Benefits and Risks of Therapeutic Cannabinoids for Neurologic Disorders

Clinical Therapeutics Home

“The Cannabis genus originated in Central Asia and is probably one of the most ancient nonfood crops to be cultivated by humans. Its medicinal properties have been recognized for centuries. Isolation of the psychoactive compound, Δ9-tetrahydrocannabinol, followed by the identification of cannabidiol, led to increased focus on the therapeutic potential of the plant. One of the prominent species, Cannabis sativa, may produce more than 100 different cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/30224192

https://www.clinicaltherapeutics.com/article/S0149-2918(18)30331-X/fulltext

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor.

Image result for molecular brain journal

“Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer.

CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke.

In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion.

These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R-/- mice. Thus, CBD displays antagonist-like activity toward σ1R to reduce the negative effects of NMDAR overactivity in the abovementioned experimental situations.”

https://www.ncbi.nlm.nih.gov/pubmed/30223868

https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-018-0395-2

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Exploring the Ligand Efficacy of Cannabinoid Receptor 1 (CB1) using Molecular Dynamics Simulations.

Scientific Reports

“Cannabinoid receptor 1 (CB1) is a promising therapeutic target for a variety of disorders. Distinct efficacy profiles showed different therapeutic effects on CB1 dependent on three classes of ligands: agonists, antagonists, and inverse agonists. To discriminate the distinct efficacy profiles of the ligands, we carried out molecular dynamics (MD) simulations to identify the dynamic behaviors of inactive and active conformations of CB1 structures with the ligands. In addition, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method was applied to analyze the binding free energy decompositions of the CB1-ligand complexes. With these two methods, we found the possibility that the three classes of ligands can be discriminated. Our findings shed light on the understanding of different efficacy profiles of ligands by analyzing the structural behaviors of intact CB1 structures and the binding energies of ligands, thereby yielding insights that are useful for the design of new potent CB1 drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/30213978

https://www.nature.com/articles/s41598-018-31749-z

“Chemical structure of the partial agonist THC, antagonist THCV, and inverse agonist Taranabant.”

Figure 1

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Role of the endocannabinoid system in drug addiction.

Biochemical Pharmacology

“Drug addiction is a chronic relapsing disorder that produces a dramaticglobal health burden worldwide. Not effective treatment of drug addiction is currently available probably due to the difficulties to find an appropriate target to manage this complex disease raising the needs for further identification of novel therapeutic approaches.

The endocannabinoid system has been found to play a crucial role in the neurobiological substrate underlying drug addiction.

Endocannabinoids and cannabinoid receptors are widely expressed in the main areas of the mesocorticolimbic system that participate in the initiation and maintenance of drug consumption and in the development of compulsion and loss of behavioral control occurring during drug addiction.

The identification of the important role played by CB1 cannabinoid receptors in drug addiction encouraged the possible used of an early commercialized CB1 receptor antagonist for treating drug addiction.

However, the incidence of serious psychiatric adverse events leaded to the sudden withdrawal from the market of this CB1 antagonist and all the research programs developed by pharmaceutical companies to obtain new CB1 antagonists were stopped.

Currently, new research strategies are under development to target the endocannabinoid system for drug addiction avoiding these side effects, which include allosteric negative modulators of CB1 receptors and compounds targeting CB2 receptors.

Recent studies showing the potential role of CB2 receptors in the addictive properties of different drugs of abuse have open a promising research opportunity to develop novel possible therapeutic approaches.”

https://www.ncbi.nlm.nih.gov/pubmed/30217570

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303952

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Endocannabinoids in the treatment of gasytrointestinal inflammation and symptoms.

 Current Opinion in Pharmacology

“The evolving policies regarding the use of therapeutic Cannabis have steadily increased the public interest in its use as a complementary and alternative medicine in several disorders, including inflammatory bowel disease.

Endocannabinoids represent both an appealing therapeutic strategy and a captivating scientific dilemma.

Results from clinical trials have to be carefully interpreted owing to possible reporting-biases related to cannabinoids psychotropic effects. Moreover, discriminating between symptomatic improvement and the real gain on the underlying inflammatory process is often challenging.

This review summarizes the advances and latest discovery in this ever-changing field of investigation, highlighting the main limitations in the current use of these drugs in clinical practice and the possible future perspectives to overcome these flaws.”

https://www.ncbi.nlm.nih.gov/pubmed/30218940

https://www.sciencedirect.com/science/article/pii/S1471489218300183?via%3Dihub

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors.

Brain, Behavior, and Immunity

“The chronic use of drugs that reduce the dopaminergic neurotransmission can cause a hyperkinetic movement disorder called tardive dyskinesia (TD). The pathophysiology of this disorder is not entirely understood but could involve oxidative and neuroinflammatory mechanisms.

Cannabidiol (CBD), the major non-psychotomimetic compound present in Cannabis sativa plant, could be a possible therapeutic alternative for TD. This phytocannabinoid shows antioxidant, anti-inflammatory and antipsychotic properties and decreases the acute motor effects of classical antipsychotics.

The present study investigated if CBD would attenuate orofacial dyskinesia, oxidative stress and inflammatory changes induced by chronic administration of haloperidol in mice. Furthermore, we verified in vivo and in vitro (in primary microglial culture) whether these effects would be mediated by PPARγ receptors.

The results showed that the male Swiss mice treated daily for 21 days with haloperidol develop orofacial dyskinesia. Daily CBD administration before each haloperidol injection prevented this effect.

Mice treated with haloperidol showed an increase in microglial activation and inflammatory mediators in the striatum. These changes were also reduced by CBD. On the other hand, the levels of the anti-inflammatory cytokine IL-10 increased in the striatum of animals that received CBD and haloperidol.

Regarding oxidative stress, haloperidol induced lipid peroxidation and reduced catalase activity. This latter effect was attenuated by CBD. The combination of CBD and haloperidol also increased PGC-1α mRNA expression, a co-activator of PPARγ receptors. Pretreatment with the PPARγ antagonist, GW9662, blocked the behavioural effect of CBD in our TD model. CBD also prevented LPS-stimulated microglial activation, an effect that was also antagonized by GW9662.

In conclusion, our results suggest that CBD could prevent haloperidol-induced orofacial dyskinesia by activating PPARγ receptors and attenuating neuroinflammatory changes in the striatum.”

“Haloperidol, marketed under the trade name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndromemania in bipolar disorder, nausea and vomiting, delirium, agitation, acute psychosis, and hallucinations in alcohol withdrawal”  https://en.wikipedia.org/wiki/Haloperidol
Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history.

Journal of Ethnopharmacology

“Cannabis sativa L. (C. sativa) is an annual dioecious plant, which shares its origins with the inception of the first agricultural human societies in Asia. Over the course of time different parts of the plant have been utilized for therapeutic and recreational purposes, for instance, extraction of healing oils from seed, or the use of inflorescences for their psychoactive effects. The key psychoactive constituent in C. sativa is called Δ-9-tetrahydrocannabinol (D9-THC). The endocannabinoid system seems to be phylogenetically ancient, as it was present in the most primitive vertebrates with a neuronal network. N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG) are the main endocannabinoids ligands present in the animal kingdom, and the main endocannabinoid receptors are cannabinoid type-1 (CB1) receptor and cannabinoid type-2 (CB2) receptor.

AIM OF THE STUDY:

The review aims to provide a critical and comprehensive evaluation, from the ancient times to our days, of the ethnological, botanical, chemical and pharmacological aspects of C. sativa, with a vision for promoting further pharmaceutical research to explore its complete potential as a therapeutic agent.

RESULTS AND CONCLUSIONS:

A detailed comparative analysis of the available resources for C. sativa confirmed its origin and traditional spiritual, household and therapeutic uses and most importantly its popularity as a recreational drug. The result of several studies suggested a deeper involvement of phytocannabinoids (the key compounds in C. sativa) in several others central and peripheral pathophysiological mechanisms such as food intake, inflammation, pain, colitis, sleep disorders, neurological and psychiatric illness. However, despite their numerous medicinal benefits, they are still considered as a menace to the society and banned throughout the world, except for few countries. We believe that this review will help lay the foundation for promoting exhaustive pharmacological and pharmaceutical studies in order to better understand the clinical relevance and applications of non-psychoactive cannabinoids in the prevention and treatment of life-threatening diseases and help to improve the legal status of C. sativa.”

https://www.ncbi.nlm.nih.gov/pubmed/30205181

https://www.sciencedirect.com/science/article/pii/S0378874118316611?via%3Dihub

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Identification of novel mouse and rat CB1R isoforms and in silico modeling of human CB1R for peripheral cannabinoid therapeutics.

Image result for aps acta pharmacologica

“Targeting peripheral CB1R is desirable for the treatment of metabolic syndromes without adverse neuropsychiatric effects.

We previously reported a human hCB1b isoform that is selectively enriched in pancreatic beta-cells and hepatocytes, providing a potential peripheral therapeutic hCB1R target. It is unknown whether there are peripherally enriched mouse and rat CB1R (mCB1 and rCB1, respectively) isoforms.

In this study, we found no evidence of peripherally enriched rodent CB1 isoforms; however, some mCB1R isoforms are absent in peripheral tissues. We show that the mouse Cnr1 gene contains six exons that are transcribed from a single promoter. We found that mCB1A is a spliced variant of extended exon 1 and protein-coding exon 6; mCB1B is a novel spliced variant containing unspliced exon 1, intron 1, and exon 2, which is then spliced to exon 6; and mCB1C is a spliced variant including all 6 exons.

Using RNAscope in situ hybridization, we show that the isoforms mCB1A and mCB1B are expressed at a cellular level and colocalized in GABAergic neurons in the hippocampus and cortex. RT-qPCR reveals that mCB1A and mCB1B are enriched in the brain, while mCB1B is not expressed in the pancreas or the liver. Rat rCB1R isoforms are differentially expressed in primary cultured neurons, astrocytes, and microglia.

We also investigated modulation of Cnr1 expression by insulin in vivo and carried out in silico modeling of CB1R with JD5037, a peripherally restricted CB1R inverse agonist, using the published crystal structure of hCB1R.

The results provide models for future CB1R peripheral targeting.”

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Role of Cannabinoids in Obesity.

ijms-logo

“Obesity is an increasing health problem worldwide. Its related comorbidities imply a high cost for the National Health System and diminish a patient’s life quality.

Adipose tissue is composed of three types of cells. White adipocytes are involved in fat storage and secretion of hormones. Brown adipocytes are involved in thermogenesis and caloric expenditure. Beige adipocytes are transitional adipocytes that in response to various stimuli can turn from white to brown and could be protective against the obesity, enhancing energy expenditure.

The conversion of white in beige adipose tissue is a potential new therapeutic target for obesity.

Cannabinoid receptors (CB) regulate thermogenesis, food intake and inflammation. CB1 ablation or inhibition helps reducing body weight and food intake. Stimulation of CB2 limits inflammation and promotes anti-obesity effects by reducing food intake and weight gain. Its genetic ablation results in adiposity development.

CB receptors are also responsible for transforming white adipose tissue towards beige or brown adipocytes, therefore their modulation can be considered potential anti-obesity target. CB1 principal localization in central nervous system represents an important limit. Stimulation of CB2, principally localized on peripheral cells instead, should facilitate the anti-obesity effects without exerting remarkable psychotropic activity.”

https://www.ncbi.nlm.nih.gov/pubmed/30201891

http://www.mdpi.com/1422-0067/19/9/2690

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous

Cannabis in palliative care: current challenges and practical recommendations.

 “Pain and symptom control challenges are common in palliative care, and the search for other therapeutic strategies is ongoing.

Unfortunately, patients and their caregivers are receiving little information or support from healthcare providers regarding the increasingly popular cannabinoid-based medicines (CBM).

Clinicians, meanwhile, feel understandably perplexed by the discrepancy between the available evidence and the rapid interest in which patients and their families have demonstrated for CBM.

There is an urgent need to address the many challenges that are delaying the appropriate integration of CBM into clinical practice, notwithstanding the obvious need for a solid general knowledge of pharmacology, mechanism of action and available clinical evidence supporting its use.

The authors will address these challenges and provide practical recommendations regarding patient assessment for the use of CBM. The authors will also make suggestions regarding patient expectations in order to define clear objectives, review the necessary precautions prior to initiating treatment, aid in selecting the appropriate strain and route of administration as well as establishing proper titration and monitoring protocols. The authors will also discuss the lesser known but potentially therapeutic psychoactive effects of cannabis.

As this class of therapeutic agents are likely to play a major role in palliative medicine in the near future, clinicians would benefit from familiarizing themselves with CBM and we can expect that patients and their caregivers will appreciate receiving support in their search for safe and effective therapeutic alternatives.”

https://www.ncbi.nlm.nih.gov/pubmed/30180728

http://apm.amegroups.com/article/view/20097

Facebook Twitter Pinterest Stumbleupon Tumblr Posterous