Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report.

“Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naïve patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety (p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus (p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus (p < 0.001, uncorrected).

These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.”

http://www.ncbi.nlm.nih.gov/pubmed/20829306

Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats.

“The present study investigated the central effects of the eCB uptake/metabolism inhibitor AM404 and the phytocannabinoid cannabidiol (CBD) on the extinction of contextual fear memories in rats…

… In conclusion, CBD, a non-psychoactive phytocannabinoid could be an interesting pharmacological approach to reduce the anxiogenic effects of stress and promote the extinction of fear memories.”

http://www.ncbi.nlm.nih.gov/pubmed/18706790

Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives.

“Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. The main psychoactive ingredient of hemp, Δ9-tetrahydrocannabinol (THC), and its synthetic cannabinoid analogs have been reported to either attenuate or exacerbate anxiety and fear-related behaviors in humans and experimental animals. The heterogeneity of cannabis-induced psychological outcomes reflects a complex network of molecular interactions between the key neurobiological substrates of anxiety and fear and the endogenous cannabinoid system, mainly consisting of the arachidonic acid derivatives anandamide and 2-arachidonoylglycerol (2-AG) and two receptors, respectively termed CB1 and CB2. The high degree of interindividual variability in the responses to cannabis is contributed by a wide spectrum of factors, including genetic and environmental determinants, as well as differences in the relative concentrations of THC and other alkaloids (such as cannabidiol) within the plant itself.

The present article reviews the currently available knowledge on the herbal, synthetic and endogenous cannabinoids with respect to the modulation of anxiety responses, and highlights the challenges that should be overcome to harness the therapeutic potential of some of these compounds, all the while limiting the side effects associated with cannabis consumption. In addition the article presents some promising patents on cannabinoid-related agents.”

http://www.ncbi.nlm.nih.gov/pubmed/22280339

Anti-Aversive Effects of Cannabidiol on Innate Fear-Induced Behaviors Evoked by an Ethological Model of Panic Attacks Based on a Prey vs the Wild Snake Epicrates cenchria crassus Confrontation Paradigm

“Research on the interaction between different compounds extracted from the plant Cannabis sativa (Cannabis) and the endocannabinoid system has revealed a series of ligands that selectively bind to cannabinoid receptors. The activation of this system causes a wide spectrum of responses, some of which could be potentially therapeutic. Recently, much attention has been given to cannabidiol (CBD), a major constituent of Cannabis that is unable to mimic all of the effects of the plant but has a wide range of pharmacological effects. In the elevated plus-maze, this drug produces an anxiolytic-like effect…

… attention has been given to the potential anxiolytic properties of cannabidiol, because of its complex actions on the endocannabinoid system together with its effects on other neurotransmitter systems. The aim of this study was to investigate the effects of cannabidiol on innate fear-related behaviors evoked by a prey vs predator paradigm…

These results show that cannabidiol modulates defensive behaviors evoked by the presence of threatening stimuli…

In summary, the data presented in this study suggest that the complex action of CBD on the endocannabinoid-mediated system, together with its putative effect on the serotonin-mediated system, could have a pivotal role in the regulation of emotional states and thus constitute a novel pharmacological target for anti-panic therapy.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242302/

The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors.

“Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic-like effects in rodents and humans after systemic administration. Previous results from our group showed that CBD injection into the bed nucleus of the stria terminalis (BNST) attenuates conditioned aversive responses. The aim of this study was to further investigate the role of this region on the anxiolytic effects of the CBD. Moreover, considering that CBD can activate 5-HT1A receptors, we also verified a possible involvement of these receptors in those effects.

CONCLUSIONS:

These results give further support to the proposal that BNST is involved in the anxiolytic-like effects of CBD observed after systemic administration, probably by facilitating local 5-HT1A receptor-mediated neurotransmission.”

http://www.ncbi.nlm.nih.gov/pubmed/20945065

5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats.

“Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa which induces anxiolytic- and antipsychotic-like effects in rodents. These effects could be mediated by facilitation of the endocannabinoid system or by the activation of 5-HT(1A) receptors. As either of these mechanisms could promote adaptation to inescapable stress, the aim of the present work was to test the hypothesis that CBD would attenuate the autonomic and behavioural consequences of restraint stress (RS). We also investigated if the responses to CBD depended on activation of 5-HT(1A) receptors.

Cannabidiol (CBD)… cannabinoid generally found in relatively high concentrations in cannabis, exhibits a somewhat different pharmacology compared with THC. CBD attenuates the psychotomimetic and anxiogenic effects of THC in humans.

 Moreover, systemic administration of CBD induced antipsychotic and anxiolytic-like effects…

CONCLUSION AND IMPLICATIONS:

The results suggest that CBD can attenuate acute autonomic responses to stress and its delayed emotional consequences by facilitating 5-HT(1A) receptor-mediated neurotransmission.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697769/

 

Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats.

“Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that induces anxiolytic effects… In addition, since CBD has been shown to inhibit anandamide metabolism, CB1 receptors could also be involved in the effects of this cannabinoid…

CBD injected into the dorsolateral periaqueductal gray (dlPAG) produced anxiolytic-like effects… The anxiolytic effect of CBD was confirmed in the  Vogel conflict test (VCT)…

CONCLUSION:

These results suggest the CBD interacts with 5HT1A receptors to produce anxiolytic effects in the dlPAG.”

http://www.ncbi.nlm.nih.gov/pubmed/18446323

Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors.

“Posttraumatic stress disorder (PTSD) is an incapacitating syndrome that follows a traumatic experience. Predator exposure promotes long-lasting anxiogenic effect in rodents, an effect related to symptoms found in PTSD patients. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa with anxiolytic effects. The present study investigated the anti-anxiety actions of CBD administration in a model of PTSD…

 Repeated administration of CBD prevented long-lasting anxiogenic effects promoted by a single predator exposure…

 In conclusion, predator exposure promotes long-lasting up-regulation of 5HT1A receptor gene expression in the hippocampus and frontal cortex. Repeated CBD administration prevents the long-lasting anxiogenic effects observed after predator exposure probably by facilitating 5HT1A receptors neurotransmission.

Our results suggest that CBD has beneficial potential for PTSD treatment and that 5HT1A receptors could be a therapeutic target in this disorder.”

http://www.ncbi.nlm.nih.gov/pubmed/22979992

Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test.

“Cannabidiol (CBD) is a major constituent of the Cannabis sativa plant. It inhibits the anxiogenic activity of high doses of Delta9-tetrahydrocannabinol and induces anxiolytic-like effects. However, the mechanisms underlying the actions of CBD are unknown. Therefore, the aim of the present study was to test the effects of CBD in the Vogel test, a widely used animal model of anxiety. 

 In conclusion, CBD induced an anticonflict effect not mediated by benzodiazepine receptors or by non-specific drug interference on nociceptive threshold or water consumption.

These results reinforce the hypothesis that this cannabinoid has anxiolytic properties.”

http://www.ncbi.nlm.nih.gov/pubmed/16876926

Endocannabinoid system dysfunction in mood and related disorders.

“The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders.

We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement.

CONCLUSION:

Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential.”

http://www.ncbi.nlm.nih.gov/pubmed/21916860