Table 1.
Methods and results of studies of CBD and THC in the treatment of Schizophrenia.
| References | Participants | Design | Substance use criteria | Primary outcome measures | Findings | Symptom scores |
|---|---|---|---|---|---|---|
| Studies of THC | ||||||
| D'Souza et al. (55) | 13 medicated outpatients with SCZ or SCZAF (DSM-IV), mean age 44.46 ± 10.4, 76.9% male. 22 HC, mean age = 29 ± 11.6, 63.6% male | RCT double blind, repeated-measures (at least 1 week apart), within-subject cross-over design of single dose intravenous Δ-9-THC 2.5 mg, 5 mg, or PLB | Excluded Lifetime CUD or recent substance abuse (3 m) or dependence (1 yr), other than nicotine. Abstain from all substances, verified via self-report and urine drug screen | Symptoms: PANSS, CADSS, VAS (high, calm and relaxed, tired, panic)Cognitive: HVLT, Gordon CPT, verbal (letter) fluency testSide effects: BAS, SAS, AIMS | THC worsened: verbal learning and recall; positive symptoms; more prominently for patient group; negative symptoms; clinician- and self-related perceptual alterations THC resulted in a trend toward increased VAS ratings of “panic” and “tired” and rigidity, worse AIMS score and akathisia, and increased plasma prolactin and cortisol | PANSS Total, screening: 34.1 ± 9.4Post THC scores not provided |
| Fischer et al. (56) | 12 medicated outpatients with SCZ and CUD (DSM-IV-TR), mean age [smoked cannabis 36.2 ± 9.6; THC capsule 32.17 ± 8.32, male), 583% male 12 HC, mean age 33.5 ± 7.8, 75% male | RCT double blind, parallel group study of smoked 3.6% THC cannabis cigarette immediately prior to scan (n = 6), or 15 mg THC capsule 3 h prior to scan (n = 6)Two scan sessions (T1, no drug; T2, drug) at least 1 week apart | Required to have a CUD and recent cannabis use. Excluded other substance use disorders. Abstain from all substances, except nicotine and caffeine >7 days prior to scan verified via TLFB, urine screens, plasma THC | Symptoms: PANSS, VAS (high, liking and craving), CWS, MCQImaging: fMRI resting state functional connectivity of BRC | Reduced connectivity at BL in patients between nucleus accumbens and prefrontal cortical BRC regions (i.e., anterior prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex). Both oral and smoked THC incr connectivity between these regions, which correlated with incr in plasma THC levels | No change after THC (PANSS scores not reported) |
| Whitfield-Gabrieli et al. (57) | Same as Fischer et al. (56) | Same as Fischer et al. (56) | Same as Fischer et al. (56) | Symptoms: PANSS, VAS (high, liking and craving), CWS, MCQCognition: LNSImaging: fMRI resting state functional connectivity of DMN | At BL, patients had DMN hyperconnectivity that correlated with positive symptoms, and reduced anticorrelation between DMN and ECN. THC reduced DMN hyperconnectivity and increased DMN-ECN anticorrelation. The magnitude of anticorrelation in controls, and in patients after THC, correlated with working memory) | PANSS Positive ScoreBL—T1 (13.82 ± 3.19) orPre-drug—T2 (12.91 ± 3.21)No change after THC (PANSS scores not provided separately from smoked cannabis and oral THC and not reported for T2 after THC) |
| Studies of CBD | ||||||
| Zuardi et al. (35) | 3 unmedicated inpatients with treatment-resistant SCZ (DSM-IV), age 21–22 years, all male | Case Series of 6 week CBD titration up to 1,280 mg/day, PLB lead in and washout, then switch to olanzapine | None reported | Symptoms: BPRS, PANSS-NFunctional: CGISide effects: BAS, SAS, UKU Side effect Rating Scale | CBD 1,280 mg/day associated with: Pt 1—trend toward improved BPRS (general, positive, and negative symptoms); Pt 2—no benefit; Pt 3—“very minimal improvement” of positive and negative symptoms In two patients, symptoms worsened after CBD discontinued. No side effects reported | BPRS Total:Patient 1: PLB 19, CBD 10Patient 2; PLB 30, CBD 28Patients 3: PLB 29, CBD 26PANSS-N scores not reported |
| Hallak et al. (58) | 28 outpatients with SCZ (DSM-IV), all BPRS scale scores <2, at least 18 years of age, 64.3% male | Single dose non-randomized, double blind, parallel group study of CBD augmentation 300 mg (n = 9) or 600 mg (n = 9) or PLB (n = 9) | History of substance abuse or adverse reaction to marijuana were excluded | Symptoms: BPRS, PANSSCognition: SCWTOther: electrodermal responsiveness | PLB and 300 mg CBD: less SCWT interference errors during 2nd session, but only a trend for 600 mg CBD group, indicating worse selective attention No group differences in electrodermal responsiveness or symptoms, but no analysis of within-group symptom change reported | BPRS Total:PLB: BL 8.6 ± 4.1, drug 7.9 ± 5.76CBD 300 mg: BL 11.3 ± 7, drug 10.9 ± 6;CBD 600 mg: BL 8.9 ± 5.1, drug 8.2 ± 5.9PANSS Total:PLB: BL 21.9 ± 6.9, drug 21.9 ± 7.2;CBD 300 mg: BL 23.6 ± 9.4, drug 23.4 ± 9.6CBD 600 mg: BL 20.2 ± 7.7, drug 19.1 ± 7.0 |
| Leweke et al. (59) | 42 acutely ill unmedicated inpatients with SCZ (DSM-IV), BPRS Total ≥ 36 and BPRS THOT ≥ 12, 18–50 years of age [CBD mean 29.7 ± 8.3 yr, amisulpride mean 30.6 ± 9.4 yr, 82.1% male | 4 week RCT, double blind, parallel group study of CBD augmentation 800 mg (n = 20) or amisulpride 800 mg (n = 19), 1 week titration and 3 weeks treatment (modified intent-to-treat) | History of SUD or positive urine drug screen (including cannabinoids) were excluded | Symptoms: BPRS, PANSSFunctional: CGISide effects: SAS, EPS | BPRS and PANSS (total, positive, negative, general scores) improved over time in both groups. CBD group had less: extrapyramidal symptoms, weight gain, and prolactin elevation Serum anandamide levels were higher in CBD than amisulpride group, with extent of increase associated with PANSS Total score improvement | PANSS Total ScoresCBD score at BL 91.2 (14.0)Changed-−18.8 (10.7) on day 14, −30.5 (16.4) on day 28Amisulpride score at BL 95.9 (17.1)Changed-−18.8 (19.9) on day 14−30.1 (24.7) day 28 |
| Leweke et al. (60) | Same participants as above 42 acutely ill unmedicated inpatients with SCZ (DSM-IV), BPRS Total ≥ 36 and BPRS THOT ≥ 12, 18–50 years of age [CBD mean 29.7 ± 8.3 yr, amisulpride mean 30.6 ± 9.4 yr, 82.1% Male | Same as above4 week RCT, double blind, parallel group study of CBD augmentation 800 mg (n = 20) or amisulpride 800 mg (n = 19), 1 week titration and 3 weeks treatment (modified intent-to-treat) | Same as above History of SUD or positive urine drug screen (including cannabinoids) | Symptoms: BPRS, PANSSFunctional: CGICognition: Visual Backward Masking Task, CPT, LNS, SOPT, DRT, AVLT, RCFT, Digit Symbol, TMT, Verbal Fluency Task | From pre- to post-treatment, both groups improved in visual memory, processing speed CBD improved sustained attention and visuomotor coordination Amisulpride improved working memory performance Changes in neurocognitive performance were not systematically associated with symptom improvements nor change in serum anandamide | Differences in cognitive improvement not statistically significant after correction for multiple testsVisual memory (CBD: 0.49, p = 0.015 vs. AMI: 0.63, p = 0.018); processing speed (CBD: 0.41, p = 0.004 vs. AMI: 0.57, p = 0.023). Sustained attention (CBD: 0.47, p = 0.013 vs. AMI: 0.52, p = 0.085); visuomotor coordination (CBD: 0.32, p = 0.010 vs. AMI: 0.63, p = 0.088). SOPT–AMI: 0.53, p = 0.043 vs. CBD: 0.03, p = 0.932 and LNS–AMI: 0.67, p = 0.017 vs. CBD: 0.08 p = 0.755) |
| Boggs et al. (61) | 36 medicated outpatients with SCZ (DSM-IV-TR), 18–65 years of age [CBD mean 48.4 ± 9.3; PLB mean 46.4 ± 9.5], 66.7% to 72.2% male | 6 week RCT, double blind, parallel group study of CBD augmentation 300 mg twice daily (n = 20) or PLB (n = 19) | Diagnosis of substance abuse within 3 months or dependence within 6 months of participation (other than nicotine) were excluded | Symptoms: PANSSCognition: MCCBSide effects: BAS, SAS, AIMS, UKU Side Effect Rating Scale | No difference in reduction in PANSS scores (Total, General, Positive, Negative) over time. PLB but not CBD group had small improvement on MCCB (Composite score, Reasoning and Problem Solving domain scores). CBD group had greater sedation compared to PLB | PANSS screening visit scores:Total: CBD 76.6 ± 17, PLB 82.7 ± 8.8Positive: CBD 18.8 ± 4.7, PLB 20.6 ± 3.8Negative: 20.7 ± 4.6, PLB 20.9 ± 4.7General: 37.1 ± 10.3, PLB 41.2 ± 5.6 |
| McGuire et al. (62) | 88 medicated outpatients with SCZ or related psychotic disorder (DSM-IV), PANSS score <60 at screening excluded, 18–65 years of age (mean 40.8 ± 11.69), 58% male | 6 week RCT, double blind, parallel group study of CBD augmentation 500 mg BID (n = 43) or PLB (n = 45) | Alcohol or substance use history allowed; use of alcohol, cannabis or other substances not prohibited during study; positive baseline urine THC test in 1 CBD and 2 PLB group patients | Symptoms: PANSS, SANSFunctional: GAF, CGI-I, CGI-SCognition: BACSSide effects: SAS | CBD group had greater reduction of positive symptoms and more likely to be rated by treating clinician as having improved and have less severe illness than PCB. CBD showed trend for greater improvement in overall level of functioning, cognition (BACS composite score and executive function domain), and motor speed. No group difference for adverse events or side effects | PANSS Total:CBD: BL 79.3 ± 12.5, end of Tx 68.1 ± 14.8PLB: BL 80.6 ± 14.9, end of Tx 71.9 ± 15.5PANSS Positive:CBD: BL 18.0 ± 3.9, end of Tx 14.8 ± 4.0; PLB: BL 17.5 ± 3.3, end of Tx 15.7 ± 3.7 |
| O'Neill et al. (63) | 15 outpatients (14 medicated) with SZ, SCZAF, or Brief Psychotic Disorder (DSM-IV) within 5 years of diagnosis, mean age 27.73 ± 4.61 years, 66.7% male 19 HC, mean age 23.89 ± 4.15 years, 57.9% male | RCT double blind, repeated-measures (1 week apart), within-subject cross-over design of single dose 600 mg oral CBD or PLB | Allowed: current cannabis abuse, dependence, or use Excluded: Current alcohol or substance dependence; or intoxicated or positive urine drug screen on the day of scanning. No alcohol for 24 h or caffeine for 12 h before sessions. No drugs except cannabis for 2 weeks prior to scan | Symptoms: PANNS, STAI-SImaging: fMRI verbal paired associate learning task completed 3 h after CBD or PLB (13 patients completed both scans) | CBD associated with trend toward reduced median PANSS Total. Compared to HC, patients on PLB had abnormal activation within prefrontal region during verbal encoding, and abnormal prefrontal and mediotemporal activation as well as greater hippocampal-striatal functional connectivity during recall. CBD resulted in partial normalization of activation in these regions, as well as reducing hippocampal-striatal hyperconnectivity | PANSS Total:PLB: T1 48.8 ± 18.9, T3 44.6 ± 18.07CBD: T1 51 ± 20, T3 41.53 ± 11PANSS Positive:PLB: T1 12.53 ± 5.62, T3 11.67 ± 4.99CBD: T1 12.93 ± 5.72, T3 10.73 ± 3.41PANSS Negative:PLB: T1 12.4 ± 6.4, T3 11.53 ± 6.06CBD: T1 12.47 ± 6.56, T3 10.2 ± 3.05Note: T1 is 60 min pre-drug and T3 270 min post-drug administration |
| O'Neill et al. (64) | Same participants as above 15 outpatients (14 medicated, 1 non-compliant) with SZ, SCZAF, or Brief Psychotic Disorder (DSM-IV) within 5 years of diagnosis, Mean age 27.73 (4.61, 66.7% male) | Same as aboveDouble-blind, randomized, placebo-controlled, repeated-measures (1 week apart) within-subject cross-over design 600 mg oral CBD or PLB | Same as above Allowed: current cannabis abuse, dependence or use | Symptoms: PANSSImaging: 1H-MRS spectra were acquired 180 min after CBD or PLB administration (13 patients completed both scans) | CBD associated with greater improvement in PANSS Total and greater hippocampal glutamate levels compared to PLB (p = 0.035). An adjusted multivariable model showed an inverse predictive relationships between hippocampal glutamate and post intervention PANSS (p = 0.047), but no relationship to CBD group | PANSS symptom scoresSame as above |
AIMS, Abnormal Involuntary Movements Scale; AMI, amisulpride; AVLT, Auditory-Verbal Learning Test; BACS, Brief Assessment of Cognition in Schizophrenia; BAS, Barnes Akathisia Scale; BPRS, Brief Psychiatric Rating Scale; BPRS THOT, BPRSD Thought Disorder factor; BRC, Brain Reward Circuit; CADSS, Clinician-Administered Dissociative States Scale; CWS, Cannabis Withdrawal Scale; CBD, cannabidiol; CGI, Clinical Global Impressions Scale; CGI-I, Clinical Global Impression-Improvement scale; CGI-S, Clinical Global Impression-Severity scale; CPT, Continuous Performance Test; CUD, cannabis use disorder; DMN, Default Mode Network; ECN, Executive Control Network; EPS, Extrapyramidal Symptom Scale; fMRI, Functional magnetic resonance imaging; GAF, Global Assessment of Functioning; HC, Healthy comparison subjects; LNS, Letter-Number Sequencing test from the Wechsler Adult Intelligence Scale-Third edition; MCCB, MATRICS Consensus Cognitive Battery; MCQ, Marijuana Craving Questionnaire; PANSS, Positive and Negative Syndrome Scale; PLB, placebo; RCT, Randomized Control Trial; RCFT, Rey-Osterrieth Complex Figure Test; SANS, Scale for the Assessment of Negative Symptoms; SAS, Simpson Angus Scale; SCZ, Schizophrenia; SCZAF, schizoaffective disorder; SCWT, Stroop Color Word Test; SOPT, Self-Ordered Pointing Task; STAI-S, State Trait Anxiety Inventory state subscale; SUD, substance use disorder; THC, Tetrahydrocannabinol; TLFB, Timeline Follow-Back; TMT, Trail Making Test.