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

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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.

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“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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Cannabis and the Anxiety of Fragmentation-A Systems Approach for Finding an Anxiolytic Cannabis Chemotype.

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“Cannabis sativa is a medicinal herb with a diverse range of chemotypes that can exert both anxiolytic and anxiogenic effects on humans. Medical cannabis patients receiving organically grown cannabis from a single source were surveyed about the effectiveness of cannabis for treating anxiety.

Patients rated cannabis as highly effective overall for treating anxiety with an average score of 8.03 on a Likert scale of 0 to 10 (0 = not effective, 10 = extremely effective).

Patients also identified which strains they found the most or least effective for relieving their symptoms of anxiety. To find correlations between anxiolytic activity and chemotype, the top four strains voted most and least effective were analyzed by HPLC-MS/MS to quantify cannabinoids and GC-MS to quantify terpenes. Tetrahydrocannabinol (THC) and trans-nerolidol have statistically significant correlations with increased anxiolytic activity.

Guiaol, eucalyptol, γ-terpinene, α-phellandrene, 3-carene, and sabinene hydrate all have significant correlations with decreased anxiolytic activity. Further studies are needed to better elucidate the entourage effects that contribute to the anxiolytic properties of cannabis varieties.”

https://www.ncbi.nlm.nih.gov/pubmed/30405331

https://www.frontiersin.org/articles/10.3389/fnins.2018.00730/full

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Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test.

SciELO - Scientific Electronic Library Online

“Cannabidiol (CBD), one of the non-psychotomimetic compounds of Cannabis sativa, causes anxiolytic-like effects in animals, with typical bell-shaped dose-response curves. No study, however, has investigated whether increasing doses of this drug would also cause similar curves in humans.

The objective of this study was to compare the acute effects of different doses of CBD and placebo in healthy volunteers performing a simulated public speaking test (SPST), a well-tested anxiety-inducing method.

Our findings confirm the anxiolytic-like properties of CBD and are consonant with results of animal studies describing bell-shaped dose-response curves. Optimal therapeutic doses of CBD should be rigorously determined so that research findings can be adequately translated into clinical practice.”

https://www.europeanneuropsychopharmacology.com/article/S0924-977X(16)31702-3/abstract

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-44462018005007102&lng=en&tlng=en

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Cannabidiol regulates the expression of hypothalamus-pituitary-adrenal axis-related genes in response to acute restraint stress.

SAGE Journals

“Research interest has grown around the potential therapeutic use of cannabidiol in mood-related disorders, due to its anxiolytic and antidepressant-like effects.

These have been partially attributed to its action as an allosteric modulator of 5-HTR1A. However, the exact mechanism supporting cannabidiol properties remains unclear.

Taken together, these data suggest the ability of cannabidiol to regulate acute stress hypothalamus-pituitary-adrenal axis activation might be explained, at least in part, by its action on 5-HTR1A receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/30324842

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