Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age.

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“Among the many cannabinoids in the cannabis plant, cannabidiol (CBD) is a compound that does not produce the typical subjective effects of marijuana.

The aim of the present review is to describe the main advances in the development of the experimental and clinical use of cannabidiol CBD in neuropsychiatry.

CBD was shown to have anxiolytic, antipsychotic and neuroprotective properties. In addition, basic and clinical investigations on the effects of CBD have been carried out in the context of many other health conditions, including its potential use in epilepsy, substance abuse and dependence, schizophrenia, social phobia, post-traumatic stress, depression, bipolar disorder, sleep disorders, and Parkinson.

CBD is an useful and promising molecule that may help patients with a number of clinical conditions. Controlled clinical trials with different neuropsychiatric populations that are currently under investigation should bring important answers in the near future and support the translation of research findings to clinical settings.”

https://www.ncbi.nlm.nih.gov/pubmed/30298064

https://www.frontiersin.org/articles/10.3389/fimmu.2018.02009/full

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Acute foot-shock stress decreased seizure susceptibility against pentylenetetrazole-induced seizures in mice: Interaction between endogenous opioids and cannabinoids.

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“Stressful conditions affect the brain’s neurotransmission and neural pathways that are involved in seizure susceptibility. Stress alters the intensity and/or frequency of seizures.

Although evidence indicates that chronic stress exerts proconvulsant effects and acute stress has anticonvulsant properties, the underlying mechanisms which mediate these effects are not well understood.

In the present study, we assessed the role of endogenous opioids, endocannabinoids, as well as functional interaction between opioid and cannabinoid systems in the anticonvulsant effects of acute foot-shock stress (FSS) against pentylenetetrazole (PTZ)-induced seizures in mice.

CONCLUSIONS:

Opioid and cannabinoid systems are involved in the anticonvulsant effects of acute FSS, and these neurotransmission systems interact functionally in response to acute FSS.”

https://www.ncbi.nlm.nih.gov/pubmed/30170259

https://www.epilepsybehavior.com/article/S1525-5050(17)30777-1/fulltext

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A Brief Background on Cannabis: From Plant to Medical Indications.

 Ingenta Connect

“Cannabis has been used as a medicinal plant for thousands of years.

As a result of centuries of breeding and selection, there are now over 700 varieties of cannabis that contain hundreds of compounds, including cannabinoids and terpenes.

Cannabinoids are fatty compounds that are the main biological active constituents of cannabis. Terpenes are volatile compounds that occur in many plants and have distinct odors.

Cannabinoids exert their effect on the body by binding to receptors, specifically cannabinoid receptors types 1 and 2. These receptors, together with endogenous cannabinoids and the systems for synthesis, transport, and degradation, are called the Endocannabinoid System.

The two most prevalent and commonly known cannabinoids in the cannabis plant are delta-9-tetrahydrocannabinol (THC) and cannabidiol.

The speed, strength, and type of effects of cannabis vary based on the route of administration. THC is rapidly distributed through the body to fatty tissues like the brain and is metabolized by the cytochrome P450 system to 11-hydroxy-THC, which is also psychoactive.

Cannabis and cannabinoids have been indicated for several medical conditions.

There is evidence of efficacy in the symptomatic treatment of nausea and vomiting, pain, insomnia, post-traumatic stress disorder, anxiety, loss of appetite, Tourette’s syndrome, and epilepsy. Cannabis has also been associated with treatment for glaucoma, Huntington’s Disease, Parkinson’s Disease, and dystonia, but there is not good evidence to support its efficacy. Side effects of cannabis include psychosis and anxiety, which can be severe.

Here, we provided a summary of the history of cannabis, its pharmacology, and its medical uses.”

https://www.ncbi.nlm.nih.gov/pubmed/30139415

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Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to Confirmation in Human Trials.

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“Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects.

Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD.

Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of Δ9-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system.

These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well.

Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD.

The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.”

https://www.ncbi.nlm.nih.gov/pubmed/30087591

https://www.frontiersin.org/articles/10.3389/fnins.2018.00502/full

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Modulation of the endocannabinoid system by sex hormones: Implications for Posttraumatic Stress Disorder.

Neuroscience & Biobehavioral Reviews

“The endocannabinoid system is an increasingly recognised pharmacological target for treating stress and anxiety disorders, including post-traumatic stress disorder (PTSD). Recent preclinical developments have implicated the endocannabinoid system in stress responses, emotional memories and fear extinction, all critical to PTSD aetiology. However, preclinical research in endocannabinoid biology has neglected the influential role of sex hormone differences on PTSD symptomology, which is particularly important given that PTSD is twice as common in women as in men. In this review, we compile and consider the evidence that the endocannabinoid system is influenced by ovarian hormones, with application to stress disorders such as PTSD. It is clear that therapeutic modulation of the endocannabinoid system needs to be approached with awareness of ovarian hormonal influences, and knowledge of these influences may enhance treatment outcomes for female PTSD populations.”

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Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity.

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“Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses.

Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD.

We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA).

The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.”

https://www.ncbi.nlm.nih.gov/pubmed/29977073

https://www.nature.com/articles/s41386-018-0135-4

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The Lateral Habenula Directs Coping Styles Under Conditions of Stress Via Recruitment of the Endocannabinoid System.

Biological Psychiatry Home

“The ability to effectively cope with stress is a critical determinant of disease susceptibility.

The lateral habenula (LHb) and the endocannabinoid (ECB) system have independently been shown to be involved in the selection of stress coping strategies, yet the role of ECB signaling in the LHb remains unknown.

CONCLUSIONS:

Alterations in LHb ECB signaling may be relevant for development of stress-related pathologies in which LHb dysfunction and stress-coping impairments are hallmark symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/29887035

https://www.biologicalpsychiatryjournal.com/article/S0006-3223(18)31473-2/fulltext

“Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood.” https://www.ncbi.nlm.nih.gov/pubmed/27317195

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Review of the neurological benefits of phytocannabinoids.

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“Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.

METHODS:

In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.

RESULTS:

Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.

CONCLUSIONS:

In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/29770251

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/

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A Naturalistic Examination of the Perceived Effects of Cannabis on Negative Affect

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“Cannabis is commonly used to alleviate symptoms of negative affect. However, a paucity of research has examined the acute effects of cannabis on negative affect in everyday life.

The current study provides a naturalistic account of perceived changes in symptoms of depression, anxiety, and stress as a function of dose and concentration of Δ9tetrahydrocannabinol (THC) and cannabidiol (CBD).

Cannabis is commonly used to alleviate depression, anxiety, and stress. Indeed, one of the most commonly reported motives for cannabis use is to cope with stress, with 72% of daily cannabis users reporting use of cannabis to relax or relieve tension.

Results from the present study indicate that medical cannabis users report a substantial and significant reduction in symptoms of negative affect shortly after using cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/29656267

https://www.sciencedirect.com/science/article/pii/S0165032718303100

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Glucocorticoid-endocannabinoid uncoupling mediates fear suppression deficits after early – Life stress.

Psychoneuroendocrinology

“Early-life stress (ELS) creates life-long vulnerability to stress-related anxiety disorders through altering stress and fear systems in the brain.

The endocannabinoid system has emerged as an important regulator of the stress response through a crosstalk with the glucocorticoid system, yet whether it plays a role in the persistent effects of ELS remains unanswered. By combining, behavioral, pharmacological and biochemical approaches in adult male rats, we examined the impact of ELS on the regulation of endocannabinoid function by stress and glucocorticoids.

These findings suggest that ELS results in an uncoupling of glucocorticoid-endocannabinoid signaling in the hippocampus, which, in turn, relates to alterations in stress regulation of memory recall. These data provide compelling evidence that ELS-induced deficits in the glucocorticoid-endocannabinoidcoupling following stress could predispose susceptibility to stress-related psychopathology.”

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