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Molecular Targets of the Phytocannabinoids: A Complex Picture.

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“For centuries, hashish and marihuana, both derived from the Indian hemp Cannabis sativa L., have been used for their medicinal, as well as, their psychotropic effects.

These effects are associated with the phytocannabinoids which are oxygen containing C21 aromatic hydrocarbons found in Cannabis sativa L.

To date, over 120 phytocannabinoids have been isolated from Cannabis.

For many years, it was assumed that the beneficial effects of the phytocannabinoids were mediated by the cannabinoid receptors, CB1 and CB2. However, today we know that the picture is much more complex, with the same phytocannabinoid acting at multiple targets.

This contribution focuses on the molecular pharmacology of the phytocannabinoids, including Δ9-THC and CBD, from the prospective of the targets at which these important compounds act.”

 https://www.ncbi.nlm.nih.gov/pubmed/28120232

Molecular Pharmacology of Phytocannabinoids.

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“Cannabis sativa has been used for recreational, therapeutic and other uses for thousands of years.

The plant contains more than 120 C21 terpenophenolic constituents named phytocannabinoids. The Δ9-tetrahydrocannabinol type class of phytocannabinoids comprises the largest proportion of the phytocannabinoid content.

Δ9-tetrahydrocannabinol was first discovered in 1971. This led to the discovery of the endocannabinoid system in mammals, including the cannabinoid receptors CB1 and CB2.

Δ9-Tetrahydrocannabinol exerts its well-known psychotropic effects through the CB1 receptor but this effect of Δ9-tetrahydrocannabinol has limited the use of cannabis medicinally, despite the therapeutic benefits of this phytocannabinoid. This has driven research into other targets outside the endocannabinoid system and has also driven research into the other non-psychotropic phytocannabinoids present in cannabis.

This chapter presents an overview of the molecular pharmacology of the seven most thoroughly investigated phytocannabinoids, namely Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabivarin, cannabinol, cannabidiol, cannabidivarin, cannabigerol, and cannabichromene.

The targets of these phytocannabinoids are defined both within the endocannabinoid system and beyond.

The pharmacological effect of each individual phytocannabinoid is important in the overall therapeutic and recreational effect of cannabis and slight structural differences can elicit diverse and competing physiological effects.

The proportion of each phytocannabinoid can be influenced by various factors such as growing conditions and extraction methods. It is therefore important to investigate the pharmacology of these seven phytocannabinoids further, and characterise the large number of other phytocannabinoids in order to better understand their contributions to the therapeutic and recreational effects claimed for the whole cannabis plant and its extracts.”

https://www.ncbi.nlm.nih.gov/pubmed/28120231

Synthesis of Phytocannabinoids.

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“The changing legal landscape including medicinal and recreational consumption of Cannabis sativa has led to renewed interest to study the chemistry and biology of cannabinoids. The chemistry in this chapter highlights approaches to cannabinoid total synthesis with an emphasis on the implementation of modern methods and tactics, which provide access to modified structures and enable investigations of the biology of the cannabinoid product family.”  https://www.ncbi.nlm.nih.gov/pubmed/28120230

Phytochemistry of Cannabis sativa L.

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“Cannabis (Cannabis sativa, or hemp) and its constituents-in particular the cannabinoids-have been the focus of extensive chemical and biological research for almost half a century since the discovery of the chemical structure of its major active constituent, Δ9-tetrahydrocannabinol (Δ9-THC).

The plant’s behavioral and psychotropic effects are attributed to its content of this class of compounds, the cannabinoids, primarily Δ9-THC, which is produced mainly in the leaves and flower buds of the plant.

Besides Δ9-THC, there are also non-psychoactive cannabinoids with several medicinal functions, such as cannabidiol (CBD), cannabichromene (CBC), and (CBG), along with other non-cannabinoid constituents belonging to diverse classes of natural products.

Today, more than 560 constituents have been identified in cannabis.

The recent discoveries of the medicinal properties of cannabis and the cannabinoids in addition to their potential applications in the treatment of a number of serious illnesses, such as glaucoma, depression, neuralgia, multiple sclerosis, Alzheimer’s, and alleviation of symptoms of HIV/AIDS and cancer, have given momentum to the quest for further understanding the chemistry, biology, and medicinal properties of this plant.

This contribution presents an overview of the botany, cultivation aspects, and the phytochemistry of cannabis and its chemical constituents. Particular emphasis is placed on the newly-identified/isolated compounds. In addition, techniques for isolation of cannabis constituents and analytical methods used for qualitative and quantitative analysis of cannabis and its products are also reviewed.”

https://www.ncbi.nlm.nih.gov/pubmed/28120229

Endocannabinoid 2-arachidonoylglycerol protects inflammatory insults from sulfur dioxide inhalation via cannabinoid receptors in the brain.

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“Sulfur dioxide (SO2) pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction. However, there are currently no effective medications targeting the harmful outcomes from chemical inhalation.

Endocannabinoids (eCBs) are involved in neuronal protection against inflammation-induced neuronal injury. The 2-arachidonoylglycerol (2-AG), the most abundant eCBs and a full agonist for cannabinoid receptors (CB1 and CB2), is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction.

Here, we indicated that endogenous 2-AG protected against neuroinflammation in response to SO2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-a), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS).

In addition, endogenous 2-AG prevented cerebral vasculature dysfunction following SO2 inhalation by inhibiting endothelin 1 (ET-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, elevating endothelial nitric oxide synthase (eNOS) level, and restoring the imbalance between thromboxane A2 (TXA2) and prostaglandin I2 (PGI2).

In addition, the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors.

Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO2 inhalation.”

https://www.ncbi.nlm.nih.gov/pubmed/28115138

β-Caryophyllene promotes osteoblastic mineralization, and suppresses osteoclastogenesis and adipogenesis in mouse bone marrow cultures in vitro.

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“Osteoporosis is induced by the reduction in bone mass through decreased osteoblastic osteogenesis and increased osteoclastic bone resorption, and it is associated with obesity and diabetes. Osteoblasts and adipocytes are derived from bone marrow mesenchymal stem cells. The prevention of osteoporosis is an important public health concern in aging populations. β-caryophyllene, a component of various essential oils, is a selective agonist of the cannabinoid receptor type 2 and exerts cannabimimetic anti-inflammatory effects in animals. The present study aimed to identify the effect of β-caryophyllene on adipogenesis, osteoblastic mineralization and osteoclastogenesis in mouse bone marrow cell cultures in vitro. Bone marrow cells obtained from mouse femoral tissues were cultured in the presence of β-caryophyllene (0.1-100 µM) in vitro. The results revealed that β-caryophyllene stimulated osteoblastic mineralization, and suppressed adipogenesis and osteoclastogenesis. Thus, β-caryophyllene may be used as a therapeutic agent for the prevention and treatment of osteoporosis.”

https://www.ncbi.nlm.nih.gov/pubmed/28105093

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

Beta-caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice.

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“Beta-caryophyllene (BCP) is a plant-derived FDA approved food additive with anti-inflammatory properties. Some of its beneficial effects in vivo reported to involve activation of cannabinoid 2 receptors (CB2) that are predominantly expressed in immune cells. Herein, we evaluated the translational potential of BCP using a well-established model of chronic and binge alcohol-induced liver injury.

CONCLUSIONS:

Given the safety of BCP in humans this food additive has a high translational potential in treating or preventing hepatic injury associated with oxidative stress, inflammation and steatosis.”

https://www.ncbi.nlm.nih.gov/pubmed/28107775

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

Modern History of Medical Cannabis: From Widespread Use to Prohibitionism and Back

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“Over the history of pharmacology there are numerous examples of drugs being widely distributed, almost ‘trendy’, prescribed by physicians in a certain period as a sort of panacea, and then neglected, forgotten, or even forbidden as they become considered dangerous in the light of clinical observations. One of these drugs is Cannabis, which was very popular in the 19th century until disappearing from the official Pharmacopoeia at the beginning of the 20th century and reviving again in the new millennium.”
http://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(16)30184-5

A case for cannabidiol in Wolf-Hirschhorn syndrome seizure management.

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“Complex, and sometimes intractable, seizures affect the quality of life and cognitive development of over 90% of individuals with Wolf-Hirschhorn syndrome (WHS). Fine resolution genotype-phenotype mapping of the WHS locus recently identified a candidate gene whose probable function has led to insights into a mechanism connecting WHS seizures with those of Dravet syndrome, a distinct condition caused by mutations in SCN1A and SCN1B. In addition to this possible molecular mechanistic connection, these disorders’ seizures share a strikingly similar constellation of features, including clinical presentation, seizure types, early age of onset, EEG pattern, and responses to specific anti-epileptic drugs. Based in part on these similarities, we suggest that a highly successful Phase III clinical trial of a formulation of cannabidiol for Dravet syndrome seizures may be directly translatable into possible benefits for WHS individuals with challenging seizure patterns.”

https://www.ncbi.nlm.nih.gov/pubmed/28102593

Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease.

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“The identification and cloning of the two major cannabinoid (CB1 and CB2) receptors together with the discovery of their endogenous ligands in the late 80s and early 90s, resulted in a major effort aimed at understanding the mechanisms and physiological roles of the endocannabinoid system (ECS). Due to its expression and localization in the central nervous system (CNS), the CB1 receptor together with its endogenous ligands (endocannabinoids (eCB)) and the enzymes involved in their synthesis and degradation, has been implicated in multiple pathophysiological events ranging from memory deficits to neurodegenerative disorders among others. In this review, we will provide a general overview of the ECS with emphasis on the CB1 receptor in health and disease. We will describe our current understanding of the complex aspects of receptor signaling and trafficking, including the non-canonical signaling pathways such as those mediated by β-arrestins within the context of functional selectivity and ligand bias. Finally, we will highlight some of the disorders in which CB1 receptors have been implicated. Significant knowledge has been achieved over the last 30 years. However, much more research is still needed to fully understand the complex roles of the ECS, particularly in vivo and to unlock its true potential as a source of therapeutic targets.”

https://www.ncbi.nlm.nih.gov/pubmed/28101004