A systematic review of cannabidiol dosing in clinical populations.

British Journal of Clinical Pharmacology banner“Cannabidiol is a cannabis-derived medicinal product with potential application in a wide-variety of contexts, however its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of cannabidiol in a variety of medical contexts.

RESULTS:

A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. 23 studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 – 50 mg/Kg/day. Plasma concentrations were not provided in any publication. Cannabidiol was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of cannabidiol on reducing seizure frequency or severity (average 15 mg/Kg/day within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n=6-62) assessing diabetes, Crohn’s disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/Kg/day) were used in these studies.

CONCLUSION:

This review highlights cannabidiol has a potential wide range of activity in several pathologies. Pharmacokinetic studies as well as conclusive phase III trials to elucidate effective plasma concentrations within medical contexts are severely lacking and highly encouraged.”

https://www.ncbi.nlm.nih.gov/pubmed/31222854

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.14038

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Cannabidiol (CBD) reduces anxiety-related behavior in mice via an FMRP1-independent mechanism.

Pharmacology Biochemistry and Behavior

“Fragile X Syndrome is a neurodevelopmental disorder which affects intellectual, social and physical development due to mutation of the Fragile X mental retardation 1 (FMR1) gene. The resultant loss of Fragile X mental retardation protein can be modelled by Fmr1 gene knockout (KO) in mice.

The current study investigated the behavioural effects of cannabidiol (CBD; a non-psychoactive phytocannabinoid) in male Fmr1 KO mice as a preclinical model for therapeutic discovery.

Overall, acute CBD at the doses chosen did not selectively normalize behavioural abnormalities in Fmr1 KO mice, but reduced anxiety-like behaviour in both Fmr1 KO and WT mice.” https://www.ncbi.nlm.nih.gov/pubmed/31063743

“Acute cannabidiol (CBD) decreased anxiety-related behaviours in both Fmr1 knockout mice and wildtype controls in the elevated plus maze. Fmr1 KO mice were hyperlocomotive, showed fewer anxiety-related behaviours and habituated more slowly to a novel environment than controls. Acute CBD had no impact on locomotion, spatial working memory or fear-associated memory in Fmr1 knockout mice or controls.”   https://www.sciencedirect.com/science/article/pii/S0091305718306464?via%3Dihub

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Cannabinoid Regulation of Fear and Anxiety: an Update.

 

“Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety.

RECENT FINDINGS:

Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging. Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.”

https://www.ncbi.nlm.nih.gov/pubmed/31030284

https://link.springer.com/article/10.1007%2Fs11920-019-1026-z

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Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of Tuberous Sclerosis Complex.

Behavioural Brain Research

“Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in the TSC1 or TSC2 genes and is characterized by widespread tumour growth, intractable epilepsy, cognitive deficits and autistic behaviour.

CBD has been reported to decrease seizures and inhibit tumour cell progression, therefore we sought to determine the influence of CBD on TSC pathology in zebrafish carrying a nonsense mutation in the tsc2 gene.

CBD treatment from 6 to 7 days post-fertilization (dpf) induced significant anxiolytic actions without causing sedation. Furthermore, CBD treatment from 3 dpf had no impact on tsc2-/- larvae motility nor their survival. CBD treatment did, however, reduce the number of phosphorylated rpS6 positive cells, and their cross-sectional cell size. This suggests a CBD mediated suppression of mechanistic target of rapamycin (mTOR) activity in the tsc2-/- larval brain.

Taken together, these data suggest that CBD selectively modulates levels of phosphorylated rpS6 in the brain and additionally provides an anxiolytic effect. This is pertinent given the alterations in mTOR signalling in experimental models of TSC. Additional work is necessary to identify upstream signal modulation and to further justify the use of CBD as a possible therapeutic strategy to manage TSC.”

https://www.ncbi.nlm.nih.gov/pubmed/30684511

https://www.sciencedirect.com/science/article/pii/S0166432818311215?via%3Dihub

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Reduction of Benzodiazepine Use in Patients Prescribed Medical Cannabis

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Benzodiazepines are a class of medication with sedative properties, commonly used for anxiety and other neurological conditions. These medications are associated with several well-known adverse effects.

This observational study aims to investigate the reduction of benzodiazepine use in patients using prescribed medical cannabis.

Within a cohort of 146 patients initiated on medical cannabis therapy, 45.2% patients successfully discontinued their pre-existing benzodiazepine therapy.

Medical cannabis remains a controversial but potentially effective treatment for patients suffering from a variety of medical conditions. Within a cohort of patients initiated on medical cannabis therapy, a large proportion successfully discontinued their pre-existing benzodiazepine therapy.

This study therefore supports the continued research of medical cannabis and urges further exploration into its therapeutic value.”

https://www.liebertpub.com/doi/10.1089/can.2018.0020

“A significant number of cannabis patients discontinue use of benzodiazepines”  https://www.psypost.org/2019/05/a-significant-number-of-cannabis-patients-discontinue-use-of-benzodiazepines-53636

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Cannabidiol in Anxiety and Sleep: A Large Case Series.

“Cannabidiol (CBD) is one of many cannabinoid compounds found in cannabis. It does not appear to alter consciousness or trigger a “high.”

A recent surge in scientific publications has found preclinical and clinical evidence documenting value for CBD in some neuropsychiatric disorders, including epilepsy, anxiety, and schizophrenia. Evidence points toward a calming effect for CBD in the central nervous system. Interest in CBD as a treatment of a wide range of disorders has exploded, yet few clinical studies of CBD exist in the psychiatric literature.

OBJECTIVE:

To determine whether CBD helps improve sleep and/or anxiety in a clinical population.

DESIGN:

A large retrospective case series at a psychiatric clinic involving clinical application of CBD for anxiety and sleep complaints as an adjunct to usual treatment. The retrospective chart review included monthly documentation of anxiety and sleep quality in 103 adult patients.

MAIN OUTCOME MEASURES:

Sleep and anxiety scores, using validated instruments, at baseline and after CBD treatment.

RESULTS:

The final sample consisted of 72 adults presenting with primary concerns of anxiety (n = 47) or poor sleep (n = 25). Anxiety scores decreased within the first month in 57 patients (79.2%) and remained decreased during the study duration. Sleep scores improved within the first month in 48 patients (66.7%) but fluctuated over time. In this chart review, CBD was well tolerated in all but 3 patients.

CONCLUSION:

Cannabidiol may hold benefit for anxiety-related disorders. Controlled clinical studies are needed.”

https://www.ncbi.nlm.nih.gov/pubmed/30624194

http://www.thepermanentejournal.org/issues/2019/winter/6960-cannabis.html

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Tempering aversive/traumatic memories with cannabinoids: a review of evidence from animal and human studies.

“Aversive learning and memory are essential to cope with dangerous and stressful stimuli present in an ever-changing environment. When this process is dysfunctional, however, it is associated with posttraumatic stress disorder (PTSD). The endocannabinoid (eCB) system has been implicated in synaptic plasticity associated with physiological and pathological aversive learning and memory.

OBJECTIVE AND METHODS:

The objective of this study was to review and discuss evidence on how and where in the brain genetic or pharmacological interventions targeting the eCB system would attenuate aversive/traumatic memories through extinction facilitation in laboratory animals and humans. The effect size of the experimental intervention under investigation was also calculated.

RESULTS:

Currently available data indicate that direct or indirect activation of cannabinoid type-1 (CB1) receptor facilitates the extinction of aversive/traumatic memories. Activating CB1 receptors around the formation of aversive/traumatic memories or their reminders can potentiate their subsequent extinction. In most cases, the effect size has been large (Cohen’s d ≥ 1.0). The brain areas responsible for the above mentioned effects include the medial prefrontal cortex, amygdala, and/or hippocampus. The potential role of cannabinoid type-2 (CB2) receptors in extinction learning is now under investigation.

CONCLUSION:

Drugs augmenting the brain eCB activity can temper the impact of aversive/traumatic experiences by diverse mechanisms depending on the moment of their administration. Considering the pivotal role the extinction process plays in PTSD, the therapeutic potential of these drugs is evident. The sparse number of clinical trials testing these compounds in stress-related disorders is a gap in the literature that needs to be addressed.”

https://www.ncbi.nlm.nih.gov/pubmed/30604182

https://link.springer.com/article/10.1007%2Fs00213-018-5127-x

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Exploiting the Multifaceted Effects of Cannabinoids on Mood to Boost Their Therapeutic Use Against Anxiety and Depression.

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“The endocannabinoid system (ECS) has been recently recognized as a prominent promoter of the emotional homeostasis, mediating the effects of different environmental signals including rewarding and stressing stimuli. The complex influences of the ECS on both the environmental and internal stimuli processing, make the cannabinoid-based drugs an appealing option to treat different psychiatric conditions. In particular, better knowledge of the multifaceted effects of cannabinoids could help to understand how to boost their therapeutic use in anxiety and depression treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30515077

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00424/full

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Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain

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“Clinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis that interacts with the serotonin (5-HT)1A receptor, may possess analgesic and anxiolytic effects.

Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/30157131

https://insights.ovid.com/crossref?an=00006396-900000000-98870

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Inhibition of Monoacylglycerol Lipase Reduces the Reinstatement of Methamphetamine-Seeking and Anxiety-Like Behaviors in Methamphetamine Self-Administered Rats.

 Image result for international journal of neuropsychopharmacology

“Methamphetamine is a highly addictive psychostimulant with reinforcing properties. Our laboratory previously found that Δ8-tetrahydrocannabinol, an exogenous cannabinoid, suppressed the reinstatement of methamphetamine-seeking behavior.

The purpose of this study was to determine whether the elevation of endocannabinoids modulates the reinstatement of methamphetamine-seeking behavior and emotional changes in methamphetamine self-administered rats.

RESULTS:

JZL184 (32 and 40 mg/kg, i.p.), an inhibitor of monoacylglycerol lipase, significantly attenuated both the cue- and stress-induced reinstatement of methamphetamine-seeking behavior. Furthermore, URB597 (3.2 and 10 mg/kg, i.p.), an inhibitor of fatty acid amide hydrolase, attenuated only cue-induced reinstatement. AM251, a cannabinoid CB1 receptor antagonist, antagonized the attenuation of cue-induced reinstatement by JZL184 but not URB597. Neither JZL184 nor URB597 reinstated methamphetamine-seeking behavior when administered alone. In the elevated plus-maze test, rats that were in withdrawal from methamphetamine self-administration spent less time in the open arms. JZL184 ameliorated the decrease in time spent in the open arms.

CONCLUSION:

We showed that JZL184 reduced both the cue- and stress-induced reinstatement of methamphetamine-seeking and anxiety-like behaviors in rats that had self-administered methamphetamine. It was suggested that a decrease in 2-arachidonoylglycerol in the brain could drive the reinstatement of methamphetamine-seeking and anxiety-like behaviors.”

https://www.ncbi.nlm.nih.gov/pubmed/30481332

https://academic.oup.com/ijnp/advance-article/doi/10.1093/ijnp/pyy086/5210886

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