Table 1 Data extraction table

fMRI: Task Based

1a

Borgwardt, S. J. et al. 2008

DBPC pseudo-randomized, repeated measures, within-subject design. 1-month washout

THC 10 mg or CBD 600 mg or placebo

1.5 T Sigma (GE)

CBD deactivated the left temporal cortex and insula. These effects were not related to changes in anxiety, intoxication, sedation, and psychotic symptoms. Trend for less anxiety following CBD relative to placebo (p = 0 .06)

1b

Bhattacharyya, S. et al. 2009

DBPC pseudo-randomized, repeated measures, within-subject design. 1-month washout

THC 10 mg or CBD 600 mg or placebo

1.5 T Sigma (GE)

CBD induced trend in modulation of insula, mediotemporal gyrus, lingual gyrus, precuneus and precentral gyrus during encoding blocks and in hippocampus during recall blocks but did not survive threshold for less than 1 false positive

1c

Bhattacharyya, S. et al. 2010

DBPC pseudo-randomized, repeated measures, within-subject design. 1-month washout

THC 10 mg or CBD 600 mg or placebo

1.5 T Sigma (GE)

CBD attenuated amygdala response while observing fearful which correlated with an anxiolytic effect (r = 0.551, p = 0.017). CBD also decrease amygdala response also correlated with reductions in galvanic skin response while and intensely fearful faces (r = 0.524; p = 0.049)

Right temporal cortex, parahipcampal gyrus, insula and caudate were augmented by CBD during response inhibition task

While listening to speech CBD the superior temporal cortex was augmented by CBD

During visual processing the occipital lobe was augmented

During verbal recall CBD was associated with a trend increase in activity in the striatum compared to placebo

1d

Bhattacharyya, S. et al. 2012

DBPC pseudo-randomized, repeated measures, within-subject design. 1-month washout

THC 10 mg or CBD 600 mg or placebo

1.5 T Sigma (GE)

CBD attenuated activation in the left medial prefrontal cortex and augmented activation in the right caudate, parahippocampal gyrus, insula, precentral gyrus and thalamus, relative to placebo during oddball salience processing. CBD also reduced response latencies

1e

Bhattacharyya, S. et al. 2014

DBPC pseudo-randomized, repeated measures, within-subject design. 1-month washout

THC 10 mg or CBD 600 mg or placebo

1.5 T Sigma (GE)

CBD increased fronto-striatal connectivity but decreased mediotemporal-prefrontal connectivity during oddball salience processing

1f

Fusar Poli et al. 2009

DBPC pseudo-randomized, repeated measures, within-subject design. 1-month washout

THC 10 mg or CBD 600 mg or placebo

1.5 T Sigma (GE)

CBD attenuated the BOLD signal in the amygdala and anterior and posterior cingulate cortex while subjects were processing intensely fearful faces, and its suppression of the amygdalar and anterior cingulate response was correlated with the concurrent reduction in SCR fluctionations. CBD also reduced activity compared to placebo in the posterior lobe of the cerebellum for 50% fearful face stimuli

1 g

Fusar-Poli, P. et al. 2010

DBPC pseudo-randomized, repeated measures, within-subject design. 1-month washout

THC 10 mg or CBD 600 mg or placebo

1.5 T Sigma (GE)

In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not D9-THC disrupted forward connectivity between these regions during the neural response to fearful faces

1 h

Winton-Brown, T. et al. 2011

DBPC pseudo-randomized, repeated measures, within-subject design. 1-month washout

THC 10 mg or CBD 600 mg or placebo

1.5 T Sigma (GE)

CBD had no significant symptomatic effects in anxiety, intoxication, and positive psychotic symptoms. CBD was associated with activation in right temporal cortex during auditory processing

2a

Wilson, R. et al. 2019

DBRPC parallel-arm study

CHR received 600 mg CBD or matched placebo, while HC received no treatment

GeneralElectric Signa HDx 3.0 T MRI scanner

CBD attenuated the hyperactivity in the left insula/parietal operculum for CHR participants and was associated with overall slowing of reaction time

2b

Davies. C 2022

DBRPC parallel-arm study

CHR received 600 mg CBD or matched placebo, while HC received no treatment

GeneralElectric Signa HDx 3.0 T MRI scanner

Healthy controls showed a significant negative relationship between cortisol and parahippocampal activation (p = 0.023). During fear processing, increases in cortisol levels induced by social stress led to lower parahippocampal activation. This relationship was significantly different in placebo compared to healthy controls (p = 0.033) but not CBD conditions vs healthy controls (p = 0.67)

2c

Bhattacharyya 2018

DBRCT, parallel-arm study

CHR received 600 mg CBD or matched placebo, while HC received no treatment

GeneralElectric Signa HDx 3.0 T MRI scanner

In the CBD group activation was greater than in the placebo group but lower than in the control group in the right caudate during encoding and in the parahippocampal gyrus and midbrain during recall. The level of activation in the CBD group was thus intermediate to that in the other 2 groups

2d

Davies C 2020

DBRCT, parallel-arm study

CHR received 600 mg CBD or matched placebo, while HC recived no treatment

GeneralElectric Signa HDx 3.0 T MRI scanner

During fear processing, CHR participants receiving CBD showed greater activation than HC but lower activation than those who received placebo in the parahippocampal gyrus. CHR participants receiving CBD showed lower activation than HC but higher activation than those who received placebo in the striatum

 3a

Lawn, W. et al. 2020

DBRPC repeated measures, crossover design

600 mg oral dose of CBD and matched placebo

3-Tesla Siemens Prisma MRI Scanner

There was insufficient evidence to suggest that CBD altered reward-related brain activity

 3b

Bloomfeild.M 2022

DBRPC repeated measures, crossover design

600 mg oral dose of CBD and matched placebo

3-Tesla Siemens Prisma MRI Scanner

There was insufficient evidence to suggest that CBD altered brain regions associated with emotional processing or responding to emotional faces

fMRI: Resting State

3c

Michael A P Bloomfield et al 2020

DBRPC repeated measures, crossover design

600 mg CBD or placebo

3-Tesla Siemens Prisma MRI Scanner

CBD increased CBF in the hippocampus (p = 0.004). There was no effect on memory task performance, but there was a significant correlation whereby greater CBD-induced increases in orbitofrontal CBF were associated with reduced reaction time on the 2-back working memory task ( r =  − 0.73, p = 0.005)

3d

Matthew B Wall 2022

DBRPC repeated measures, crossover design

600 mg CBD or placebo

3-Tesla Siemens Prisma MRI Scanner

Compared to placebo, CBD was associated with a relative increase between areas in the posterior parietal lobes, parietooccipital sulcus, the left posterior cingulate and areas of the striatum involved in association

CBD also led to decreased connectivity was found in the right hemisphere insula and lateral frontal cortex. Furthermore, CBD relatively decreased connectivity from the striatum sensorimotor seed-region and left cerebellum

4

Grimm, O. et al. 2018

Subject observer- blinded, RCT Crossover

10 mg THC vs CBD 600 mg vs placebo

3-Tesla Siemens Trio

Increase in front striatal coupling during intake of 600 mg CBD. ROI-putamen showed increased activity with three clusters in the frontal lobe

5a

Pretzsch, C. M. et al. 2019

DBRPC, repeated-measures, cross-over study

600 mg CBD or placebo

3 T GE Excite II

Primarily driven by the ASD group, with no significant change in controls, CBD significantly increased fALFF in the right fusiform gyrus (p = 0.041) and in the cerebellar vermis VI (p = 0.048). Within the ASD group only, CBD also significantly altered vermal functional connectivity with several of its subcortical (striatal) and cortical targets

MRS

5b

Pretzsch, C. M. et al. 2019

DBRPC, repeated-measures, cross-over study

600 mg CBD or placebo

3 T GE Excite II

Across regions, CBD increased GABA + in controls, but decreased GABA + in ASD; the group difference in change in GABA + in the DMPFC was significant

PET

6

Crippa J. et al. 2004

DBRCT

400 mg CBD

Double-detector SOPHAs DST system

CBD was associated with an increased parahippocampal gyrus blood flow. CBD conditions also showed decreased blood flow to a mediotemporal cluster including the left amygdala-hippocampal complex, hypothalamus, and a cluster in the left posterior cingulate gyrus blood flow