Results
The PRISMA flow chart visualizing the literature selection process is depicted in
[Fig. 1]. The search strategy resulted in
a total of 150 publications, of which 54 were included in this review (see [Table 1]
[2]
[3]
[4]). In some cases, several articles were
published reporting different aspects of the results of the same study; thus, the
publications included are based on 40 separate study populations. Of the 54
publications, 16 studies focused exclusively on the effects of CBD in healthy
subjects. Thirty-eight studies investigated CBD as a treatment option in people with
a psychiatric condition in the form of a case study (5), case series (2), open-label
clinical trial (2), or RCT (29).
Fig. 1 Adapted Preferred Reporting Items for Systematic Reviews and
Meta-Analysis (PRISMA) flowchart [19]
illustrating the literature selection process.
Table 1 Clinical investigations on CBD for the treatment of
schizophrenia and psychosis.
Reference
|
Study Design
|
Participants
|
Treatment
|
Scales, questionnaires, paradigms
|
Outcomes
|
Psychosis
|
Zuardi et al., 1995
[25]
|
Case study
|
1 individual with SCZ
|
Up to 1500 mg CBD per day over 26 days
|
BPRS, IOSPI
|
Improvement in psychotic symptoms.
|
Zuardi, 2006
[26]
|
Case series
|
3 individuals with TRS
|
Day 1–5: placebo; day 6–35: CBD (starting at 40
mg/day, titrated up to 1280 mg/day); day
36–40: placebo, followed by a minimum of 15 days of
treatment with olanzapine
|
BPRS
|
Only mild symptom improvement in one patient.
|
Zuardi et al., 2009
[27]
|
Open-label clinical trial
|
6 Parkinson’s patients with psychosis for a minimum of 3
months
|
150–400 mg/day CBD (dose increased over 4-week
treatment period)
|
BPRS, PPQ, UPDRS, MMSE, FAB, CGI-I
|
Significant decrease of psychotic symptoms in Parkinson’s
patients under CBD administration.
|
Makiol and Kluge, 2019
[28]
|
Case study
|
1 patient with TRS
|
Up to 1500 mg/day CBD as an add-on to clozapine and
lamotrigine for 8 months
|
PANSS
|
Significant improvement in psychotic symptoms after 2.5 weeks of
treatment and after 8 months of ongoing treatment.
|
*Leweke et al., 2012
[10]
|
RCT, parallel-arm design
|
39 acutely psychotic patients
|
800 mg/day CBD (stepwise increase starting at 200
mg/day) or amisulpride for 28 consecutive days
|
PANSS, BPRS, SAS, EPS
|
Both interventions led to significant clinical improvement; CBD
presented with a clear superior side-effect profile.
|
*Leweke et al., 2021
[29]
|
RCT, parallel-arm design
|
39 acutely psychotic patients
|
800 mg/day CBD (stepwise increase starting at 200
mg/day) or amisulpride for 28 consecutive days
|
VBM, CPT, LNS, SOPT, DRT, AVLT, ROFT, DSC, TMT, VF
|
Both interventions improved neurocognitive functioning. CBD and
amisulpride both improved visual memory performance and
processing speed. CBD additionally improved sustained attention
and visuomotor coordination. Amisulpride enhanced working memory
performance.
|
McGuire et al., 2018
[30]
|
RCT, parallel-arm design
|
88 SCZ patients treated with standard antipsychotics
|
1000 mg CBD per day or placebo for 6 weeks
|
PANSS, BACS, GAF, SANS, CGI-I
|
CBD administration led to significant clinical improvements
without increased occurrence of adverse events compared to
placebo.
|
Boggs et al., 2018
[31]
|
RCT, parallel-arm design
|
36 chronic SCZ patients with stable antipsychotic medication
|
600 mg CBD or placebo for 6 weeks
|
MCCB, PANSS, several safety assessments for motor side
effects
|
No improvement in MCCB or PANSS scores in patients treated with
CBD compared to placebo.
|
van Boxel et al., 2023
[32]
|
RCT, parallel-arm design
|
31 stable recent-onset (<5 years) psychosis patients
|
600 mg/day CBD or placebo for 28 days
|
PANSS, HAM-D, YMRS, CGI, GAF, SOFAS, BACS, resting state and
reward fMRI, monetary incentive delay task
|
In the CBD group, decreased positive symptom severity was
correlated with diminishing glutamate and N-acetyl-aspartate
levels; compared to placebo, CBD treatment affected default mode
network functional connectivity.
|
O’Neill et al., 2021
[49]
|
RCT, cross-over design
|
15 psychosis patients, 19 healthy controls
|
600 mg CBD or placebo, single dose
|
PANSS, STAI, and fMRI during the verbal paired associate learning
task
|
Patients showed significantly different neural activation
compared to healthy controls in a verbal recall task; CBD
improved activation patterns but failed to reach the results of
the healthy controls.
|
Clinically high risk (CHR) for psychosis
|
Koethe et al., 2023
[36]
|
Case study
|
1 antipsychotic-naïve man with CHR
|
600 mg CBD per day for 4 weeks
|
PANSS, SPI-A, SIPS, neuropsychological tests, cerebral glucose
metabolism
|
Significant clinical improvement, improved cognitive performance,
and increased cerebral glucose metabolism after 4 weeks of
treatment.
|
*Appiah-Kusi et al., 2020
[38]
|
RCT, parallel-arm design
|
32 CHR patients
|
600 mg CBD or placebo for 1 week
|
TSST, STAI, SSDPS, serum cortisol levels
|
Patients showed significantly different cortisol reactivity
compared to healthy controls; CBD administration in patients
showed some improvements in anxiety and public speaking stress
compared to placebo but did not significantly improve cortisol
reactivity.
|
*Davies et al., 2022
[39]
|
RCT, parallel-arm design
|
33 CHR patients and 19 healthy controls
|
600 mg/day CBD or placebo for 1 week
|
CAARMS, STAI, fMRI during fearful-faces task, TSST
|
Healthy controls showed a significant negative relationship
between cortisol levels and parahippocampal activation, which
was significantly altered in CHR patients; oral CBD failed to
restore this relationship in CHR patients.
|
*Bhattacharyya et al., 2018
[37]
|
RCT, parallel-arm design
|
33 antipsychotic-naïve CHR patients, 19 healthy
controls
|
600 mg CBD or placebo, single dose
|
fMRI during the verbal paired associate learning task
|
Significantly decreased neural activation in three brain regions
associated with psychosis state in patients compared to healthy
controls; CBD increased neural activation in all three brain
regions but did not reach the same activation as healthy
controls.
|
*Wilson, 2019
[47]
|
RCT, parallel-arm design
|
33 antipsychotic-naïve CHR patients, 19 healthy
controls
|
600 mg CBD or placebo, single dose
|
fMRI during reward processing tasks, CAARMS
|
Patients showed an abnormal activation in the left insula
/ parietal oculum compared to healthy controls, which
was reduced by oral CBD administration.
|
*Davies et al., 2020
[48]
|
RCT, parallel-arm design
|
33 antipsychotic-naïve CHR patients, 19 healthy
controls
|
600 mg CBD or placebo, single dose
|
fMRI during a fearful face-processing task, CAARMS, STAI
|
Patients showed significantly different neural activation
compared to healthy controls; CBD improved activation patterns
in patients but failed to match the results of healthy
controls.
|
Healthy volunteers (EEG/MEG, MRI/fMRI, and
PET/SPECT studies)
|
*Borgwardt et al., 2008
[43]
|
RCT, repeated measures within-subject design
|
15 healthy individuals
|
600 mg CBD, 10 mg ∆9-THC, or placebo, single
dose
|
VAMS, STAI, AIS, PANSS, physiological measurements, fMRI
activation during Go/No-Go Task
|
∆9-THC led to the deactivation of brain
regions involved in response inhibition; CBD did not affect
those brain regions; ∆9-THC significantly
increased VAMS, AIS, STAI, and PANSS scores compared to placebo;
CBD did not affect corresponding ratings.
|
*Bhattacharyya et al., 2010
[44]
|
RCT, repeated measures within-subject design
|
Experiment 1: 15 healthy individuals with minimal previous
cannabis exposure; Experiment 2: 6 healthy individuals
|
Experiment 1: 600 mg CBD, 10 mg ∆9-THC, or
placebo, single dose; Experiment 2: 5 mg i. v. CBD vs.
placebo immediately before 1.25 mg i. v.
∆9-THC, single dose
|
fMRI measurements during verbal memory, response inhibition, and
sensory processing tasks and when viewing fearful faces;
PANSS
|
Opposite effects of ∆9-THC and CBD on neural
activation patterns; CBD administration prevented
∆9-THC-inducd psychotic symptoms.
|
*Winton-Brown et al., 2011
[45]
|
RCT, cross-over design
|
14 healthy volunteers
|
600 mg CBD, 10 mg ∆9-THC, or placebo, single
dose
|
VAMS, STAI, VAIS, PANSS, and physiological measurements; fMRI
measurements during sensory stimulation paradigm
|
No significant symptomatic effects after CBD administration; CBD
and ∆9-THC differentially modulated brain
functions in areas related to induced psychosis.
|
Grimm et al., 2018
[46]
|
RCT, cross-over design
|
16 healthy individuals
|
600 mg CBD, 10 mg ∆9-THC, or placebo, single
dose
|
EPI, fMRI
|
CBD administration produced significantly increased
fronto-stratial connectivity; ∆9-THC and
placebo showed no effects.
|
If not stated otherwise, the treatment was administered orally. Studies that
refer to the same participants are marked with an asterisk. Abbreviations:
AIS = Analogue Intoxication Scale; AVLT = Auditory Verbal
Learning Task; BACS = Brief Assessment of Cognition in
Schizophrenia; BPRS = Brief Psychiatric Rating Scale; CAARMS
= Comprehensive Assessment of At-Risk Mental States; CGI-I =
Clinical Global Impression Improvement; CHR = clinically high risk
for psychosis; CPT = Continuous Performance Task; DRT =
delayed response task; DSC = Digit Symbol Coding; EEG =
electroencephalography; EPI = echo-planar imaging; EPS =
Extrapyramidal Symptoms Rating Scale; FAB = Frontal Assessment
Battery; fMRI = functional magnetic resonance imaging; GAF =
Global Assessment of Functioning scale; HAM-D = Hamilton Depression
Scale; IOSPI = Interactive Observation Scale for Psychiatric
Inpatients; LNS = Letter Number Sequencing; MCCB = MATRICS
Consensus Cognitive Battery; MEG = magnetoencephalography; MMSE
= Mini-Mental Status Evaluation; PANSS = Positive and
Negative Syndrome Scale; PET = positron emission tomography; PPQ
= Parkinson Psychosis Questionnaire; PSI = Psychotomimetic
Stress Inventory; RCT = randomized controlled trial; ROFT =
Rey-Osterrieth complex Figure Task; SANS = Scale for the Assessment
of Negative Symptoms; SAS = Social Anxiety Scale; SCZ =
schizophrenia; SIPS = Structured Interview for Prodromal Syndromes;
SOFAS = Social and Occupational Functioning Assessment; SOPT
= Subject Ordered Pointing Task; SPECT = single-photon
emission computerized tomography; SPI-A = Schizophrenia Proneness
Instrument – Adult; SSDPS = Self-Statements During Public
Speaking Scale; STAI = State Trail Anxiety Inventory; TLFB =
Timeline Followback; TMT = Trail-Making Task; TRS =
treatment-resistant schizophrenia; TSST = Tier Social Stress Test;
UPDRS = Unified Parkinson’s Disease Rating; VAIS =
Visual Analog Intoxication Scale; VAMS = Visual Analog Mood Scale;
VAS = Visual Analog Scale; VBM = visual backward masking
task; VF = Verbal Fluency; YMRS = Young Mania Rating
Scale.
Table 2 Clinical investigations on CBD for the treatment of
substance use disorder.
Reference
|
Study Design
|
Participants
|
Treatment
|
Scales, questionnaires, paradigms
|
Outcomes
|
Healthy Volunteers
|
Lawn et al., 2020
[54]
|
RCT, repeated measures within-subject design
|
23 healthy individuals
|
600 mg CBD or placebo
|
fMRI measurements during monetary incentive delay task, BDI,
AUDIT, FTND, WTAR
|
CBD administration did not lead to altered reward-related brain
activity compared to placebo.
|
Cannabis Use Disorder
|
Crippa et al., 2013
[55]
|
Case study
|
1 female (19-year-old) cannabis-dependent patient
|
Day 1: 300 mg; day 2–10: 600 mg; day 11: 300 mg CBD
|
WDS, MWSC, BAI, BDI, AIS
|
Cannabis withdrawal symptoms, anxiety, and dissociative quickly
decreased during treatment; relapse of cannabis use at 6-month
follow-up, although at a lower frequency.
|
Shannon et al., 2015
[56]
|
Case study
|
1 male cannabis-dependent patient with bipolar disorder
|
24 mg CBD from oral spray per day, later decreased to 18 mg per
day
|
PSQI, HAM-A
|
With CBD oil administration, the patient stopped cannabis
consumption; positive changes in anxiety and sleep behaviour
were noted.
|
*Freeman et al., 2020
[57]
|
RCT, parallel-arm design
|
77 cannabis-dependent individuals
|
200, 400, or 800 mg/day CBD or placebo for 4 weeks
|
Motivational interviewing, CWS, TLFB, PSQI, BDI, BAI
|
Cannabis abstinence increased by 0.27 days/week with 800
mg/day CBD treatment.
|
*Lees et al., 2023
[58]
|
RCT, parallel-arm design
|
70 cannabis-dependent individuals
|
200, 400, or 800 mg/day CBD or placebo for 4 weeks
|
Motivational interviewing, TLFB, CUD symptoms, prose recall, stop
signal, trail-making, digit-span, and verbal fluency tasks
|
No difference in delayed verbal memory measurements between CBD
and placebo groups; no significant dose-effect for any secondary
outcome.
|
*Hua et al., 2023
[59]
|
RCT, parallel-arm design
|
70 individuals with cannabis use disorder
|
400 or 800 mg/day CBD or placebo for 4 weeks
|
Plasma anandamide, TLFB, CWS, BAI, BDI
|
400 mg/day CBD and placebo groups showed a significant
reduction in plasma anandamide levels, while concentrations in
individuals receiving 800 mg/day CBD did not change over
the 28-day intervention.
|
Cocaine Use Disorder
|
de Meneses-Gaya et al., 2021
[60]
|
RCT, parallel-arm design
|
31 individuals with crack-cocaine dependence
|
300 mg/day CBD or placebo, single dose
|
CCQ-Brief, MCCS, ASSIST, BDI, BAI, VAS, UKU-SERS
|
CBD administration significantly reduced signs of cravings
compared to placebo; no effect on anxiety, depression, or sleep
behaviour.
|
*Mongeau-Pérusse et al., 2021
[61]
|
RCT, parallel-arm design
|
78 individuals with moderate to severe cocaine use disorder
|
800 mg/day CBD or placebo, single dose
|
Drug-cue induced craving, time-to-cocaine relapse, VAS-C, TLFB,
cocaine use, SAFTEE
|
No significant differences in cocaine craving or relapse between
CBD and placebo groups.
|
*Rizkallah et al., 2022
[62]
|
RCT, parallel-arm design
|
78 individuals with moderate to severe cocaine use disorder
|
800 mg/day CBD or placebo, single dose
|
CANTAB: SST, CGT, PRM
|
No significant differences in cognitive outcomes between CBD and
placebo groups.
|
*Mongeau-Pérusse et al., 2022
[63]
|
RCT, parallel-arm design
|
78 individuals with moderate to severe cocaine use disorder
|
800 mg/day CBD or placebo, single dose
|
Cue-induced craving sessions, relapse prevention group sessions,
physiological measurements, VAS-A, BAI
|
No significant differences in anxiety symptoms and cortisol
levels between CBD and placebo groups.
|
Nicotine Dependence
|
Morgan et al., 2013
[64]
|
RCT, parallel-arm design
|
24 healthy cigarette smokers
|
ad libitum CBD or placebo from an inhaler for 1 week
|
SDS, STAI, BDI, BIS, TCQ, MRS, total cigarettes smoked
|
Participants inhaling CBD reduced their cigarette consumption by
approximately 40%, while placebo inhalators showed no
effect; positive effects of CBD inhalation were maintained
throughout the 21-day follow-up appointment.
|
Hindocha et al., 2018
[65]
|
RCT, cross-over design
|
30 non-treatment seeking healthy smokers
|
800 mg CBD or placebo, single dose
|
Pleasantness ratings, MPSS, QSU-B, VAS, FTND, STAI, BDI
|
CBD reversed attentional bias due to tobacco abstinence compared
to satiety; CBD reduced the pleasantness of cigarette images; no
effect on craving and withdrawal outcomes.
|
Heroin Use Disorder
|
Hurd et al., 2019
[66]
|
RCT, parallel-arm design
|
42 drug-abstinent individuals with heroin use disorder
|
400 or 800 mg CBD or placebo for 3 consecutive days
|
HCQ, VAS-A, COWS, VAS-C, PANAS, physiological measurements,
neutral and drug-related cue sessions, cognitive test
sessions
|
Both doses of CBD significantly reduced cue-induced craving and
anxiety compared to placebo; results protracted until the 1-week
follow-up.
|
If not stated otherwise, the treatment was administered orally. Studies that
refer to the same participants are marked with an asterisk. Abbreviations:
AIS = Athens Insomnia Scale; ARCI = Addiction Research
Center Inventory; ASI = Addiction Severity Index; ASI-R =
Anxiety Sensitivity Index – Revised; ASSIST = Alcohol,
Smoking, and Substance Involvement Screening Test; AUDIT = Alcohol
Use Disorders Identification Test; BAI = Beck Anxiety Inventory; BDI
= Beck Depression Inventory; BIS = Behaviour Impulsivity
Scale; BIS-11 = Barrat Impulsiveness Scale; BPI = Brief Pain
Inventory; BPRS = Brief Psychiatric Rating Scale; BSI =
Brief Symptom Inventory; BTOM-SFS = Brief Treatment Outcome
Measure-Social Functioning Scale; CANTAB = Cambridge
Neuropsychological Test Automated Battery; CCQ = Cannabis Craving
Questionnaire; CGT = Cambridge Gambling Task; CPQ = Cannabis
Problems Questionnaire; CUD = Cannabis Use Dependence; CWC =
Cannabis Withdrawal Checklist; CWS = Cannabis Withdrawal Scale; DASS
= Depression, Anxiety, and Stress Scale; DEQ = Drug Effects
Questionnaire; DTS = Distress Tolerance Scale; fMRI =
functional magnetic resonance imaging; FTND = Fagerstrom Test for
Nicotine Dependence; HAM-A = Hamilton Anxiety Rating Scale; ISI
= Insomnia Severity Index; HAM-D = Hamilton Depression
Rating Scale; HCQ = Heroin Craving Questionnaire; HDRS =
Hamilton Depression Rating Scale; MCCS = Minnesota Cocaine Craving
Scale; MCQ = Marijuana Craving Questionnaire; MET/CBT
= Motivational Enhancement Therapy and Cognitive Behavioral Therapy;
MNWS = Minnesota Nicotine Withdrawal Scale; MPSS = Mood and
Physical Symptoms Scale; MRS = Mood Rating Scale; MWC =
Marijuana Withdrawal Checklist; MWSC = Marijuana Withdrawal Symptom
Checklist; PANAS = Positive and Negative Affect Schedule; POMS
= Profiles of Mood States; PRM = Pattern Recognition Memory;
PSQI = Pittsburgh Sleep Quality Index; QCQ = Quitting
Cannabis Questionnaire; QSU-B = Questionnaire of Smoking Urges
– Brief; RCT = randomized controlled trial; SAFTEE =
Systematic Assessment for Treatment Emergent Events; SDS = Severity
of Dependence Scale; SF-36 Pain Factor = Short-Form-36 Pain Factor;
SMHSQ = St. Mary’s Hospital Sleep Questionnaire; SST
= Stop Signal Task; STAI = State Trail Anxiety Inventory;
TCQ = Tiffany Craving Questionnaire; TLFB = Timeline
Followback; TQSU = Tiffany Questionnaire of Smoking Urges; UKU-SERS
= UKU Side Effects Rating Scale; VAS = Visual Analog Scale:
VAS-A = Visual Analog Scale for Anxiety; VAS-C = Visual
Analog Scale for Craving; WDS = Withdrawal Discomfort Score; WTAR
= Wechsler Test for Adult Reading.
Table 3 Clinical investigations on CBD for the treatment of
social anxiety disorder and PTSD.
Reference
|
Study Design
|
Participants
|
Treatment
|
Scales, questionnaires, paradigms
|
Outcomes
|
Healthy Volunteers
|
Spinella et al., 2021
[74]
|
Open-label RCT, crossover-design
|
43 healthy individuals
|
Self-administration of CBD-free hempseed oil or CBD-containing
hempseed oil
|
MAST, CBD belief ratings, NRS for subjective stress, STAI-S-SF,
I-PANAS, B-BAES
|
The expectation of CBD’s effects alone led to subjective
and physiological anxiolytic responses.
|
Zuardi et al., 1982
[75]
|
RCT, cross-over design
|
8 healthy individuals
|
∆9-THC (0.5 mg/kg), CBD (1
mg/kg), a combination thereof, diazepam (10 mg), or
placebo, single dose
|
STAI, ARCI-Ma, pulse, the analogue self-rating scale for
subjective feelings, the self-rating scale of bodily
symptoms
|
CBD addition caused a significant reduction in anxiety, state of
intoxication, and subjective effects of
∆9-THC, while having no effects when
administered alone. The physiological effects of
∆9-THC were not altered by CBD.
|
Zuardi et al., 1993
[76]
|
RCT, parallel-arm design
|
40 healthy individuals
|
300 mg CBD, 5 mg ipsapirone, 10 mg diazepam, or placebo, single
dose
|
VAMS, STAI, BSS, digital-symbol substitution test, simulated
public speaking paradigm
|
CBD significantly reduced anxiety after a public speaking test,
similar to ipsapirone.
|
Linares et al., 2018
[77]
|
RCT, parallel-arm design
|
57 healthy male individuals
|
150, 300, or 600 mg CBD or placebo, single dose
|
VAMS, physiological measurements, simulated public speaking
test
|
300 mg CBD significantly reduces subjective anxiety, while 150 mg
and 600 mg had no significant effects compared to placebo.
|
Crippa et al., 2004
[78]
|
RCT, cross-over design
|
10 healthy individuals
|
400 mg oral CBD or placebo 90 minutes before rCBF measurements,
single dose
|
VAMS, SPECT
|
Significant reduction in subjective state of anxiety and
increased mental sedation upon CBD administration compared to
placebo; effects were correlated with neural activity in limbic
and paralimbic brain regions.
|
*Fusar-Poli et al., 2009
[79]
|
RCT, cross-over design
|
15 healthy individuals
|
10 mg ∆9-THC, 600 mg CBD, or placebo, single
dose
|
fMRI and SCR measurements during fearful-faces intervention,
VAMS, STAI, AIS, PANSS, physiological measurements
|
∆9-THC and CBD showed opposing effects on
neural, electrodermal, and symptomatic responses to fearful
faces; ∆9-THC administration led to an
increased state of anxiety, while CBD acted anxiolytic.
|
*Fusar-Poli et al., 2010
[80]
|
RCT, cross-over design
|
15 healthy individuals
|
10 mg ∆9-THC, 600 mg CBD, or placebo, single
dose
|
fMRI and SCR measurements during fearful-faces intervention,
VAMS, STAI, AIS, PANSS, physiological measurements
|
Anxiolytic effects of CBD were correlated to a disruption in the
prefrontal-subcortical connectivity, which did not appear after
∆9-THC administration.
|
Bloomfield et al., 2022
[81]
|
RCT, cross-over design
|
24 healthy individuals
|
600 mg CBD or placebo, single dose
|
fMRI measurements during face rating and mental arithmetic tasks,
VAS
|
No significant effects of CBD administration on brain responses,
cognitive measures, or experimentally induced anxiety.
|
Hundal et al., 2018
[86]
|
RCT, parallel-arm design
|
32 non-clinical individuals with high-paranoid traits
|
600 mg CBD or placebo 130 minutes prior to controlled 3D virtual
reality scenario, single dose
|
SSPS, CAPE-state, UMACL, BAI, several cognitive tasks, controlled
3D virtual reality scenario
|
No impact of CBD on physiological and behavioral symptoms of
anxiety and paranoia.
|
Das et al., 2013
[87]
|
RCT, parallel-arm design
|
48 healthy individuals
|
Inhalation of 32 mg CBD pre- or post-extinction, or placebo,
single dose
|
BDI, STAI, spot-the-word and prose recall tasks, MRS, BSS, fear
conditioning, and fear extinction task
|
Enhanced consolidation of extinction learning upon CBD
administration.
|
Rossi et al., 2023
[85]
|
RCT, parallel-arm design
|
17 healthy individuals
|
600 mg CBD or placebo 90 minutes prior to oral ayahuasca (1
ml/kg) administration, single dose
|
REFE and empathy tasks
|
Significant decreases in reaction times, anxiety, sedation,
cognitive deterioration, and discomfort in both groups without
between-group differences.
|
Social Anxiety Disorder
|
Crippa et al., 2011
[88]
|
RCT, cross-over design
|
10 treatment-naïve individuals with SAD
|
400 mg CBD or placebo, single dose
|
VAMS, SPECT
|
Significant improvements in subjective anxiety ratings upon CBD
administration were correlated to specific neural signaling
patterns.
|
Bergamaschi et al., 2011
[89]
|
RCT, parallel-arm design
|
24 treatment-naïve individuals with SAD, 12 healthy
controls
|
600 mg CBD or placebo, single dose
|
VAMS, SSPS-N, and physiological measurements during simulated
public speaking test
|
CBD administration significantly reduced anxiety, cognitive
impairment, discomfort, and alert levels compared to placebo;
results of CBD-treated patients were similar to non-treated
healthy controls.
|
Masataka et al., 2019
[90]
|
RCT, parallel-arm design
|
37 late teenagers (18–19 years) with SAD
|
Oral cannabis oil with 300 mg CBD or placebo for four weeks
|
FNE, LSAS
|
CBD administration led to significant decreases in anxiety
compared to placebo.
|
Kwee et al., 2022
[91]
|
RCT, parallel-arm design
|
80 treatment-refractory individuals with SAD and panic
disorder
|
300 mg CBD or placebo, single dose
|
Exposure therapy sessions, FQ, BAI, CGI, BDI-II, SPAI-18, LSAS,
motivational interviewing
|
No effects of CBD administration on treatment outcome.
|
Berger et al., 2022
[92]
|
Clinical study, open-label, single-arm
|
31 treatment-resistant individuals with SAD
|
CBD titrated from 200 mg/day up to 800 mg/day
over the course of 12 weeks
|
CGI-I, CGI-S OASIS, HARS, QIDS-A, SOFAS
|
Significant reduction in anxiety severity, as well as significant
improvements in depressive symptoms, CGI-severity scores, and
functioning.
|
Post-traumatic Stress Disorder
|
Elms et al., 2019
[93]
|
Case series
|
11 individuals with PTSD
|
CBD capsules or oral spray over 8 weeks in a flexible dosing
regimen; mean starting dose: 33.18 mg/day: mean final
dose: 48.64 mg/day
|
PCL-5, subjective reports
|
PTSD symptom reduction upon CBD administration in addition to
routine psychiatric care.
|
*Bolsoni, et al., 2022
[94]
|
RCT, cross-over design
|
33 individuals with PTSD
|
300 mg CBD or placebo before recall of traumatic event, single
dose
|
PCL-5, VAMS, STAI, physiological measurements during trauma
recall scenario
|
No significant effects of CBD on states of anxiety, alertness,
and discomfort, or physiological measurements compared to
placebo.
|
*Bolsoni, et al., 2022
[95]
|
RCT, parallel-arm design
|
33 individuals with PTSD, separated into sexual and non-sexual
trauma groups
|
300 mg CBD or placebo, single dose
|
PCL-5, VAMS, physiological measurements during trauma recall
scenario
|
The nonsexual-related PTSD group showed lower anxiety and
cognitive impairment when receiving CBD rather than a placebo;
no significant effects were found in the sexual-related PTSD
group.
|
If not stated otherwise, the treatment was administered orally. Studies that
refer to the same participants are marked with an asterisk. Abbreviations:
AIS = Analog Intoxication Scale; ARCI-Ma = Addiction
Research Center Inventory for Marihuana Effects; BAI = Beck Anxiety
Inventory; B-BAES = Brief Biphasic Alcohol Effects Scale; BDI
= Beck Depression Inventory; BSS = Bodily Symptoms Scale;
CAPE = Community Assessment of Psychic Experiences; CGI-I =
Clinical Global Impressions – Improvement Scale; CGI-S =
Clinical Global Impressions – Severity Scale; fMRI =
functional magnetic resonance imaging; FNE = Fear of Negative
Evaluation Scale; FQ = Fear Questionnaire; HARS = Hamilton
Anxiety Rating Scale; I-PANAS = International Positive and Negative
Affect Schedule; LSAS = Liebowitz Social Anxiety Scale; MAST
= Maastricht acute stress test; NRS = Numerical Rating
Scale; OASIS = Overall Anxiety Severity and Impairment Scale; PANSS
= Positive and Negative Syndrome Scale; MRS = Mood Rating
Scale; PCL-5 = Post-Traumatic Stress Disorder Checklist for the
DSM-5; PTSD = Post-Traumatic Stress Disorder; QIDS-A = Quick
Inventory of Depressive Symptoms, Adolescent Version; QOL = Quality
of Life; rCBF = regional cerebral blood flow; RCT =
randomized controlled trial; REFE = Recognition of Emotions in
Facial Expressions; SAD = Social Anxiety Disorder; SCR =
Skin Conductance Response; SF = short form; SOFAS = Social
and Occupational Functioning Scale; SPAI = Social Phobia and Anxiety
Inventory; SPECT = single-photon emission computed tomography: SSPS
= State Social Paranoia Scale; SSPS-P/N =
positive/negative Self-Statements during Public Speaking Scale; STAI
= Spielberger’s State-Trait Anxiety Inventory; UMACL
= University of Wales Mood Adjective Checklist; VAMS =
Visual Analog Mood Scale; VAS = Visual Analog Scale.
Table 4 Clinical investigations on CBD for the treatment of
autism spectrum disorder.
Reference
|
Study Design
|
Participants
|
Treatment
|
Scales, questionnaires, paradigms
|
Outcomes
|
*Pretzsch et al., 2019
[99]
|
RCT, cross-over design
|
34 healthy individuals (17 with ASD and 17 neurotypical)
|
600 mg CBD or placebo, single dose
|
MRS measurements to determine neurotransmitter concentrations
|
CBD administration resulted in significantly increased GABA
activation in healthy controls, but decreased GABA activation in
people with ASD.
|
*Pretzsch et al., 2019
[100]
|
RCT, cross-over design
|
34 healthy individuals (17 with ASD and 17 neurotypical)
|
600 mg CBD or placebo, single dose
|
MRI measurements of neural activation
|
CBD administration resulted in altered fractional amplitude of
low-frequency fluctuations and functional connectivity in
regions correlated to ASD.
|
If not stated otherwise, the treatment was administered orally. Studies that
refer to the same participants are marked with an asterisk. Abbreviations:
ASD = Autism Spectrum Disorder; CBD = Cannabidiol; GABA
= γ-Aminobutyric Acid; MRI = Magnetic Resonance
Imaging; MRS = Magnetic Resonance Spectroscopy; RCT =
Randomized Clinical Trials.
There were no reports on the effects of pure CBD on alcohol use disorder, borderline
personality disorder, depression, dementia, and
attention-deficit/hyperactivity disorder. In two women with bipolar
affective disorder, CBD was ineffective in improving symptoms of a manic phase [20], but apart from this case report, there are
no other studies to date.
Of the studies investigating CBD as a treatment option for psychiatric conditions, 20
studies focused on schizophrenia and psychotic disorders or clinically high-risk
mental state (CHR) for psychosis, 13 on different types of substance use disorders,
19 on anxiety and post-traumatic stress disorder (PTSD), and 2 on autism spectrum
disorder (ASD).
Schizophrenia and psychotic disorders
Psychosis is a syndrome characterized by the loss of connection to reality and
has many underlying conditions [21]. The
term schizophrenia describes those severe mental disorders characterized by
psychotic symptoms (e. g., altered perceptions, delusional perceptions,
hallucinations, diminished emotional expression, motivation, and social
withdrawal) and cognitive impairments due to causes that have not yet been
identified or ascribed. Approximately 3% of people worldwide will
develop a psychotic disorder at some point in their lives, but less than
1% will be diagnosed with schizophrenia [22]. The development of antipsychotic medications went along with
establishing the dopamine hypothesis of schizophrenia, resulting in drugs
modulating dopaminergic and serotonergic signalling. However, the success of
these medications is restricted by their limited effectiveness in many patients
and the common occurrence of (severe) adverse effects [23]. Interestingly, various preclinical and
clinical studies suggest a connection between the disease and specific
pathological alterations in the ECS, including changes in serum and
cerebrospinal fluid endocannabinoid levels and altered expression of
CB1Rs [17]
[24]. Therefore, alternative pharmacological
interventions modulating the ECS (e. g., CBD) rather than the
dopaminergic or serotonergic system have been explored in recent years to
provide better treatment options for people with psychotic disorders.
Cannabidiol as a potential antipsychotic medication
The first antipsychotic effects of CBD were reported by Zuardi et al. in 1995
[23] in a single case with
schizophrenia, who was treated with up to 1,500 mg CBD per day over 4 weeks,
leading to an improvement in psychotic symptoms [25]. This initial positive observation
was followed by a case series of three individuals with treatment-resistant
schizophrenia [26]. After an initial
5-day placebo treatment, the three young men received up to 1,280 mg of CBD
per day for 30 days, followed by another 5-day placebo administration and
subsequent treatment with olanzapine for a minimum of 15 days. CBD treatment
resulted in only mild symptom relief in one person, while the other two
showed no clinical improvement [26].
In six cases with a diagnosis of Parkinson’s disease and psychotic
symptoms for at least 3 months, open-label CBD treatment (flexible dosing
regimen of up to 400 mg/day) resulted in a significant reduction in
psychotic symptoms as assessed by the Brief Psychiatric Rating Scale (BPRS)
[27]. Although previous case
series suggested that patients with a long history of disease would not
profit from CBD treatment, a successful case study was recently published
[28] of a patient with a 21-year
history of treatment-resistant schizophrenia. Seven weeks of CBD treatment
(1,000 mg/day) as an adjunct to clozapine and lamotrigine resulted
in markedly softened but continuous acoustic hallucinations and reduced
negative symptoms. The hallucinations gradually disappeared after another
2.5 weeks with an increased CBD dose (1,500 mg/day). After 8 months,
the patient still benefited from continued CBD add-on treatment [28]. However, while open-label case
reports may direct research interest, they are very limited in terms of
evidence.
Leweke et al. (2012) conducted the first RCT with a parallel-group design, in
which 42 acutely psychotic patients received oral CBD or amisulpride
(treatment regimen for both compounds: starting dose of 200 mg/day,
titrated up to 800 mg/day within 4 days) for 28 days. Both
interventions led to similar, significant improvements in positive and
negative symptoms of psychosis (assessed by the Positive and Negative
Syndrome Scale [PANSS] and BPRS). However, CBD demonstrated a distinctly
superior side-effect profile compared to amisulpride treatment. Notably, the
clinical improvements were strongly associated with higher serum anandamide
levels in patients receiving CBD [10].
An additional secondary outcome analysis reported the effects of CBD and
amisulpride on neurocognitive performance [29]. At baseline, both groups showed comparable performance in
all neurocognitive tests. Both treatments improved visual memory and
processing speed. While CBD enhanced sustained attention and visuomotor
coordination, improvements in working memory performance were observed after
amisulpride treatment. In 88 individuals with schizophrenia on stable
antipsychotic medication, 1,000 mg/day of oral CBD (Epidiolex) as
adjunctive therapy for 6 weeks also led to significant improvements in
clinical symptoms (evaluated by PANSS and Clinical Global Impression Scale
[CGI]) compared to placebo [30].
However, in 36 people with chronic schizophrenia on stable antipsychotic
medication, a 6-week treatment with 600 mg/day oral CBD did not
improve MATRICS Consensus Cognitive Battery (MCCB) performance or PANSS
scores compared to placebo [31].
Similarly, in people with recent-onset schizophrenia (<5 years), a
4-week treatment with 600 mg/day oral CBD did not affect any
clinical assessment (PANSS, Hamilton Depression Scare, Young Mania Rating
Scale, CGI, Global Assessment of Functioning Scale, and Social and
Occupational Functioning Assessment Scale) or cognitive performance
evaluated by the Brief Assessment of Cognition in Schizophrenia [32].
Cannabidiol as an antipsychotic in clinical-high-risk (CHR) mental state
for psychosis
Individuals in a CHR mental state for psychosis present with attenuated
psychotic symptoms (APS) or brief, limited intermittent psychotic symptoms
(BLIPS), as well as more generalized and nonspecific psychiatric symptoms,
and often show neurocognitive and functional impairment [33]
[34]. To date, no pharmacological treatment has been approved
because the condition has long been considered a risk status for psychosis
rather than a disorder in its own right [35]. As a result, off-label use of various pharmacological
interventions such as antipsychotics or antidepressants is common. However,
given the functional impairment of these young people, clinical management
of individuals with persistent subthreshold psychotic symptoms is
indicated.
The first successful treatment with CBD in an antipsychotic-naïve
young man with CHR was reported by Koethe et al. [36]. The 4-week CBD treatment (600
mg/day orally) resulted in a significant clinical improvement as
evidenced by reduced PANSS scores and improved cognitive performance on
various neuropsychological tests. The improvement in clinical symptoms was
also accompanied by an increase in cerebral glucose metabolism as assessed
by [18F]fluoro-2-deoxyglucose PET. The authors concluded that
activation of the ECS via anandamide is likely to enhance the homeostatic
effect of this system, the“eby “normal”
zing” systemic function and simultaneously upregulating cerebral
glucose utilization.
To date, no controlled studies investigating the treatment efficacy of CBD in
CHR have been completed.
However, one controlled observational study [37] investigated the effect of a single administration of CBD in
a fMRI paradigm. The study results are discussed in more detail in the next
chapter of this review. In a subset of the young people with CHR included in
this study, Appiah-Kusi et al. [38]
examined the cortisol response to social stress (Trier Social Stress Test)
in 32 CHR patients receiving either 600 mg oral CBD or a placebo over 1
week, rather than receiving a single dose only, at the level of fluid
biomarkers. They compared the results with cortisol reactivity in 26 healthy
controls. Although CBD administration led to some improvements in anxiety
and the experience of public speaking stress in CHR patients compared to
placebo, the effects were not reflected in significant improvements in
cortisol reactivity [38]. Similarly,
based on data from the same study, Davies et al. reported that 33 people
with CHR failed to restore the clear negative relationship between cortisol
levels and parahippocampal response seen in healthy controls [39].
Neurobiological background of the antipsychotic effects of
cannabidiol
As early as 1932, Kurt Beringer introduced the term ‘model
psychosis’ for psychosis-like symptoms intentionally induced by
psychotomimetic drugs [40]. The
‘altered states of consciousness’ induced in model
psychosis, i. e., symptoms of withdrawal from reality often
accompanied by perceptual disturbances, thought disorders, delusional ideas,
and sometimes hallucinations, are a long-established approach to improving
our understanding of certain aspects of schizophrenia [41].
It has been a long-standing clinical observation that both acute and chronic
administration of cannabis or ∆9-THC can induce
dose-dependent behavioral, cognitive, or electroencephalographic changes
reminiscent of those observed in severe psychiatric disorders, particularly
psychosis [41]
[42]. Therefore, the
∆9-THC-induced model psychosis is often used to study
the neurobiological basis of the antipsychotic properties of CBD.
Several fMRI studies have visualized the fundamentally different
neurobiological effects of CBD and ∆9-THC. Borgwardt et
al. [43] conducted a pseudo-randomized
controlled trial with within-subject repeated measures in 15 healthy
volunteers receiving either 10 mg ∆9-THC, 600 mg CBD, or
placebo before a Go/No-Go task. ∆9-THC
administration led to reduced activation of brain regions mediating response
inhibition (right inferior frontal and anterior cingulate gyrus), while CBD
administration had similar effects on the left temporal cortex and insula,
two brain regions usually not involved in response inhibition. In the same
participants, CBD and ∆9-THC also showed opposing effects
compared to placebo on several regional brain functions measured by
blood-oxygen-level-dependent (BOLD) hemodynamic responses during the verbal
recall condition of a verbal memory task, response inhibition
(Go/No-Go task), sensory processing after visual and auditory
stimulation, and viewing of fearful faces [44]. During auditory and visual processing tasks in the same
healthy volunteers, 600 mg CBD and 10 mg ∆9-THC also
resulted in differential activation of brain regions associated with induced
psychotic symptoms [45]. Compared to
placebo, ∆9-THC reduced activation in the temporal cortex
during auditory processing and the secondary visual cortex during visual
stimulus processing. In addition, ∆9-THC increased the
activation in occipital cortex areas (primary visual cortex). Decreased
right temporal cortex activation and increased occipital cortex area
activation correlated with increases in PANSS total and PANSS positive
scores, respectively. In contrast, CBD increased temporal cortex and right
occipital lobe activation during auditory and visual processing,
respectively. The direct comparison showed that ∆9-THC
and CBD had opposite effects, particularly in the right posterior superior
temporal cortex, the right-sided homolog of Wernicke’s area.
In another cross-over RCT [46], an
acute dose of 600 mg CBD increased fronto-striatal resting-state
connectivity in healthy individuals compared to placebo. This network is
relevant to executive function, decision-making, salience generation, and
motivation. However, ∆9-THC administration (10 mg,
orally) showed no effects. The authors concluded that the plasma levels
achieved before the fMRI scan (75 min after study drug intake) had not
reached sufficient concentration.
Wilson et al. [47] investigated the
effects of acute CBD administration in 33 antipsychotic-naïve CHR
individuals in an fMRI study on reward processing, which is commonly
dysregulated in psychosis. Compared to 19 healthy controls, the individuals
with CHR showed abnormal activation of the left insula/parietal
operculum, which was alleviated by the acute oral CBD administration (600
mg, n=16) but not by placebo (n=17) [47]. Bhattacharyya et al. [37] showed in the same participants
that individuals with CHR have differential BOLD responses in three brain
regions associated with psychosis disease states – the striatum
(during a verbal encoding task), the mediotemporal lobe, and the midbrain
(during verbal recall). Acute CBD administration attenuated the activation
patterns without reaching the BOLD response levels observed in healthy
controls [37]. Furthermore, in a
fearful face processing paradigm, these CHR individuals showed significantly
increased activation in the left lingual gyrus and bilateral parahippocampal
gyri and attenuated activation in the striatum compared to healthy controls
when treated with a placebo. Again, acute CBD administration partially
normalized the activation patterns but did not reach the levels seen in
healthy controls [48].
O’Neill et al. [49] supported
these results found in CHR in 15 individuals with psychosis on standard
antipsychotic treatment (RCT with within-subject, cross-over design).
Compared to the 19 healthy controls, the psychosis individuals showed
altered prefrontal and mediotemporal BOLD responses and greater
mediotemporal-striatal functional connectivity during a verbal recall task.
The altered activation was normalized in parts after acute CBD intake (600
mg) but did not reach the same BOLD response levels as those observed in
healthy controls [49]. In 31 people
with recent-onset psychosis, van Boxel et al. [32] found a significant alteration in
default mode network connectivity after 28 days of CBD treatment (600
mg/day) adjunctive to standard antipsychotic medication. The authors
suggested that the therapeutic effects of CBD may be based on the observed
changes in default mode network connectivity [31].
Substance use disorder (SUD)
SUD is a chronic medical condition characterized by recurrent and compulsive
substance use despite adverse consequences. It encompasses a range of
substance-related problems, impacting various aspects of the life and well-being
of an individual [50]. The ECS has been
shown to play a critical role in mediating rewarding effects by modulating
neurotransmission in key areas of the mesocorticolimbic system involved in the
initiation and maintenance of drug use and in the development of the compulsions
and loss of behavioral control that occur during drug dependence [51]. Despite the definitive addictive
potential of cannabis, CBD itself does not pose a risk of developing dependence
or tolerance, as has been concluded in clinical interventions [52]
[53].
However, in an RCT with a repeated-measures design involving 23 healthy
volunteers performing a monetary incentive fMRI task, acute oral CBD
administration (600 mg) had no effects on neural correlates of reward expectancy
and feedback compared to placebo [54].
Cannabis use disorder (CUD)
The first case report on the possible beneficial effects of CBD on CUD and
associated withdrawal symptoms was published in 2013 by Crippa et al. [55]. A 19-year-old female with severe
cannabis withdrawal syndrome was treated with oral CBD for 11 days (day 1:
300 mg, day 2–10: 600 mg, day 11: 300 mg), resulting in no symptoms
of withdrawal, anxiety, or dissociation during the detoxification process.
Therefore, CBD was considered effective against withdrawal symptoms.
However, at a 6-month follow-up, the young woman reported a relapse of
cannabis use, albeit at a lower frequency of once or twice a week compared
to daily use before CBD treatment. A man diagnosed with bipolar disorder and
a severe CUD was treated with daily administration of a low CBD dose (24 mg)
as an oral spray [56]. The dose was
gradually tapered to 18 mg over 2 months. He reported being able to avoid
smoking cannabis while on CBD oil treatment and experienced improvements in
anxiety, sleep, and social and occupational functioning.
A larger RCT partially confirmed these two anecdotal observations in 82
individuals with CUD [57]. In the
initial trial phase, 48 participants received 200, 400, or 800 mg oral CBD
or placebo for 4 weeks during a cessation attempt. An interim analysis
showed that the two higher doses, but not 200 mg CBD, were more effective
than placebo in reducing cannabis use [57]. Therefore, in the second phase of the study, new
participants (n=34) were randomized to receive 400 or 800 mg CBD or
placebo. Compared to placebo, CBD doses of 400 and 800 mg decreased the
THC-COOH:creatinine ratios by 94.21 ng/mL and 72.02 ng/mL,
respectively, and increased average cannabis abstinence by 0.48 and 0.27
days per week, respectively [57]. The
results suggest that doses > 200 mg (400–800 mg/day)
are required for adequate cannabis withdrawal support. However, results for
secondary endpoints were mixed and dose-dependent [57]. While 400 mg CBD reduced the
number of cigarettes smoked per week compared to placebo, the same CBD dose
increased Pittsburgh Sleep Quality Index scores, indicating poorer sleep
quality in participants taking CBD. On the other hand, the higher CBD dose
(800 mg) had no effect on these outcomes but reduced cannabis withdrawal
symptoms and showed anxiolytic effects on the Beck Anxiety Inventory. In the
same study, CBD administration did not affect delayed verbal memory scores
and other cognitive outcomes (400 or 800 mg/day), except for the
backward digit span, which increased following 800 mg CBD [58]. Therefore, the authors concluded
that 800 mg/day may improve working memory performance in people
with CUD. A recent publication based on the same RCT reported that
anandamide levels decreased over time in CUD individuals taking a placebo
during the cessation attempt, while there was no change in anandamide levels
in the 800 mg CBD group [59]. No
evidence was found for a similar effect of 400 mg CBD compared to placebo.
However, the serum anandamide concentrations were not correlated with
overall improvement of anxiety, depression, cannabis use, or withdrawal
symptoms [59].
Cocaine use disorder
The potential benefits of CBD in treating SUDs have also been investigated in
cocaine use disorder. An exploratory, placebo-controlled, double-blind study
in 31 individuals with crack-cocaine dependence [60] found no CBD-specific effect.
Although 300 mg of oral CBD for 10 days significantly reduced craving, no
differences were found between the CBD and placebo groups. Furthermore,
indicators of anxiety, depression, and sleep alterations did not differ
between the groups. In a long-term intervention in 78 adults with moderate
to severe cocaine use disorder, oral CBD administration (800 mg/day
for 92 days, oral solution) did not reduce cocaine craving or relapse cases
compared to placebo [61]. Separate
analyses of the same trial also found no differences in cognitive outcomes
[62] or anxiety symptoms and
cortisol levels [63].
Nicotine dependence
Chronic tobacco smokers typically experience intense withdrawal symptoms when
attempting to reduce their dose or quit smoking altogether. In a
double-blind RCT [64], 24 smokers
receiving ad libitum CBD or placebo via an inhaler were monitored for their
subsequent tobacco self-administration, craving (assessed using the Tiffany
Craving Questionnaire), and sedation, depression, and anxiety status (Mood
Rating Scale). CBD consumption significantly reduced cigarette smoking by
approximately 40% during the 1-week intervention, and the effect was
maintained at the 21-day follow-up visit, while placebo inhalers showed no
impact on cigarette smoking [64].
However, CBD did not affect craving or sedation, depression, and anxiety
scores [64].
A double-blind, placebo-controlled, cross-over study investigated the
potential of a single oral dose of 800 mg CBD to target processes relevant
to smoking cessation in 30 non-treatment-seeking, dependent cigarette
smokers [65]. Following overnight
cigarette abstinence, CBD reversed the attentional bias to cigarette cues so
that it was no different from the attentional bias when the participants
were allowed to smoke before the test. The authors concluded that this
reduction in the implicit salience of drug cues may be the potential
underlying mechanism by which CBD exerts its antiaddictive effects [65]. Furthermore, CBD reduced the
pleasantness of cigarette cues compared to placebo without affecting craving
and withdrawal symptoms or cardiovascular measures.
Heroin use disorder
Hurd et al. tested the short-term effects of oral CBD (Epidiolex, 400 or 800
mg/day) versus placebo in 42 drug-abstinent individuals with heroin
use disorder [66]. Compared to
placebo, acute CBD administration significantly reduced craving and anxiety
induced by salient drug cues compared to neutral cues. In the 3-day
intervention, participants also experienced significant reductions in
cue-induced craving and anxiety when treated with either dose of CBD
compared to placebo. The positive effects persisted through the 7-day
follow-up.
Anxiety and post-traumatic stress disorder
PTSD and anxiety are distinct but somehow related mental health conditions with
significant implications for affected individuals. PTSD arises after
experiencing or witnessing a traumatic event, leading to intrusive memories,
avoidance behaviours, negative mood changes, and increased arousal. Anxiety
disorders involve heightened arousal, fear, and nervousness, affecting daily
functioning and overall quality of life. Both conditions can manifest with
physical symptoms, further exacerbating distress and impairing coping abilities.
Timely recognition, appropriate treatment, and ongoing support are crucial in
managing PTSD and anxiety, facilitating recovery, and enhancing overall
well-being. Standard treatment methods for PTSD and anxiety include,
e. g., cognitive-behavioral therapy and antidepressants, modulating
serotonin, and norepinephrine reuptake in the neurons [67]. The ECS is important in modulating
emotional behaviours and regulating fear, anxiety, and stress-coping processes
by modulating synaptic activity at many ‘nodes’ of the neural
circuits involved [68]
[69]. In addition, alterations of eCBs and
respective lipid levels in serum [70],
plasma [71], and hair [72] of individuals with PTSD as well as
elevated CB1R availability [73]
detected in PET scans suggest an involvement of the ECS in the pathology of
PTSD.
Anxiolytic effects of cannabidiol in healthy individuals
First, the importance of controlled studies must be emphasized, as the mere
expectation of the effects of CBD led to significant physiological and
subjective anxiolytic effects [74]. In
a cross-over RCT, all participants always received sublingual CBD-free
hempseed oil but were informed that they would self-administer CBD-free
hempseed oil in one session and CBD-containing hempseed oil in the other.
Although no systematic changes in subjective stress or anxiety were observed
concerning the expected condition, the expected CBD condition was associated
with increased sedation and a different pattern of heart rate variability,
indicating reduced anticipatory stress. Notably, participants who were a
priori convinced that CBD has anxiolytic properties reported a significant
decrease in anxiety in the CBD expectancy condition [74].
The first report on the possible anxiolytic effects of CBD was published in
1982 by Zuardi et al. [75]. The
authors administered oral ∆9-THC (0.5 mg/kg), CBD
(1 mg/kg), a combination of the two, diazepam (10 mg), or placebo to
8 participants in an RCT (cross-over design) before several physiological
and behavioral examinations. CBD administration had no anxiolytic effect per
se but appeared to reduce anxiety and other subjective alterations triggered
by ∆9-THC. Notably, the authors did not observe any
CBD-related changes in the physiological effects of
∆9-THC, suggesting that CBD does not block the activity
of ∆9-THC but rather acts through separate mechanisms to
alleviate the unpleasant effects associated with cannabis use [75]. A simulated public speaking test
in 40 healthy individuals showed comparable anxiolytic effects (assessed
using the Visual Analog Mood Scale [VAMS] and State-Trait Anxiety Inventory
[STAI]) of CBD and ipsapirone, an antidepressant and anxiolytic compound
commonly used in RCTs as an active comparator [76]. To establish the dose-response
curve for the anxiolytic effect of CBD, they later tested three different
doses (150 mg, 300 mg, and 600 mg) versus placebo in 57 healthy male
subjects [77]. Notably, the previously
established dose of 300 mg proved effective again in a simulated public
speaking test, while the two alternative doses did not show significant
changes in subjective anxiety ratings (VAMS), thus representing an inverted
U-shaped dose-response curve for the anxiolytic effects of CBD [77].
Crippa et al. investigated the effects of CBD on regional cerebral blood flow
(rCBF) measured by SPECT in an RCT with a cross-over design. SPECT is a
neuroimaging technique involving tracer injection, which, according to the
authors, often leads to increased anticipatory anxiety in subjects compared
to during or after image acquisition [78]. Compared to placebo, 10 healthy volunteers reported
decreased subjective anxiety and increased mental sedation following a
single oral ingestion of 400 mg CBD before the SPECT scan started. In
addition, CBD modulated resting-state activities in limbic and paralimbic
cortical brain areas commonly implicated in the pathophysiology of anxiety.
However, changes in rCBF did not correlate with subjective anxiety scores
[78]. Compared to
∆9-THC (10 mg, oral), CBD administration (600 mg,
oral) showed opposite effects on neural, electrodermal, and symptomatic
responses to fearful faces in 15 healthy subjects [79]. However, while
∆9-THC also increased feelings of anxiety, CBD only
tended to reduce anxiety levels. The authors hypothesized that the
alternation between neutral and fearful faces in the fMRI paradigm elicited
only a transient anxious response to each stimulus without producing
sustained changes in subjective anxiety levels [79]. However, a separate analysis of
the same data showed that CBD attenuated the amygdalar response to fearful
faces, an effect that correlated with the trend level of anxiolytic effect
for CBD [44]. Later, dynamic causal
modelling (DCM), a method for assessing effective connectivity in
neuroimaging data, was used to re-evaluate these fMRI data and led to the
suggestion that the potential anxiolytic effects of CBD may be
neurophysiologically based on a disruption of prefrontal-subcortical
connectivity [80].
In contrast, in 24 healthy individuals receiving either 600 mg CBD or
placebo, no effects of acute CBD administration were found on emotional
processing (using an fMRI paradigm based on neutral, fearful, and happy
faces), cognitive activity (using a mental arithmetic task to measure
emotional responses to stress and a face rating test with neutral, angry and
happy expressions), and subjective response to experimentally induced
anxiety [81]. The negative outcomes
has been suggested to result from insufficient CBD blood concentrations, as
CBD was administered in a fasted state, and several pharmacokinetic
investigations indicate that the bioavailability of CBD without any food
consumption is extremely low [82]
[83]
[84]. When combined with the psychoactive brewed drink ayahuasca,
known for its anxiolytic and antidepressant effects, both CBD (600 mg) and
placebo administration in 17 healthy individuals resulted in significantly
decreased reaction times in a computerized facial expressions recognition
task and a multifaceted empathy test, and a reduction in subjective anxiety,
sedation, cognitive deterioration, and discomfort ratings [85]. Thus, a CBD-specific effect was
not observed.
Furthermore, 32 non-clinical individuals with high paranoid traits did not
benefit from a single oral dose of 600 mg CBD (Epidiolex) before a
controlled 3D virtual-reality scenario as measured by levels of anxiety
(Beck Anxiety Inventory), cortisol, blood pressure, and heart rate [86].
In summary, studies investigating acute subjective and objective anxiolytic
effects of CBD in healthy volunteers show conflicting results. Nevertheless,
CBD may still be an interesting compound for treating anxiety disorders when
combined with specific therapies.
In a Pavlovian fear conditioning paradigm assessing extinction and
consolidation of conditioned fear memory in 48 healthy subjects, inhalation
of 32 mg CBD after the extinction task (post-extinction) attenuated fear
responses rated by shock expectancy compared to placebo. Both pre- and
post-extinction CBD inhalation tended to reduce skin conductance responses
during the reinstatement task. These results indicate that CBD can
potentiate the consolidation of extinction memory [87]. Of note, the attenuation of fear
responses following CBD inhalation after the extinction task was not
associated with reduced anxiety. Therefore, the authors concluded that CBD
may be a valuable adjunct to extinction-based therapies for anxiety
disorders [87].
Results in people with social anxiety disorder (SAD)
To test the anxiolytic effect of CBD in SAD, 15 treatment-naïve
people with SAD received a single oral dose of CBD (400 mg) or placebo in a
cross-over RCT. As predicted, CBD also attenuated the rCBF in the left
parahippocampal gyrus and hippocampus and increased it in the right
posterior cingulate gyrus. However, subjective anxiety ratings were not
correlated with these specific neural signalling patterns [88]. The anxiolytic properties of CBD
were also confirmed in an anxiety-provoking simulated public speaking test
in 24 treatment-naïve individuals with SAD who received either a
single oral dose of 600 mg CBD or placebo [89]. Furthermore, 4 weeks of treatment with 300 mg CBD per day
significantly reduced anxiety scores on the Fear of Negative Evaluation
questionnaire and the Liebowitz Social Anxiety Scale compared to placebo in
37 adolescents with SAD [90]. In
contrast, in 80 individuals with treatment-refractory SAD or panic disorder,
the acute oral administration of 300 mg CBD before eight separate exposure
therapy sessions did not improve treatment outcomes compared to placebo
[91]. Therefore, in the absence of
an adequate control group, the significant anxiety reduction, as well as
improvements in depressive symptoms, CGI-severity scores, and functioning in
31 young individuals with treatment-resistant SAD that were measured after a
12-week open-label intervention with add-on CBD administration (starting
dose: 200 mg/day; titrated up to 800 mg/day) could also be
attributed to the fact that the participants were informed about the
treatment and simply expected the intervention to be effective [92].
Implications for individuals with post-traumatic stress disorder
A retrospective, open-label case series of 11 adults with PTSD who received
low-dose oral CBD capsules or spray (flexible dosing regimen; mean starting
dose: 33.18 mg/day; mean final dose: 48.64 mg/day [range:
2–100 mg]) for 8 weeks in addition to routine psychiatric
interventions (with frequent changes in concurrent psychiatric medications
for the study) resulted in improved PTSD symptoms in 10 out of 11
participants, as indicated by a 28% reduction in PTSD Checklist for
the DSM-5 scores [93]. In a recent
RCT, a single dose of 300 mg oral CBD administered to 33 individuals with
PTSD before being exposed to playbacks of their own recall of traumatic
experiences had no effect compared to placebo [94]. However, when the participants
were divided into two groups based on whether they had experienced sexual or
non-sexual trauma, the non-sexual trauma group showed significantly reduced
levels of subjective anxiety and cognitive impairment (both assessed by the
VAMS) when given CBD versus placebo, while the sexual trauma group did not
benefit from treatment [95].
Autism spectrum disorder
ASD is a neurodevelopmental condition characterized by challenges in social
communication and repetitive patterns of behaviour, interests, or activities.
Individuals with ASD can exhibit a wide range of abilities and differences in
their interactions with the world around them [96]. While there is no cure for ASD, early intervention, and tailored
therapies, such as behavioral interventions, speech and language therapy,
occupational therapy, and social skills training, can significantly improve the
quality of life and functioning of individuals with ASD [97]. Since children with ASD appear to have
lower plasma levels of anandamide than healthy children [98], raising anandamide levels
(e. g., by using CBD) may be a promising treatment alternative.
However, to date, only one observational single-dose study has been conducted,
investigating the effects of a single oral CBD dose (600 mg) or placebo in 17
people with ASD and 17 neurotypical controls [99]
[100]. Magnetic resonance
spectroscopy scans revealed that CBD shifted the levels of both the excitatory
(glutamate and glutamine) and inhibitory (γ-aminobutyric acid (GABA) and
macromolecules [GABA +]) neurotransmitters in both groups. While
CBD increased glutamine levels in the basal ganglia and decreased them in
dorsomedial prefrontal cortex (DMPFC) in both groups, it had opposite effects on
GABA+ in each participant group. More specifically, CBD decreased
GABA+ in both brain regions analysed (basal ganglia and DMPFC) in ASD
and increased it in healthy controls, with the effect being significant only in
the DMPFC [99]. In the same observational
study, the authors found a significant increase in the “fractional
amplitude of low-frequency fluctuations” (fALFF) and functional
connectivity in regions associated with ASD [100]. This increase was most pronounced in ASD and not significant in
controls.
Discussion
This critical review found that despite the considerable interest in the ECS and CBD,
only 38 studies have investigated CBD as a treatment option in people with a
psychiatric condition, including 29 publications on RCTs based on 18 distinct
clinical trials. Notably, only nine of these clinical trials, as well as seven case
reports and two open-label studies, investigated the effects of multiple doses of
CBD (3 days to 6 weeks in RCTs and up to 8 months in a case report), demonstrating
that the acute effects of CBD have been primarily studied to date. However, to
understand the therapeutic impact and long-term safety, more RCTs are urgently
needed where patients with psychiatric conditions are treated with multiple,
sufficient doses of CBD for a duration appropriate for the respective condition.
The potential efficacy of CBD and the underlying neurobiological processes have been
primarily investigated in schizophrenia or associated psychotic disorders
(e. g., schizophrenia, CHR, or model psychosis) (for references, see [Table 1]). Distinct neurobiological effects
from ∆9-THC suggest the potential benefits of CBD in modulating
brain regions associated with psychosis. Notably, RCT results suggest the efficacy
of CBD at a dose of ≥ 800 mg/day to treat psychosis successfully
[10]
[30].
The studies now available on SUDs - particularly CUD - and anxiety and stress-related
disorders (SAD and PTSD) report conflicting results ([Table 2]
[3]). While some studies show promising effects of CBD, others have not
been able to prove its efficacy.
For SUDs ([Table 2]), oral doses of ≥
400 mg appear to be necessary to successfully facilitate cessation [57]. In both cannabis and nicotine dependence
disorders, CBD reduced consumption and the pleasantness of drug stimuli but not
subjective craving. In contrast, a significant reduction in craving was observed in
heroin use disorder [66]. However, no
beneficial effects of CBD were found in cocaine use disorder. The lack of efficacy
in these studies may be driven by insufficient daily dosages of CBD.
CBD does not appear to have anxiolytic properties per se but may reduce anxiety in
anxiety-provoking situations, including ∆9-THC administration,
simulated public speaking tests, or examinations such as SPECT, which are associated
with increased anticipatory anxiety ([Table
3]). One study in healthy volunteers suggested that CBD may improve the
consolidation of extinction memory and concluded that CBD may be a beneficial
adjunct treatment during extinction-based therapy [87]. On the other hand, experimentally induced anxiety-provoking
situations must not be mistaken as elaborated models of anxiety disorders.
Therefore, using CBD as an anxiolytic is not backed by sufficient evidence [101]. The potential of CBD to enhance
extinction memory consolidation may also be key for treating PTSD. However, a
single-dose study suggests that only people with PTSD who have not experienced
sexual trauma may benefit from CBD treatment [95]. Of note, there is no research yet on whether prolonged CBD treatment
is also beneficial for people with PTSD associated with sexual trauma.
Interestingly, CBD doses of 300–600 mg may be effective ([Table 3]), indicating that the molecular
mechanisms involved in the antipsychotic effect of CBD and its
stress/anxiety-reducing effects may differ. Again, the limited number of
studies, the limited treatment duration, and the lack of dose-finding studies, make
it difficult even to consider this evidence-based.
In ASD ([Table 4]), CBD affected
neurotransmitter levels, the fALFF, and the functional connectivity in certain brain
regions differently between ASD individuals and healthy controls [99]
[100],
but further RCTs are required to assess the potential benefits of CBD in ASD.
Although no clinical trials have been conducted to date, the preclinical evidence for
the potential benefits of CBD in other neuropsychiatric conditions, like alcohol use
disorder [102]
[103]
[104]
[105], ADHD [106], and depression [107], as well
as its generally mild side effect profile [108]
[109], provide a reason to
vigorously pursue research in this area, whereby particularly RCTs on subacute and
chronic CBD administration are needed. Specifically, due to the insufficient and
unsatisfying treatment options available for many people living with chronic
psychiatric conditions, who often experience a wide range of side effects or a lack
of treatment efficacy [110]
[111]
[112], more research is needed to find alternative treatment approaches to
ultimately allow people to live with and manage a diagnosis that often equates to
life-long psychiatric care and medication.
Seeing the broad spectrum of psychiatric conditions that CBD might positively affect
is interesting. One approach to explaining the complex mode of action of CBD and its
effects on neural activity patterns is its impact on the ECS. The complexity of the
ECS and the wide range of bodily functions and pathways it is involved in have yet
to be understood. However, we do have some idea of its effects on the immune system
[113], metabolic functions [114], inflammatory pathways [115], and the central nervous system [116]. In some psychiatric conditions, an
imbalance in some aspects of the ECS has also been shown to be associated with the
disease state [17]
[24]
[70]
[71]
[73]
[98]
[117]
[118]
[119]
[120]. Whether this imbalance
represents a pathophysiological, causal mechanism, or results of respective disease
pathologies requires further investigation, as this will contribute to understanding
the spectrum and potential use of targeting the ECS in different conditions.
This critical review provides a comprehensive overview of the existing literature on
the use of CBD in psychiatric conditions and highlights the limitations of the
published data, the potential benefits, and the limitations of CBD in clinical
practice. In summary, while the review suggests promising aspects of CBD in treating
certain psychiatric conditions, it emphasizes the need for more extensive and
rigorous research, including long-term studies and RCTs, to establish its potential
effectiveness, safety, and mechanisms of action in various clinical settings.