Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies

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Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases. Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson’s disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases. Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

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Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

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Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3–4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.

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Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

/by

Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3–4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.

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Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

/by

Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3–4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.

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A single-center real-life study on the use of medical cannabis in patients with dystonia

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While cannabis-based medicine is being commonly used in patients with movement disorders, there is a scarcity of publications regarding the effect of cannabis on dystonia. We aimed to describe medical cannabis use in patients with dystonia and related pain. We employed a structured interview to obtain data on the cannabis treatment regimen, perception of effectiveness and side effect profile. Eligible participants were patients diagnosed with dystonia from the movement disorders unit at the Tel-Aviv Medical Center who had used licensed medical cannabis between January 2019 and January 2021.

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Cannabidiol in the acute phase of Febrile Infection-Related Epilepsy Syndrome (FIRES)

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Febrile infection-related epilepsy syndrome (FIRES) is a prolonged refractory status epilepticus (SE) that develops among healthy individuals after a febrile infection.

FIRES treatment is challenging due to its poor response to anti-seizure medications (ASMs) and anesthetic drugs. The use of cannabidiol (CBD) as an adjunctive treatment has been suggested, albeit data about its role in the acute phase is lacking. This report describes the use of purified CBD in the acute phase of two pediatric cases of FIRES and their long-term outcome.

Both children were treated with several ASMs, immunomodulators, anesthetics, and non-pharmacological treatment (ketogenic diet). CBD was administered, as an adjunctive treatment, through nasogastric tube about 30 days after onset. SE resolved within three days of reaching the target dose and both were seizure-free for one year after.

Although it is difficult to define the extent to which each previous therapy contributed to recovery, in both cases CBD therapy was a turning point, reinforcing its potential role as add-on treatment in the acute phase of FIRES.

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The Polypharmacological Effects of Cannabidiol

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Cannabidiol (CBD) is a major phytocannabinoid present in Cannabis sativa (Linneo, 1753). This naturally occurring secondary metabolite does not induce intoxication or exhibit the characteristic profile of drugs of abuse from cannabis like Δ9-tetrahydrocannabinol (∆9-THC) does. In contrast to ∆9-THC, our knowledge of the neuro-molecular mechanisms of CBD is limited, and its pharmacology, which appears to be complex, has not yet been fully elucidated. The study of the pharmacological effects of CBD has grown exponentially in recent years, making it necessary to generate frequently updated reports on this important metabolite. In this article, a rationalized integration of the mechanisms of action of CBD on molecular targets and pharmacological implications in animal models and human diseases, such as epilepsy, pain, neuropsychiatric disorders, Alzheimer’s disease, and inflammatory diseases, are presented. We identify around 56 different molecular targets for CBD, including enzymes and ion channels/metabotropic receptors involved in neurologic conditions. Herein, we compiled the knowledge found in the scientific literature on the multiple mechanisms of actions of CBD. The in vitro and in vivo findings are essential for fully understanding the polypharmacological nature of this natural product.

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Cannabidiol for neurodegenerative disorders: A comprehensive review

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This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.

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Intracellular Molecular Targets and Signaling Pathways Involved in Antioxidative and Neuroprotective Effects of Cannabinoids in Neurodegenerative Conditions

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In the last few decades, endocannabinoids, plant-derived cannabinoids and synthetic can- nabinoids have received growing interest as treatment options in neurodegenerative conditions. In various experimental settings, they have displayed antioxidative, anti-inflammatory, antiapoptotic, immunomodulatory, and neuroprotective effects. However, due to numerous targets and down- stream effectors of their action, the cellular and molecular mechanisms underlying these effects are rather complex and still under discussion.

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A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid

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The endocannabinoid system (ECS), a conserved physiological system emerged as a novel pharmacological target for its significant role and potential therapeutic benefits ranging from neurological diseases to cancer. Among both, CB1 and CB2R types, CB2R have received attention for its pharmacological effects as antioxidant, anti-inflammatory, immunomodulatory and antiapoptotic that can be achieved without causing psychotropic adverse effects through CB1R.

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The Potential Benefits of Palmitoylethanolamide in Palliation: A Qualitative Systematic Review.

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Authors: Mellar P. Davis, Bertrand Behm, Zankhana Mehta, Carlos Fernandez
American Journal of Hospice and Palliative Medicine, December 2019
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Palmitoylethanolamide (PEA) is a nutraceutical endocannabinoid that was retrospectively discovered in egg yolks. Feeding poor children with known streptococcal infections prevented rheumatic fever. Subsequently, it was found to alter the course of influenza. Unfortunately, the…

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A Systematic Review of the Effectiveness of Medical Cannabis for Psychiatric, Movement and Neurodegenerative Disorders.

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Authors: Keane Lim, Yuen Mei See, and Jimmy Lee
Clinical Psychopharmacology and Neuroscience, 30 November 2017
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The discovery of endocannabinoid’s role within the central nervous system and its potential therapeutic benefits have brought forth rising interest in the use of cannabis for medical purposes. The present review aimed to synthesize and evaluate the available evidences on the e…

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