain NR 0·37(2·153) 0·865 ANCOVA (2005)22 scale (0-100) (-3·87, 4·61)

Nurmikko Nabiximols Neuropathic pain NR -8·03 0·007 ANCOVA (2007)76 scale (0-100) (-13·83, -2·23)

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Berman (2007)87 Nabiximols NRS (0-10) NR -0·08 (-0·51, 0·708 ANCOVA 0·35 Johnson Nabiximols NRS (0-10) NR -0·67 0·0014 ANCOVA (2010)69 (-1·21, -0·14)

THC NR -0·32 (-0·86, 0·245 ANCOVA 0·22)

Rog (2005)80 Nabiximols NRS (0-10) NR -1·25(-2·11, -0 0·005 ANCOVA ·39)

Lynch (2014)85 Nabiximols NRS (0-10) -0·38 (-1·59, NR NR NR 0·83) Portenoy Nabiximols NRS (0-10) NR -0·75 0·006 ANCOVA (2012)67 (1-4 sprays) (-1·28, -0·22) Nabiximols (6- NR -0·36 (-0·89, 0·187 10 sprays) 0·18)

Nabiximols NR -0·09(-0·62, (11-16 sprays) 0·44) 0·75 Ware (2010)68 THC (2·5%) NRS (0-10) -0·13 (-0·83, NR NR Generalised 0·56) linear model THC (6%) -0·09(-0·78, NR NR 0·60) THC (9·4%) -0·71(-1·40, -0· NR NR 02) Nurmikko Nabiximols NRS (Dynamic NR -0·82 0·042 ANCOVA (2007)76 allodynia) (-1·60, -0·03)

Pinsger (2006)78 Nabilone NRS (Increase of NR 0·093 NR Wilcoxon signed number of rank headache-free days in last 4 weeks) Berman (2004)81 Nabiximols NRS (Mean diary -0·58 NR 0·005 ANCOVA BS-11 pain score) (-0·98, -0·18)

Berman (2004)81 THC NRS (Mean diary -0·64 NR 0·002 NR BS-11 pain score) (-1·03, -0·24) Nurmikko Nabiximols NRS (mean pain NR -0·96 0·004 ANCOVA (2007)76 NRS score) (-1·59, -0·32)

Langford Nabiximols NRS (NRS 0-10 NR 0·17(-0·62, 0·47 NR (2013)65 scale) 0·29)

Narang (2008)73 Dronabinol NRS (pain NR -0·9 <0·001 Linear (10mg) intensity (0-10)) regression (fixed effects) Dronabinol NR -1·5 <0·001 Linear (20mg) regression (fixed effects)

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Nurmikko Nabiximols NRS (Punctate NR -0·87 0·021 ANCOVA (2007)76 allodynia) (-1·62, -0·13)

Pinsger (2006)78 Nabilone NRS (Reduction of NR 0·006 NR Wilcoxon signed current spine pain rank intensity) Pinsger (2006)78 Nabilone NRS (Reduction of NR 0·241 NR Wilcoxon signed mean headache rank intensity in last 4 weeks) Pinsger (2006)78 Nabilone NRS (Reduction of NR 0·196 NR Wilcoxon signed mean spine pain rank intensitiy in last 4 weeks) Narang (2008)73 Dronabinol NRS (SPID) NR -23·8 <0·01 Linear (10mg) regression (fixed effects) Svendsen Dronabinol NRS (Spontaneous -0·60 (-1·8, 0·0) NR 0·02 NR (2004)82 pain score.)

Noyes (1975)84 THC (5mg) NRS (Total Pain 2·1 (1·4, 2·8) NR NR NR Reduction THC (10mg) 1·8 (1·08, 2·52) NR NR

THC (15mg) 3·2 (2·56, 3·84) NR NR

THC (20mg) 8·2 (7·37, 9·03) NR NR

Berman (2004)81 Nabiximols Pain Box Scale-11 -0·8 NR 0·005 ANCOVA (-1·23, -0·23)

THC -0·6 NR 0·02 NR (-1·08, -0·09)

Ellis (2009)71 THC VAS (0-10) NR NR <0·001 Wilcoxon's signed rank test

Wilsey (2013)66 Cannabis VAS (0-100) NR -10 0·0018 Repeated (3·53%) measures model Cannabis NR -11 0·0018 (1·29)

Turcotte Nabilone VAS (0-100) NR NR <0.001 NR (2015)121 Langford Nabiximols Pain disability NR 2·79 0·058 (2013)65 index (PDI) Nurmikko Nabiximols Pain disability NR -5·85 0·003 ANCOVA (2007)76 index (PDI) (-9·62, -2·09) GW Pharma Ltd Nabiximols Pain disability -2·79 (-8·14, NR 0·30 ANCOVA (2012)23 index (PDI) 2·56) Parallel group

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Berman (2004)81 Nabiximols Pain disability -2·0 (-4·32, NR 0·181 ANCOVA index (PDI) 0·83)

THC 0·3 (-2·12, 2·98) NR 0·739 Narang (2008)73 Dronabinol Pain relief 8·3 NR <0·05 Linear (10mg) ((integral relief regression scores)) (fixed effects) Dronabinol 10·6 NR <0·01 (20mg) Narang (2008)73 Dronabinol Pain relief 0·8 NR <0·01 Linear (10mg) (Average relief regression scale (0-10)) (fixed effects) Dronabinol 0·9 NR <0·01 (20mg) Svendsen Dronabinol Pain relief (NRS 2·5 (0·5, 4·5) NR 0·035 NR (2004)82 (0-10)) Nurmikko Nabiximols Pain at allodynic NR 29·03 (13·79, 0·001 ANCOVA (2007)76 site 44·67) Selvarajah Nabiximols Superficial pain NR 9·10(-15·30, 0·72 Linear (2010)70 (100mm VAS 21·93) regression scale) Selvarajah Nabiximols Total pain score NR 9·50(-11·30, 0·40 Linear (2010)70 (Average of 27·80) regression superficial, deep and muscular pain scores) GW Pharma Ltd Nabiximols Total pain score 0·18 (-47·62, 0) NR 0·006 NR (2012)23 (median treatment difference, % of days) Wallace THC (1%) Total sponaneous -0.44 (NR) NR 0.031 ANCOVA (2013)86 THC (4%) pain score -0.42 (NR) NR 0.04 THC (7%) -1.2 (NR) NR <0.001 QoL Johnson Nabiximols EORTC QLQ-C30 NR 2·47 (-3·87, 0·443 ANCOVA (2010)69 global health 8·81) status THC NR 0·84 (-5·46, 0·793 7·13)

Langford Nabiximols EQ-5D (health NR -0·01 0·396 NR (2013)65 status index) Selvarajah Nabiximols EQ-5D (Health -0·06 (-0·21, NR 0·87 Linear (2010)70 status index) 0·09) regression GW Pharma Ltd Nabiximols EQ-5D (Health NR -0·01 (0·021) 0·523 ANCOVA (2005)22 status index) (-0·06, 0·03) Serpell (2014)88 Nabiximols EQ-5D (Health NR -0·01 (-0·06, 0·617 ANCOVA status index) 0·04) Langford Nabiximols EQ-5D (Health NR 1·94 0·383 NR (2013)65 status VAS) Selvarajah Nabiximols EQ-5D (Health 1·70 (-10·35, NR 0·92 Linear

Downloaded From: https://jamanetwork.com/ on 09/29/2021 (2010)70 status VAS) 13·75) regression Serpell (2014)88 Nabiximols EQ-5D (health NR -0·75 (-5·60, 0·760 ANCOVA status VAS) 4·09) Ware (2010)68 THC (2·5%) EQ-5D (health -5·50 (-16·99, NR NR NR status VAS) 5·99) THC (6%) -1·20 (-13·77, NR NR NR 11·37) THC (9·4%) 2·20 (-9·73, NR NR NR 14·13) GW Pharma Ltd Nabiximols MSQoL (Spitzer 0·28 (-0·36, NR 0·387 ANCOVA (2012)23 QoL index scores) 0·91) Berman (2007)87 Nabiximols MSQoL (Spitzer -0·04 (-0·49, NR 0·847 ANCOVA QoL index scores) 0·40) Pinsger (2006)78 Nabilone Other (Score NR 0·902 NR Wilcoxon signed Cross-over (Mezzich & rank Cohen, German translation 2003)) Portenoy Nabiximols Patient NR NR 0·226 NR (2012)67 (1-4 sprays) assessment of Nabiximols (6- Consitpation NR NR -0·10 NR 10 sprays) quality of life 0·493 Nabiximols NR NR 0·139 NR (11-16 sprays) Frank (2008)75 Nabilone SF36 (Bodily pain) -5·2 (-10·1, -0·4) NR 0·03 NR

Langford Nabiximols SF36 (Bodily pain) NR 1·35 0·494 NR (2013)65 Selvarajah Nabiximols SF36 (Bodily pain) -5·60 (-20·98, NR 0·64 Linear (2010)70 9·78) regression Svendsen Dronabinol SF36 (Bodily pain) 9·8 (0·0, 21·5) NR 0·037 NR (2004)82 Frank (2008)75 Nabilone SF36 (Change in 0·0 (-0·2, 0·2) NR 0·88 NR health)

Frank (2008)75 Nabilone SF36 (General 0·8 (-3·1, 4·6) NR 0·70 NR health)

Langford Nabiximols SF36 (General NR -1·70 0·264 NR (2013)65 health) Selvarajah Nabiximols SF36 (General 4·50 (-9·25, NR 0·78 Linear (2010)70 health) 18·25) regression Svendsen Dronabinol SF36 (General 0·0 (-6, 5) NR 0·95 NR (2004)82 health) Frank (2008)75 Nabilone SF36 (General 0·8(-3·1, 4·6) NR 0·7 NR pain) Frank (2008)75 Nabilone SF36 (mental 2·5 (-2·7, 7·6) NR 0·35 NR health) Langford Nabiximols SF36 (Mental NR -0·56 0·733 NR (2013)65 health) Selvarajah Nabiximols SF36 (Mental 5·00 (-9·90, NR 0·76 Linear (2010)70 health) 19·90) regression Svendsen Dronabinol SF36 (Mental 8(0, 12) NR 0·023 NR

Downloaded From: https://jamanetwork.com/ on 09/29/2021 (2004)82 health) Lynch (2014)85 Nabiximols SF36 (Mental) 10·96 (4·03, NR NR NR 17·89) Frank (2008)75 Nabilone SF36 (Physical -1·2 (-4·5, 2·1) NR 0·48 NR functioning)

Langford Nabiximols SF36 (Physical NR -0·45 0·785 NR (2013)65 Functioning) Selvarajah Nabiximols SF36 (Physical -6·00 (-22·86, NR 0·63 Linear (2010)70 functioning) 10·86) regression Svendsen Dronabinol SF36 (Physical 5·0 (0·0, 7·5) NR 0·06 NR (2004)82 functioning) Frank (2008)75 Nabilone SF36 (Role -1·2(-11·8, 9·5) NR 0·83 NR emotional) Langford Nabiximols SF36 (Role NR -3·33 0·216 NR (2013)65 emotion) Selvarajah Nabiximols SF36 (Role 7·20 (-27·36, NR 0·76 Linear (2010)70 emotional) 41·76) regression Svendsen Dronabinol SF36 (Role 0 (-33, 0) NR 0·46 NR (2004)82 emotional) Frank (2008)75 Nabilone SF36 (Role 8·9 (1·1, 16·7) NR 0·03 NR physical) Langford Nabiximols SF36 (Role NR -0·89 0·694 NR (2013)65 physical) Lynch (2014)85 Nabiximols SF36 (Role -11·0 (-17·3, - NR NR NR physical) 4·87) Selvarajah Nabiximols SF36 (Role -26·80 (-56·60, NR 0·12 Linear (2010)70 physical) 3·00) regression Svendsen Dronabinol SF36 (Role 0·0 (-25·0, 12·5) NR 0·73 NR (2004)82 physical) Frank (2008)75 Nabilone SF36 (Social 3·4 (-4·1, 10·8) NR 0·37 NR functioning)

Langford Nabiximols SF36 (Social NR -5·75 0·020 NR (2013)65 functioning) Selvarajah Nabiximols SF36 (Social -11·60 (-30·91, NR 0·08 Linear (2010)70 functioning) 7·71) regression Svendsen Dronabinol SF36 (Social 6·3 (0·0, 12·5) NR 0·17 NR (2004)82 functioning) Frank (2008)75 Nabilone SF36 (Vitality) -2·0 (-7·2, 3·3) NR 0·46 NR

Langford Nabiximols SF36 (Vitality) NR -2·75 0·095 NR (2013)65 Selvarajah Nabiximols SF36 (Vitality) -5·70 (-20·92, NR 0·45 Linear (2010)70 9·52) regression Svendsen Dronabinol SF36 (Vitality) 2·5 (-5·0, 10·0) NR 0·52 NR (2004)82 Global impression Narang (2008)73 Dronabinol Patient global NR 2 <0·05 Linear (10mg) impression regression Dronabinol NR 2 <0·05 (fixed effects)

Downloaded From: https://jamanetwork.com/ on 09/29/2021 (20mg)

Wilsey (2013)66 Cannabis Patient global 0·69 NR 0·0001 Repeated (3·53%) impression measures (Global model Cannabis impression of pain 0·55 NR 0·0001 (1·29) relief scale of -3 to +3) Portenoy Nabiximols Patient global NR NR 0·268 NR (2012)67 (1-4 sprays) impression Nabiximols (6- (Patient global NR NR 0·664 10 sprays) assessment of Nabiximols change) NR NR (11-16 sprays) 0·538 Nurmikko Nabiximols Patient global NR 29·03 (13·79, ≤0·001 ANCOVA (2007)76 impression (PGIC 44·67) (all neuropathic pain)) ANCOVA: analysis of covariance; AUC: area under the curve; BP-11: box pain 11: VAS: visual analogue scale; BPI-SF: brief pain inventory – short form; MSQoL: multiple sclerosis quality of life; NRS: numerical rating scale; PGIC: patients’ global impression of change; SF36: Short form 36 health survey; SF-MPQ: short form McGill pain questionnaire; SPID: sum of pain intensity difference; NR: not reported Quantitative data reported based on information available in primary studies

Downloaded From: https://jamanetwork.com/ on 09/29/2021 e Appendix 6. Spasticity in MS and Paraplegia A. STUDY CHARACTERISTICS

Study Details Country RCT N Duration Patient details Intervention 1 Intervention Comparator Risk Design (weeks) 2 of Bias Berman (2007)19,87 Romania, UK Parallel 117 3 Paraplegia (non-acute spinal cord Nabiximols Placebo  group injury); ; Not specified (Sativex); Max 48

sprays/24h Collin (2007)127,141 UK and Parallel 189 6 MS; Spasticity in ≥2 muscle groups; Nabiximols Placebo ? Romania group Ashworth score≥2 (Sativex); Max 48 sprays/24h Collin (2010)125,137,142 UK and Czeck Parallel 337 14 MS; Mean daily score ≥4 on spasticity Nabiximols Placebo ? republic group NRS for 6 days (Sativex); max 24 sprays/24h Corey-Bloom USA Cross- 37 3 days MS; Ashworth score ≥ 3 at the elbow, THC; one 800mg Placebo  (2012)124,139,147 over (11 day hip, or knee; cigarette washout)

Hagenbach (2003)17 Switzerland Parallel 13 6 Paraplegia (spinal cord injury); Dronabinol Placebo ? group Ashworth score >3 (Marinol); max

dose unclear appeared to be 10mg daily Killestein (2002)132,135 Netherlands Cross- 16 4 (4) MS; Ashworth score ≥ 2 in at least one THC/CBD Dronabinol Placebo  over limb capsules; max (Marinol); dose 10mg/day max dose

10mg/day Langford (2013)65,91 UK, Czech Parallel 339 14 MS; Not specified Nabiximols Placebo ? Republic, group (Sativex); max 12

Canada, Spain sprays/24h Leocani (2014)148 Italy Cross- 43 4 (2 Progressive MS; Modified Ashworth >1 Nabiximols Placebo  over washout) (Sativex); dose NR

Pooyania (2010)126,144 Canada Cross- 12 4 (2 Paraplegia (Spinal cord injury); Nabilone Placebo ? over washout) Ashworth ≥ 3 (Cesamet); max

dose 1mg/day

Van Amerongen Netherlands Parallel 24 4 Primary or secondary progressive MS; Novel oral Placebo 

Downloaded From: https://jamanetwork.com/ on 09/29/2021 (2014)149 group Not specified formulation of Δ9-THC (ECP002A); individualised dose Vaney (2004)130 Switzerland Cross- 57 9 days (4 MS; ≥ one joint scoring ≥ 2 on the THC/CBD Placebo  over day Ashworth scale capsules; max washout) dose 30mg/day Wade (2004)129,138,143 UK Parallel 160 6 MS; Not specified Nabiximols Placebo  group (Sativex); max 48

sprays/24h Zajicek UK (CAMS Parallel 657 15 MS; Ashworth score of ≥2 in ≥ 2 limb THC/CBD Dronabinol Placebo  (2003)122,128,131,145 study) group muscle groups capsules; max (Marinol); 25mg/day max

25mg/day Zajicek UK (MUSEC Parallel 279 12 MS; Not specified THC/CBD Placebo  (2012)123,133,134,136,140,146 study) group capsules; max 25mg/day CBD: cannabidiol; MS: multiple sclerosis; NR: not reported; RCT: randomised controlled trial; THC: tetrahydrocannabinol  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

Downloaded From: https://jamanetwork.com/ on 09/29/2021 B. DICHOTOMOUS OUTCOMES RESULTS

Study Details Intervention Outcome Interventio Placebo OR (95% CI) n Events/ n Events/n

Spasticity Collin (2007)127 Nabiximols NRS(≥ 50% reduction) 21/120 6/64 1·9 (0·76, 4·95) NRS(≥30% reduction) 48/120 14/64 2·3 (1·17, 4·63) Collin (2010)125 Nabiximols NRS(≥50% improvement) 21/166 18/169 1·2 (0·62, 2·34) NRS(≥30% improvement) 51/166 42/169 1·3 (0·82, 2·15) Leocani (2014)148 Nabiximols Modified Ashworth 14/34 4/34 5.25 (1.51, 18.27) (≥20% improvement) Zajicek (2003)131 THC/CBD Patient assessment of 121/197 91/198 1·8 (1·25, 2·78) Dronabinol whether there was a 108/181 91/198 1·7 (1·15, 2·60) treatment benefit Zajicek(2012)123 THC/CBD Spasm severity (0-3 on 44/143 18/134 2·8 (1·53, 5·15) an 11 point category rating scale) General disease specific symptoms Zajicek(2012)123 THC/CBD Muscle stiffness (0-3 on 42/143 21/134 2·2 (1·23, 3·96) an 11 point category rating scale) Zajicek (2003)131 THC/CBD Relapse: MS relapse or 1 (1)/211 7 (8)/213 0·1 (0·03, 1·14) Dronabinol possible relapse 1 (1)/206 7 (8)/213 0·2 (0·03, 1·17) Global impression Berman (2007)87 Nabiximols Patient global 30/56 12/60 4·47 (1·98, 10·05) impression Collin (2007)127 Nabiximols Patient global 66/124 31/65 1·2 (0·68, 2·26) impression Langford (2013)65 Nabiximols Patient Global NR NR 1·47 (0·99, 2·18) Impression Wade (2004)129 Nabiximols Patient global 32/79 21/77 1·7 (0·92, 3·50) impression Collin (2010)125 Nabiximols Carer global impression 72/167 56/170 1·5 (0·98, 2·39) CBD: cannabidiol; NR: not reported; NRS: numerical rating scale; THC: tetrahydrocannabinol Quantitative data reported based on information available in primary studies

C. CONTINUOUS OUTCOME RESULTS

Study Intervention Outcome MD at follow-up MD change p-value Analysis Details Details from baseline: Spasticity: Berman Nabiximols Ashworth NR -0·14 (-0·33, 0·142 ANCOVA (2007)87 (modified) 0·05)

Collin Nabiximols Ashworth NR -0·11 (-0·29, 0·218 ANCOVA (2007)127 0·07) Collin Nabiximols Ashworth NR -0·16 (-1·94, 0·857 ANCOVA (2010)125 (modified) 1·61)

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Killestein Dronabinol Ashworth -0·07 (-0·35, 0·21) NR >0·05 Mixed linear (2002)132 model THC/CBD Ashworth -0·07 (-0·37, 0·23) NR >0·05 Mixed linear model Leocani Nabiximols Modified -1.66 (-2.85, - NR 0.009 NR (2014)148 Ashworth 0.47) Pooyania Nabilone Ashworth (most -0·91(-1·41, -0·41) NR 0·003 Mann-Whitney/ (2010)126 involved muscle Wilcoxon test group) Vaney THC/CBD Ashworth NR -0·80 (-2·1, 0·2379 Linear (2004)130 0·5) regression; Wade Nabiximols Ashworth 0·22 (-0·50, 0·94) 0·22 (-3·78, 0·55 NR (2004)129 (modified) 4·22) Zajicek Dronabinol Ashworth NR -0·94 (- NR ANCOVA (2003)131 1·83, -0·05) THC/CBD Ashworth NR -0·32 (- NR 1·21, -0·57,) Berman Nabiximols NRS (0-10) NR 0·07 (-0·61, 0·830 ANCOVA (2007)87 0·75) Collin Nabiximols NRS (0-10) NR -0·52 0·048 ANCOVA (2007)127 (-1·029, -0·0 04) Collin Nabiximols NRS (0-10) NR -0·23 (-0·59, 0·220 ANCOVA (2010)125 0·14) Langford Nabiximols NRS (0-10) NR -0·10 0·667 NR (2013)65 Pooyania Nabilone VAS score (0-100) -9·09(-19·12, NR 0·76 Mann-Whitney/ (2010)126 0·94) Wilcoxon test

Wade Nabiximols VAS score (0-100) -22·79 NR 0·001 NR (2004)129 (-35·52, -10·07) Langford Nabiximols Spasm severity NR -0·14 0·548 NR (2013)65 (NRS) Berman Nabiximols Spasm severeity NR 0·05 (-0·54, 0·860 ANCOVA (2007)87 (NRS) 0·65) Collin Nabiximols Spasm severity NR -0·01 0·955 ANCOVA (2010)125 (NRS) Zajicek THC/CBD Spasm severity -0·70 (-1·35, -0·05 -0·80 (- NR NR (2012)123 (NRS) 1·21, -0·39) Collin Nabiximols Spasm Frequency NR -0·17(-0·39, 0·141 ANCOVA (2007)127 Scale 0·06) Wade Nabiximols Spasm Frequency NR -1·27(-16·90, 0·869 ANCOVA (2004)129 Scale 14·30) Pooyania Nabilone Spasm Frequency 0·0 (-0·11, 0·11) NR 0·369 Mann-Whitney/ (2010)126 Scale Wilcoxon test Corey-Bloo THC Ashworth -2·53 (-4·08, - -2·74 NR ANCOVA m (2012)124 (modified) (Scores 0·98) (-3·14, -2·20) 0-30) Hagenbach Dronabinol Ashworth -4·89 NR 0·001 NR (2003)17 (summed scores) Pooyania Nabilone Ashworth -2·55(-2·70, -2·40) NR 0·001 Mann-Whitney/ (2010)126 (Ashworth in 8 Wilcoxon test

Downloaded From: https://jamanetwork.com/ on 09/29/2021 muscle groups) Wade Nabiximols Spasm severity NR -0·08 0·992 ANCOVA (2004)129 (Primary symptom (-17·28, VAS score) 17·11) Wade Nabiximols Spasms -5·30 (-19·81, NR 0·464 NR (2004)129 9·22) Berman Nabiximols Percentage of NR -0·64 0·873 ANCOVA (2007)87 days on which (-0·856, spasm was 7·27) experienced Berman Nabiximols Percentage of NR 0·4 (-4·08, 0·860 ANCOVA (2007)87 days on which 4·88) spasticity was experienced Collin Nabiximols Motricity Index NR 1·30 (-7·47, 0·766 ANCOVA (2007)127 Score (Arms) 10·07) Collin Nabiximols Motricity Index NR 3·86(-0·06, 0·054 ANCOVA (2007)127 Score (Legs) 7·78) Pooyania Nabilone Wartenberg -0·004(-0·21, NR 0·6397 t-test (2010)126 Pendulum Test 0·20) (Rotational damping ratio, sitting) Pooyania Nabilone Wartenberg 0·498(-0·03, 1·02) NR 0·018 t-test (2010)126 Pendulum Test (Rotational natural frequency, sitting, pendulum variable) Zajicek THC/CBD Multiple Sclerosis 0·50 (-1·24, 2·24) -0·20 (-1·15, NR NR (2012)123 Spasticity Scale 0·75) (MSSS-88) (Social functioning) Zajicek THC/CBD MSSS-88 0·20 (-2·64, 3·04) -0·30 (-1·84, NR NR (2012)123 (Feelings) 1·24) Zajicek THC/CBD MSSS-88 (Body -1·20 (-3·44, 1·04) -2·10 (- NR NR (2012)123 movement) 3·44, -0·76) Zajicek THC/CBD MSSS-88 (Ability -2·60 (-4·32, - -1·60 (- NR NR (2012)123 to walk) 0·88) 2·31, -0·89) Zajicek THC/CBD MSSS-88 (Daily 0·00 (-2·30, 2·30) 0·30 (-1·09, NR NR (2012)123 activities) 1·69) Zajicek THC/CBD MSSS-88 (Muscle -1·40 (-4·13, 1·33) -3·10 (- NR NR (2012)123 spasms) 4·66, -1·54) Zajicek THC/CBD MSSS-88 -0·80 (-2·59, 0·99) -1·40 (- NR NR (2012)123 (Pain/discomfort) 2·45, -0·35) Zajicek THC/CBD MSSS-88 (Muscle -2·40 (-4·61, - -3·70 (- NR NR (2012)123 stiffness) 0·19) 5·04, -2·36) QoL Collin Nabiximols EQ-5D (Health NR 0·02 0·175 ANCOVA (2010)125 state index) Langford Nabiximols EQ-5D (EQ-5D NR -0·01 0·396 NR (2013)65 health status

Downloaded From: https://jamanetwork.com/ on 09/29/2021 index) Collin Nabiximols EQ-5D (Health NR 1·42 0·538 ANCOVA (2010)125 status VAS score) Langford Nabiximols EQ-5D (Health NR 1·94 0·383 NR (2013)65 status VAS) Berman Nabiximols MSQoL (Spitzer -0·04 (-0·49, 0·40) 0·00 (-0·33, 0·847 ANCOVA (2007)87 Quality of Life 0·33) Index Score) Collin Nabiximols MSQoL NR -3·09 0·312 ANCOVA (2010)125 (MSQoL-54 mental health composite) Collin Nabiximols MSQoL NR -1·51 0·549 ANCOVA (2010)125 (MSQoL-54 (physical health composite)) Langford Nabiximols SF36 (Role NR -0·89 0·694 NR (2013)65 physical) Langford Nabiximols SF36 (Mental NR -0·56 0·733 NR (2013)65 health) Langford Nabiximols SF36 (Role NR -3·33 0·216 NR (2013)65 emotion) Langford Nabiximols SF36 (Social NR -5·75 0·020 NR (2013)65 functioning) Langford Nabiximols SF36 (Vitality) NR -2·75 0·095 NR (2013)65 Langford Nabiximols SF36 (Bodily pain) NR 1·35 0·494 NR (2013)65 Langford Nabiximols SF36 (Physical NR -0·45 0·785 NR (2013)65 Functioning) Langford Nabiximols SF36 (General NR -1·70 0·264 NR (2013)65 health) Mobility/ Disability: Collin Nabiximols Barthel Index of NR -0·15 (-1·95, 0·867 ANCOVA (2010)125 activities of daily 1·64) living (ADL) Zajicek Dronabinol Barthel Index of -0·73 (-2·33, 0·87) 0·23 (-0·13, NR NR (2003)131 activities of daily 0·59) living (ADL) THC/CBD Barthel Index of -0·62 (-2·23, 0·99) -0·03 (-0·39, NR NR activities of daily 0·33) living (ADL) Wade Nabiximols Barthel Index of -0·47 (-1·01, 0·07) NR 0·09 NR (2004)129 activities of daily living (ADL) Collin Nabiximols Walk time (10m NR 0·0 (-2, 1) 0·624 ANCOVA (2010)125 walk) Wade Nabiximols Walk time (10m -2·35 (-5·16, 0·46) NR 0·07 Mann-Whitney/ (2004)129 walk) Wilcoxon test

Corey-Bloo THC Walk time 1·19 (-3·23, 5·61) 1·20 (0·15, NR ANCOVA m (2012)124 (distance unclear) 4·31)

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Zajicek Dronabinol Walk time (10m -1·01 -4·02 NR NR (2003)131 walk) Zajicek THC/CBD Walk time (10m -1·01 -0·02 NR NR (2003)131 walk) Killestein Dronabinol Acitivities of daily NR NR 0·08 Mixed linear (2002)132 living (VAS model "walking score") Wade Nabiximols Acitivities of daily -0·52 (-1·58, 0·55) NR 0·16 Mann-Whitney/ (2004)129 living (Nine-hole Wilcoxon test peg test of manual dexterity) Zajicek THC/CBD Multiple sclerosis -10·90 (-15·85, - -7·30 (- NR NR (2012)123 walking scale 5·95) 9·40, -5·20) (MSWS-12) (Total score) Zajicek Dronabinol UK neurological 1·23 (-0·53, 2·99) 0·61 (-0·17, NR NR (2003)131 disability score 1·39) Zajicek THC/CBD UK neurological 0·51 (-1·17, 2·19) -0·35 (-1·13, NR NR (2003)131 disability score 0·43) Zajicek Dronabinol Rivermead 0·06 (-0·87, 0·99) 0·19 (0·00, NR NR (2003)131 Mobility Index 0·38)

Zajicek THC/CBD Rivermead -0·18 (-1·09, 0·73) 0·01 (-0·18, NR NR (2003)131 Mobility Index 0·20)

General disease specific symptoms: Corey-Bloo THC Perceived deficits 2·07 (-3·70, 7·84) 1·70 (-3·23, NR ANCOVA m (2012)124 PDQ score (0-80) 6·07) Corey-Bloo THC Brief symptom 4·57 (-1·17, -2·87 (-9·63, NR ANCOVA m (2012)124 inventory (BSI) 10·31) 4·58) score (0-208) Wade Nabiximols Guys Neurological 1·81 (0·02, 3·60) NR 0·048 NR (2004)129 Disability Scale (GNDS) Wade Nabiximols Primary Symptom -5·93 (-13·52, NR 0·124 NR (2004)129 Score (PSS) 1·65) Zajicek THC/CBD Muscle stiffness -1·00 (-1·61, - -1·10 (- NR NR (2012)123 (11 point scale) 0·39) 1·51, -0·69) Zajicek THC/CBD Multiple Sclerosis 1·60 (-4·51, 7·71) -2·50 (-6·36, NR NR (2012)123 Impact Scale 1·36) (MSIS-29) (Psychological impact) Zajicek THC/CBD Multiple Sclerosis -3·80 (-9·50, 1·90) -5·90 (- NR NR (2012)123 Impact Scale 9·03, -2·77) (MSIS-29) (Physical impact) Global impression Killestein(20 Dronabinol Patient global -266 (-485, -47) NR 0·01 Mixed linear 02)132 impression (scale model unclear, negative indicates

Downloaded From: https://jamanetwork.com/ on 09/29/2021 worsening) THC/CBD Patient global -238 (-467, -9) NR 0·02 Mixed linear impression model Pooyania Nabilone Patient global 0·49 (-0·17, 1·15) NR 0·312 Mann-Whitney/ (2010)126 impression (7 Wilcoxon test point scale) Pooyania Nabilone Clinical global 0·18(-0·51, 0·87) NR 0·789 Mann-Whitney/ (2010)126 impression Wilcoxon test Wade Nabiximols General Health 0·72 (-2·38, 3·82) NR 0·65 NR (2004)129 Questionnaire 12 Zajicek Dronabinol General Health 0·75 (-1·65, 3·15) -0·19 (-1·92, NR NR (2003)131 Questionaire 30 1·54) Zajicek THC/CBD General Health 0·77 (-1·64, 3·18) 0·70 (-1·03, NR NR (2003)131 Questionaire 30 2·43) ANCOVA: analysis of covariance; CBD: cannabidiol; MSIS: multiple sclerosis impact scale; MSSS: multiple sclerosis spasticity scale; MSWS 12: multiple sclerosis walking scale; NR: not reported; NRS: numerical rating scale; PSS: primary symptom score; SF36: short form 36 health survey; THC: tetrahydrocannabinol; VAS: visual analogue scale

eAppendix 7. Depression No included studies; results are from other indications that reported data for this outcome

A. CONTINUOUS OUTCOME MEASURES

Study Details Intervention Outcome MD at follow- MD change p- Analysis Details up from baseline: value*

Depression outcomes reported in chronic pain/MS studies Portenoy Nabiximols Depression NR 1·80 (-0·32, NR NR (2012)67 (1-4 sprays) (MADRS) 3·92) Nabiximols NR 1·90 (-0·22, NR NR (6-10 sprays) 4·02) Nabiximols NR 2·50 (0·38, NR NR (11-14 4·62) sprays) Narang Dronabinol HADS depression NR -4·20 NR NR (2008)73 (10mg) score Dronabinol NR -2·00 NR NR (20mg) Frank (2008)75 Nabilone HADS depression NR -0·2 (1·20, 0·9) NR NR score Rog (2005)80 Nabiximols HADS depression NR 0·15 (-1·0, NR NR score 1·31) Wade Nabiximols Beck Depression NR 0·69 (-0·76, NR NR (2004)129 Inventory 2·14) HADS: hospital anxiety and depression scale; MADRS: Montgomery Asberg depression rating scale; NR: not reported

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Study Country Design N Duration Patient details Intervention Comparator Risk Details 1 of Bias Bergamaschi Brazil Parallel 24 Took place Generalized Social Anxiety Disorder Cannabidiol Placebo  (2011)150 group over public (SAD); ≥ 6 points on self-assessed (single dose speaking short version of the Social Phobia of 600mg) event Inventory named MINISPIN.  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

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Study Details Intervention Outcome MD at follow- MD change p-value Analysis Details up from baseline:

Anxiety Bergamaschi Cannabidiol Visual analogue NR -16·52 0·012 ANCOVA (2011)150 mood scale (VAMS): anxiety factor Anxiety outcomes reported in chronic pain studies Frank (2008)75 Nabilone FIQ anxiety -0·6 (-1·4, 0·3) NR 0·19 NR subscale Narang Dronabinol HADS anxiety NR -2·6 >0·05 NR (2008)73 (10mg) Dronabinol NR 3·7 >0·05 NR (20mg) Rog (2005)80 Nabiximols HADS anxiety NR -0·65 (-1·78, 0·249 NR 0·47) Skrabeck Nabilone HADS anxiety NR -16·52 <0·02 NR (2008)74 ANCOVA: analysis of covariance; FIQ: fibromyalgia impact questionnaire; HADS: hospital anxiety and depression scale; NR: not reported; VAMS: visual analogue mood scale Quantitative data reported based on information available in primary studies

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Study Details Country Design N Duration Patient details Intervention 1 Comparator Risk of Bias Prasad (2011)18 USA Parallel 22 3 Obstructive sleep Dronabinol Placebo  group apnea syndrome (Marinol); max 10mg/day Ware Canada Cross-over 32 2 (2 Chronic pain Nabilone Amitriptyline:  (2010)63,64,89,90 washout) conditions (Cesamet); 10mg/day

(fibromyalgia) 0.5mg/day  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

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Study Details Intervention Outcome Intervention Placebo OR (95% CI) Events/ n Events/n

Zajicek (2012)123 THC/CBD Improvement in sleep quality 48/143 26/134 2·1(1·2, 3·6)

Zajicek (2003)131 THC/CBD Improvement in sleep 82/164 59/163 1·76 (1·13, 2·73)

CBD: cannabidiol; THC: tetrahydrocannabinol

C. CONTINUOUS OUTCOMES RESULTS

Study Details Intervention Outcome MD at follow- MD change p- Analysis up from baseline: value* Details

Sleep Prasad (2011)18 Dronabinol Sleep NR -19·64 0·018 NR Apnoea/hypopnea

(AHI (apnea hypopnea index)) Ware (2010)64 Nabilone Insomnia severity NR -3·25 (- NR Linear index (ISI)() 5·26, -1·24) regression

Ware (2010)64 Nabilone Leeds Sleep NR 0·48 (0·01, NR Linear Evaluation 0·95) regression

Questionnaire (LSEQ)(Restfulness of sleep (100 mm VAS)) Ware (2010)64 Nabilone Leeds Sleep NR -0·70 (-1·36, NR Linear Evaluation 0·03) regression

Questionnaire (LSEQ)(Speed of getting to sleep (100 mm VAS)) Ware (2010)64 Nabilone Leeds Sleep NR -0·70(-1·40, NR Linear Evaluation 0·02) regression

Questionnaire (LSEQ)(Ease of getting to sleep (100 mm VAS)) Sleep outcomes in studies that enrolled patienst with MS or Chronic Pain Corey-Bloom THC Fatigue (mFIS NR -1·8 (-8·29, NR Paired (2012)124 score (0-84)) 3·56) t-test

Collin (2010)125 Nabiximols Fatigue(NRS) NR 0·35 0·185 ANCOVA

Langford Nabiximols Fatigue(NRS) NR 0·32 0·176 NR

Downloaded From: https://jamanetwork.com/ on 09/29/2021 (2013)65 Wade (2004)129 Nabiximols Feeling upon -1·36 (-8·80, NR 0·717 ANCOVA waking(VAS scale: 6·07)

Feeling upon waking) Ware (2010)68 THC (2·5%) Leeds Sleep -2·80(-3·76, - NR NR NR Evaluation 1·84)

THC (6%) Questionnaire 0·80(-0·27, NR NR (LSEQ)(Feeling 1·87) THC (9·4%) now (tired - alert). -0·10(-1·06, NR NR 0·86) Rog (2005)80 Nabiximols Numerical rating NR -1·39(- 0·003 ANCOVA scale(0-10) 2·27, -0·5) Collin (2010)125 Nabiximols Numerical rating NR -0·07(-0·55, 0·734 ANCOVA scale(0-10) 0·40) Serpell (2014)88 Nabiximols Numerical rating NR -0·83(- 0·007 ANCOVA scale(0-10) 1·43, -0·23) GW Pharma Ltd Nabiximols Sleep NR 0·052 ANCOVA (2012)23 disturbance(Sleep -0·34(-0·68, disturbance score 0·00) (QoL)) Nurmikko Nabiximols Sleep NR -0·43(- 0·001 ANCOVA (2007)76 disturbance(NRS) 0·67, -0·19) Berman (2007)87 Nabiximols Sleep NR -0·03 (-0·27, NR disturbance(NRS) 0·21) Vaney (2004)130 THC/CBD Sleep NR 1·69(0·63, 0·308 Linear disturbance("Waki 4·59) regression ng up again") Berman (2004)81 Nabiximols (Sativex) Sleep NR -0·20(- 0·017 ANCOVA disturbance(4- 0·37, -0·04)

THC point-scale) NR -0·30(- 0·017 0·37, -0·04) Portenoy Nabiximols (1-4 Sleep NR -2·5 0·003 NR (2012)67 sprays) disturbance(Sleep disruption NRS) Nabiximols (6-10 NR -0·10 0·260 sprays) Nabiximols(11-16 NR 0·10 0·784 sprays) Wade (2004)129 Nabiximols Sleep quality(VAS -7·1(-14·1, - NR 0·047 ANCOVA scale: Quality of 0·08) sleep) Blake (2006)79 Nabiximols Sleep quality(NRS NR -1·17 (-2·20, - 0·027 Linear (0-10)) 0·14) regression GW Pharma Ltd Nabiximols Sleep quality(NRS NR -0·45(-1·04, 0·139 ANCOVA (2005)22 (0-10)) 0·15) Johnson THC Sleep quality(NRS NR 0·02(-0·64, 0·95 ANCOVA (2010)69 (0-10)) 0·68) Nabiximols (Sativex) -0·31(-0·97, 0·346 0·34)

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Vaney (2004)130 THC/CBD Sleep NR 2·13(0·95, 0·073 Linear quality("Falling 4·74) regression

asleep fast") Berman (2004)81 Nabiximols (Sativex) Sleep NR 0·60(0·09, 0·019 ANCOVA quality(Sleep 1·01) THC Quality BS-11) 0·70(0·33, <0·001 1·24) Langford Nabiximols (Sativex) Sleep quality(NRS NR 0·05 0·833 NR (2013)65 (0-10)) Zajicek (2012)123 THC/CBD Sleep quality(11 -0·5(-1·20, NR NR NR point category 0·20) rating scale) Wade (2004)129 Nabiximols (Sativex) Sleep -4·53 (-11·45, NR 0·198 ANCOVA quantity(VAS 2·40) scale: How much sleep) Frank (2008)75 Nabilone (Cesamet) Sleep 0·20(-0·10, 0·5) NR 0·2 ANCOVA quantity(number of hours slept per night) AHI: apnea hypopnea index; ANCOVA: analysis of covariance; ISI: insomnia severity index; LSEQ: Leeds sleep evaluation questionnaire; MFIS: modified fatigue impact scale; NR: not reported; NRS: numerical rating scale; VAS: visual analogue scale Quantitative data reported based on information available in primary studies

Downloaded From: https://jamanetwork.com/ on 09/29/2021 e Appendix 10. Psychosis A. STUDY CHARACTERISTICS

Study Country RCT N Duration Patient details Intervention Comparator Risk Details Design 1 of Bias Leweke Germany Parallel 42 4 DSM-IV criteria of acute paranoid CBD (max Amisulpride  (2012)151- group 800mg/day) (max schizophrenia or schizophreniform 156 800mg/day) psychosis; ≥36 in the BPRS total score and Rohleder Germany Cross- 29 2 (each DSM-IV criteria of acute paranoid CBD (max Placebo  (2012)21,155- over period, 600mg/day) schizophrenia or schizophreniform 158 washout psychosis; ≥36 in the BPRS total score NR) and CBD: cannabidiol; DSM: diagnostic and statistical manual of mental disorders; RCT: randomised controlled trial; THC: tetrahydrocannabinol  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

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Study Details Intervention Outcome MD at follow- MD change p- Analysis Details up from baseline: value*

Psychological measurements Leweke Cannabidiol Mental health NR -0·10(-9·20, 0·977 NR (2008)151 (Brief Psychiatric 8·90) Rating Scale) Mood (PANSS NR 1(-12·60, 0·884 NR (positive and 14·60) negative syndrome scale)) Rohleder Cannabidiol Mood (PANSS NR 2·40 (-3·48, NR NR (2012)155 (positive and 8·28) negative syndrome scale)) PANSS: positive and negative syndrome scale; NR: not reported

Downloaded From: https://jamanetwork.com/ on 09/29/2021 eAppendix 11. Glaucoma A. STUDY CHARACTERISTICS

Study Country RCT N Duration Patient details Intervention Intervention Intervention Comparator Risk Details Design 1 2 3 of Bias Tomida UK Cross- 6 12 hours Ocular hypertension THC CBD CBD Placebo ? (2006) over or early open angle oromucosal oromucosal oromucosal glaucoma, with mild spray (5mg) spray (20 spray (40

visual defect in at mg) mg) least one eye CBD: cannabidiol; RCT: randomised controlled trial; THC: tetrahydrocannabinol  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

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Study Details Intervention Outcome MD at follow- MD change p- Analysis Details up from baseline: value*

Intraocular pressure Tomida THC (5mg) Intraocular -0·58 (-5·39, NR NR NR (2006)159 pressure (Average 4·23) Cannabidiol of both eyes per 0·12 (-5·09, NR NR (20 mg) patient) 5·33) Cannabidiol -0·25 (-5·23, NR NR (40 mg) 4·73) THC: tetrahydrocannabinol; NR: not reported Quantitative data reported based on information available in primary studies

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Study Country Desig N Duratio Patient Interventio Interventio Interventio Interventio Comparat Ris Details n n details n 1 n 2 n 3 n 4 or k of Bia s Müller- German Parall 2 6 Tourette THC Placebo  Vahl y el 4 s capsules (2003)160,1 group syndrom (max dose 61 e DSM- 10mg) III R criteria

Müller- German Cross- 1 2 days Tourette THC Placebo ? Vahl y over 2 s capsules (2001)162,1 syndrom (max dose 63 e DSM- 10mg) III R criteria

DSM: diagnostic and statistical manual of mental disorders; THC: tetrahydrocannabinol  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

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Study Details Intervention Outcome MD at follow- MD change p-value Analysis Details up from baseline:

Tic severity Müller-Vahl THC capsule Shapiro Tourette NR -0·70 0·033 Mann-Whitney/ (2003)160,161 Syndrome Wilcoxon test Severity Scale (STSSS) Müller-Vahl THC capsule Tourette NR -16·2 <0·05 Mann-Whitney/ (2003)160,161 syndrome Wilcoxon test symptom list (tic rating) TSSL Müller-Vahl THC capsule Yale Global Tic NR -12·03 0·061 Mann-Whitney/ (2003)160,161 Severity Scale Wilcoxon test (YGTSS) Müller-Vahl THC capsule Tourettes NR -0·57 0·008 Mann-Whitney/ (2003)160,161 syndrome clinical Wilcoxon test global impression scale (TS-CGI) Müller-Vahl, THC capsule Tourette's NR -9·08 (- NR NR (2001)162 syndrome 12·87, -5·29) symptoms list (TSSL) - Global score Müller-Vahl THC capsule Shapiro Tourette's NR -0·67 (- NR NR (2001)162 syndrome severity 1·04, -0·30) scale Müller-Vahl THC capsule Tourette's NR -6·50 (- NR NR (2001)162 syndrome global 10·76, -2·24) scale (TSGS) Müller-Vahl THC capsule Yale global tic NR -6·50 (- NR NR (2001)162 severtiy scale 11·66, -1·34) (YGTSS)- perfome d by an examiner

Obsessive compulsive behaviour Müller-Vahl THC capsule Obsessive 4·40 (-4·49, NR NR NR (2001)162 compulsive 13·29) behaviours (OCB), (SCL-90-R checklist) SCL-90-R: symptom checklist 90 revised; STSSS: Shapiro tourette syndrome severity scale; THC: tetrahydrocannabinol; TS-CGI: tourettes syndrome clinical global impression scale; NR: not reported; TSGS: tourette's syndrome global scale; TSSL: tourette syndrome symptom list; YGTSS: Yale global tic severity scale Quantitative data reported based on information available in primary studies

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Study Details RISK OF BIAS Random Allocation Participant/ Outcome Incomplete Selective Overall sequence concealment Personnel assessor outcome outcome generation blinding blinding data reporting a. Nausea and vomiting due to chemotherapy Ahmedzai(1983)45 ? ?  ?    Broder(1982)15 ? ? ? ? ? ? ? Chan(1987)28 ? ?  ?    Dalzell(1986)30 ? ?  ?    Duran(2010)24  ?  ?    Einhorn(1981)40 ? ?  ?    Frytak (1979)44    ?    George(1983)35  ?  ?   ? Heim(1984)33 ? ?  ?    Herman (1979)57 ? ?      Hutcheon(1983)34 ? ?  ?   ? Johansson(1982)38 ? ? ? ?    Jones(1982)36 ? ? ? ?    Lane(1991)26 ? ?  ?    Levitt(1982)51 ? ? ? ?  ?  Long(1982)16 ? ? ? ?    McCabe (1988)27,56 ? ?      Meiri(2007)25 ? ?  ?    Melhem-  ?  ?   ? Bertrandt(2014)58 Niederle(1986)31 ? ? ? ?    Niiranen(1985)32 ? ?  ?    Orr(1980)39,41 ? ?  ?    Pomeroy(1986)29 ? ?  ?    Sallan(1980)43 ? ?  ?    Sheidler(1984)47 ? ?      Steele(1980)42 ? ? ? ?    Ungerleider(1982)46  ? ? ?   ? Wada(1982)37 ? ?  ?    b. HIV/AIDS Abrams(2003)59   /?* /?*    Beal (1995)62 ? ? ? ? /$   Struwe(1993)61 ? ? ? ?    Timpone(1997)60 ? ?      c. Chronic pain Abrams(2007)77  ?  ?    Berman(2007)87 ? ?  ?    Berman(2004)81    ?    Blake(2006)79  ? ? ? ?  ? Ellis(2009)71 ? ? ? ?    Frank(2008)75 ? ?  ?    GW Pharma Ltd(2005)22 ? ? ? ?    GW Pharma ? ? ?     NCT01606176(2012)23

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Johnson(2010)69 ? ? ? ?    Karst(2003)83        Langford(2013)65  ?     ? Lynch(2014)85        Narang(2008)73  ?  ?    Noyes(1975)84 ? ? ? ?   ? Nurmikko(2007)76    ?    Pinsger(2006)78 ? ? ? ?   ? Portenoy(2012)67  ? ? ?   ? Rog(2005)80  ?     ? Selvarajah(2010)70 ? ? ? ?   ? Serpell(2014)88  ?     ? Skrabek(2008)74 ? ?      Svendsen(2004)82  ?     ? Turcotte (2015)121        Wallace(2015){#24577}86    ?    Ware(2010)68 ? ? ? ?    Ware(2010)64        Wilsey(2013)66        Wilsey(2011)72        d. Spasticity in patients with MS and paraplegia Berman(2007)87 ? ?  ?    Collin(2007)127 ? ?  ?   ? Collin(2010)125  ?     ? Corey-Bloom(2012)124 ? ? ? ?    Hagenbach(2003)17 ? ? ? ? ? ? ? Killestein(2002)132 ? ?      Langford(2013)65  ?     ? Leocani (2014)148 ? ? ? ?    Pooyania(2010)126  ?  ?   ? Van Amerongen ? ? ? ? ?   (2014)149 Vaney(2004)130        Wade(2004)129  ?      Zajicek(2003)131        Zajicek(2012)123        e. Depression f. Anxiety disorder Bergamaschi(2011)150    ?    g. Sleep disorder Prasad(2011)18 ? ? ? ?    Ware(2010)64        h. Psychosis Leweke (2012)151  ? ? ?    Rohleder(2012)155 ? ? ? ?    i. Glaucoma Tomida(2006)159 ? ? ? ?   ? j. Tourette Syndrome Müller-Vahl(2003)160 ? ?      Müller-Vahl (2001)162 ? ?     

Downloaded From: https://jamanetwork.com/ on 09/29/2021 *This study was judged at high risk of bias for blinding for the marijuana cigarette group and unclear for the dronabinol group $This study was judged at high risk of bias for outcomes that were analysed on a per-protocol basis and low risk of bias for outcomes analysed on an ITT  = low risk of bias;  = high risk of bias; ? = unclear risk of bias

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