Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration-effect relations using the IB-de-risk tool

BACKGROUND: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Dosing guidelines to inform future human studies are however lacking. AIM: We aimed to predict the therapeutic window for anxiety-reducing effects of CBD in humans based on preclinical models. METHODS: We conducted two systematic searches in PubMed and Embase up to August 2021, into pharmacokinetic (PK) and pharmacodynamic (PD) data of systemic CBD exposure in humans and animals, which includes anxiety-reducing and potential side effects. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. A control group was an inclusion criterion in outcome studies. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool for a translational integration of outcomes. RESULTS: We synthesised data from 87 studies. For most observations (70.3%), CBD had no effect on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiety-reducing effects seemed to be clustered in certain concentration ranges, which differed between species. DISCUSSION: A straightforward dosing recommendation was not possible, given variable concentration-effect relations across species, and no consistent linear effect of CBD on anxiety reduction. Currently, these results raise questions about the broad use as a drug for anxiety. Meta-analytic studies are needed to quantitatively investigate drug efficacy, including aspects of anxiety symptomatology. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations

Testing the effects of Delta9-THC and D-cycloserine on extinction of conditioned fear in humans

Item does not contain fulltextPreclinical evidence implicates several neurotransmitter systems in the extinction of conditioned fear. These results are of great interest, because the reduction of acquired fear associations is critical in therapies for anxiety disorders. We tested whether findings with respect to the N-methyl-D-aspartate (NMDA) and cannabinoid receptor (CB) systems in animals carry over to healthy human subjects. To that end, we administered selected doses of D-cycloserine (partial NMDA receptor agonist, 250 mg), delta-9-tetrahydrocannabinol (THC, CB(1) receptor agonist, 10 mg), or placebo prior to the extinction session of a 3-day conditioning protocol. D-cycloserine did not affect within-session extinction, or the retention of extinction in healthy human participants, in contrast with patient data but in line with previous reports in healthy volunteers. During extinction training, Delta9-THC reduced conditioned skin conductance responses, but not fear-potentiated startle. This effect was not retained at the retention test 2 days later, suggesting it was dependent on acute effects of the drug. Our findings implicate that facilitation of the CB(1) or NMDA system with the substances used in this study does not affect conditioned fear extinction lastingly in healthy humans. The apparent discrepancy between these findings and the results from (pre-)clinical trials is discussed in terms of room for improvement in these systems in healthy volunteers, and the lack of specificity of THC as a CB(1) agonist

Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration-effect relations using the IB-de-risk tool

BACKGROUND: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Dosing guidelines to inform future human studies are however lacking. AIM: We aimed to predict the therapeutic window for anxiety-reducing effects of CBD in humans based on preclinical models. METHODS: We conducted two systematic searches in PubMed and Embase up to August 2021, into pharmacokinetic (PK) and pharmacodynamic (PD) data of systemic CBD exposure in humans and animals, which includes anxiety-reducing and potential side effects. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. A control group was an inclusion criterion in outcome studies. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool for a translational integration of outcomes. RESULTS: We synthesised data from 87 studies. For most observations (70.3%), CBD had no effect on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiety-reducing effects seemed to be clustered in certain concentration ranges, which differed between species. DISCUSSION: A straightforward dosing recommendation was not possible, given variable concentration-effect relations across species, and no consistent linear effect of CBD on anxiety reduction. Currently, these results raise questions about the broad use as a drug for anxiety. Meta-analytic studies are needed to quantitatively investigate drug efficacy, including aspects of anxiety symptomatology. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (β = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (β = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens

sj-xlsx-7-jop-10.1177_02698811221124792 – Supplemental material for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool

Supplemental material, sj-xlsx-7-jop-10.1177_02698811221124792 for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool by Caroline MB Kwee, Joop MA van Gerven, Fleur LP Bongaerts, Danielle C Cath, Gabriël Jacobs, Johanna MP Baas and Lucianne Groenink in Journal of Psychopharmacolog

Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (β = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (β = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens

sj-xlsx-9-jop-10.1177_02698811221124792 – Supplemental material for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool

Supplemental material, sj-xlsx-9-jop-10.1177_02698811221124792 for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool by Caroline MB Kwee, Joop MA van Gerven, Fleur LP Bongaerts, Danielle C Cath, Gabriël Jacobs, Johanna MP Baas and Lucianne Groenink in Journal of Psychopharmacolog

sj-xlsx-10-jop-10.1177_02698811221124792 – Supplemental material for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool

Supplemental material, sj-xlsx-10-jop-10.1177_02698811221124792 for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool by Caroline MB Kwee, Joop MA van Gerven, Fleur LP Bongaerts, Danielle C Cath, Gabriël Jacobs, Johanna MP Baas and Lucianne Groenink in Journal of Psychopharmacolog

sj-xlsx-5-jop-10.1177_02698811221124792 – Supplemental material for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool

Supplemental material, sj-xlsx-5-jop-10.1177_02698811221124792 for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool by Caroline MB Kwee, Joop MA van Gerven, Fleur LP Bongaerts, Danielle C Cath, Gabriël Jacobs, Johanna MP Baas and Lucianne Groenink in Journal of Psychopharmacolog

sj-xlsx-6-jop-10.1177_02698811221124792 – Supplemental material for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool

Supplemental material, sj-xlsx-6-jop-10.1177_02698811221124792 for Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration–effect relations using the IB-de-risk tool by Caroline MB Kwee, Joop MA van Gerven, Fleur LP Bongaerts, Danielle C Cath, Gabriël Jacobs, Johanna MP Baas and Lucianne Groenink in Journal of Psychopharmacolog