Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant.

molecules-logo “Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound-Δ9-tetrahydrocannabinol (Δ9-THC)-as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS).

Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa.

However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself.

In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.”



Molecular Mechanism and Cannabinoid Pharmacology.

 “Since antiquity, Cannabis has provoked enormous intrigue for its potential medicinal properties as well as for its unique pharmacological effects.

The elucidation of its major cannabinoid constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), led to the synthesis of new cannabinoids (termed synthetic cannabinoids) to understand the mechanisms underlying the pharmacology of Cannabis.

These pharmacological tools were instrumental in the ultimate discovery of the endogenous cannabinoid system, which consists of CB1 and CB2 cannabinoid receptors and endogenously produced ligands (endocannabinoids), which bind and activate both cannabinoid receptors.

CB1 receptors mediate the cannabimimetic effects of THC and are highly expressed on presynaptic neurons in the nervous system, where they modulate neurotransmitter release. In contrast, CB2 receptors are primarily expressed on immune cells.

The endocannabinoids are tightly regulated by biosynthetic and hydrolytic enzymes. Accordingly, the endocannabinoid system plays a modulatory role in many physiological processes, thereby generating many promising therapeutic targets.

An unintended consequence of this research was the emergence of synthetic cannabinoids sold for human consumption to circumvent federal laws banning Cannabis use. Here, we describe research that led to the discovery of the endogenous cannabinoid system and show how knowledge of this system benefitted as well as unintentionally harmed human health.”



A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol.

 Scientific Reports“(-)-Trans-Δ9-tetrahydrocannabinol (Δ9-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ9-THC with a longer side chain have shown cannabimimetic properties far higher than Δ9-THC itself. In the attempt to define the phytocannabinoids profile that characterizes a medicinal cannabis variety, a new phytocannabinoid with the same structure of Δ9-THC but with a seven-term alkyl side chain was identified. The natural compound was isolated and fully characterized and its stereochemical configuration was assigned by match with the same compound obtained by a stereoselective synthesis. This new phytocannabinoid has been called (-)-trans-Δ9-tetrahydrocannabiphorol (Δ9-THCP). Along with Δ9-THCP, the corresponding cannabidiol (CBD) homolog with seven-term side alkyl chain (CBDP) was also isolated and unambiguously identified by match with its synthetic counterpart. The binding activity of Δ9-THCP against human CB1 receptor in vitro (Ki = 1.2 nM) resulted similar to that of CP55940 (Ki = 0.9 nM), a potent full CB1 agonist. In the cannabinoid tetrad pharmacological test, Δ9-THCP induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating a THC-like cannabimimetic activity. The presence of this new phytocannabinoid could account for the pharmacological properties of some cannabis varieties difficult to explain by the presence of the sole Δ9-THC.”



The heterogeneity and complexity of Cannabis extracts as antitumor agents

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“The Cannabis plant contains over 100 phytocannabinoids and hundreds of other components. The biological effects and interplay of these Cannabis compounds are not fully understood and yet influence the plant’s therapeutic effects.

Here we assessed the antitumor effects of whole Cannabis extracts, which contained significant amounts of differing phytocannabinoids, on different cancer lines from various tumor origins.

Our results show that specific Cannabis extracts impaired the survival and proliferation of cancer cell lines as well as induced apoptosis.

Our findings showed that pure (-)-Δ9trans-tetrahydrocannabinol (Δ9-THC) did not produce the same effects on these cell lines as the whole Cannabis extracts. Furthermore, Cannabis extracts with similar amounts of Δ9-THC produced significantly different effects on the survival of specific cancer cells.

In addition, we demonstrated that specific Cannabis extracts may selectively and differentially affect cancer cells and differing cancer cell lines from the same organ origin. We also found that cannabimimetic receptors were differentially expressed among various cancer cell lines and suggest that this receptor diversity may contribute to the heterogeneous effects produced by the differing Cannabis extracts on each cell line.

Our overall findings indicate that the effect of a Cannabis extract on a specific cancer cell line relies on the extract’s composition as well as on certain characteristics of the targeted cells.”


“Many previous reports highlight and demonstrate the anti-tumor effects of cannabinoids. In the last decade, accumulating evidence has indicated that phytocannabinoids might have antitumor properties. A number of in vitro and in vivo studies have demonstrated the effects of phytocannabinoids on tumor progression by interrupting several characteristic features of cancer. These studies suggest that specific cannabinoids such as Δ9-THC and CBD induce apoptosis and inhibit proliferation in various cancer cell lines.”


Cannabimimetic plants: are they new cannabinoidergic modulators?

“Phytochemicals and secondary metabolites able to interact with the endocannabinoid system (Cannabimimetics) have been recently described in a broad range of plants and fruits. These findings can open new alternative avenues to explore for the development of novel therapeutic compounds. The cannabinoids regulate many physiological and pathological functions in both animals and plants. Cannabis sativa is the main plant that produces phytocannabinoids inside resins capable to defend the plant from the aggression of parasites and herbivores. Animals produce anandamide and 2-arachidonoyl glycerol, which thanks to binding with main receptors such as type-1 cannabinoid receptor (CB1R) and the type-2 cannabinoid receptor (CB2R) are involved in inflammation processes and several brain functions. Endogenous cannabinoids, enzymes for synthesis and degradation of cannabinoids, and CB1R and CB2R constitute the endocannabinoid system (ECS). Other plants can produce cannabinoid-like molecules such as perrottetinene extracted from Radula perrottetii, or anandamide and 2-arachidonoyl glycerol extracted from some bryophytes. Moreover, several other secondary metabolites can also interact with the ECS of animals and take the name of cannabimimetics. These phytoextracts not derived from Cannabis sativa can act as receptor agonists or antagonist, or enzyme inhibitors of ECS and can be involved in the inflammation, oxidative stress, cancer, and neuroprotection. Finally, given the evolutionary heterogeneity of the cannabimimetic plants, some authors speculated on the fascinating thesis of the evolutionary convergence between plants and animals regarding biological functions of ECS. The review aims to provide a critical and complete assessment of the botanical, chemical and therapeutic aspects of cannabimimetic plants to evaluate their spread in the world and medicinal potentiality.”



β-Amyrin, the cannabinoid receptors agonist, abrogates mice brain microglial cells inflammation induced by lipopolysaccharide/interferon-γ and regulates Mφ1/Mφ2 balances.

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“Inflammation is a primary response to infection that can pathologically lead to various diseases including neurodegenerative diseases.

The purpose of this study was to evaluate the effect of β-Amyrin, a naturally occurring pentacyclic triterpenoid compound, on inflammation induced by lipopolysaccharide (LPS) and interferone-γ (IFN-γ) in rat microglial cells.


β-Amyrin reduces inflammation in microglial cells and can be used as a potential anti-inflammatory agent in central nervous system neurodegenerative diseases such as Alzheimer and multiple sclerosis, by affecting the inflammatory cytokine and differentiation of microglia as resident CNS macrophages.”


“Amyrin and the endocannabinoid system. The canonical triterpene amyrin was recently suggested to bind to CB1 receptors and to significantly mediate cannabimimetic effects in animal models of pain.”   http://gertschgroup.com/blog/entry/3188293/amyrin-and-the-endocannabinoid-system

“The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting CB receptors”   https://www.researchgate.net/publication/225079976_The_antinociceptive_triterpene_b-amyrin_inhibits_2-arachidonoylglycerol_2-AG_hydrolysis_without_directly_targeting_CB_receptors

“Finally, pentacyclic triterpenes such as β-amyrin and cycloartenol have been shown to possess numerous biological activities including anti-bacterial, anti-fungal, anti-inflammatory and anti-cancer properties.” https://www.linkedin.com/pulse/cannabis-has-terpenes-say-what-pure-hempnotics

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Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea.

Oxford University Press

“There remains an important and unmet need for fully effective and acceptable treatments in obstructive sleep apnea (OSA). At present, there are no approved drug treatments. Dronabinol has shown promise for OSA pharmacotherapy in a small dose-escalation pilot study.

Here, we present initial findings of the Phase II PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial, a fully-blinded parallel groups, placebo-controlled randomized trial of dronabinol in patients with moderate or severe OSA.

These findings support the therapeutic potential of cannabinoids in patients with OSA. In comparison to placebo, dronabinol was associated with lower AHI, improved subjective sleepiness and greater overall treatment satisfaction. Larger scale clinical trials will be necessary to clarify the best potential approach(es) to cannabinoid therapy in OSA”   https://www.ncbi.nlm.nih.gov/pubmed/29121334

“These findings support the therapeutic potential of cannabinoids in patients with obstructive sleep apnea (OSA).” https://academic.oup.com/sleep/article-abstract/doi/10.1093/sleep/zsx184/4600041?redirectedFrom=fulltext

Cannabinoid May Be First Drug for Sleep Apnea” https://www.medscape.com/viewarticle/891821

Actions and Regulation of Ionotropic Cannabinoid Receptors.

“Almost three decades have passed since the identification of the two specific metabotropic receptors mediating cannabinoid pharmacology. Thereafter, many cannabinoid effects, both at central and peripheral levels, have been well documented and characterized. However, numerous evidences demonstrated that these pharmacological actions could not be attributable solely to the activation of CB1 and CB2 receptors since several important cannabimimetic actions have been found in biological systems lacking CB1 or CB2 gene such as in specific cell lines or transgenic mice. It is now well accepted that, beyond their receptor-mediated effects, these molecules can act also via CB1/CB2-receptor-independent mechanism. Cannabinoids have been demonstrated to modulate several voltage-gated channels (including Ca2+, Na+, and various type of K+ channels), ligand-gated ion channels (i.e., GABA, glycine), and ion-transporting membranes proteins such as transient potential receptor class (TRP) channels. The first direct, cannabinoid receptor-independent interaction was reported on the function of serotonin 5-HT3 receptor-ion channel complex. Similar effects were reported also on the other above mentioned ion channels. In the early ninety, studies searching for endogenous modulators of L-type Ca2+ channels identified anandamide as ligand for L-type Ca2+ channel. Later investigations indicated that other types of Ca2+ currents are also affected by endocannabinoids, and, in the late ninety, it was discovered that endocannabinoids activate the vanilloid receptor subtype 1 (TRPV1), and nowadays, it is known that (endo)cannabinoids gate at least five distinct TRP channels. This chapter focuses on cannabinoid regulation of ion channels and lays special emphasis on their action at transient receptor channels.”


Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice.

 Image result for Oncotarget“Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (-/-) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)-/- mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.”


Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation?

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“The endocannabinoid system (ECS) is a major lipid signaling network that plays important pro-homeostatic (allostatic) roles not only in the nervous system but in peripheral organs.

Increasing evidence points towards a dietary component in the modulation of the ECS.

Cannabinoid receptors in hominids co-evolved with diet and the ECS constitutes a feedback loop for food selection and energy metabolism.

Here it is postulated that the mismatch of ancient lipid genes of hunter-gatheres and pastoralists with the high carbohydrate diet introduced by agriculture could be compensated via dietary modulation of the ECS.

In addition to the fatty acid precursors of endocannabinoids the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed.

Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid-type 2 (CB2) receptors may provide adaptive metabolic advantages and counteract inflammation.

Food able to modulate the CB1/CB2 receptor activation ratio may thus play a role in the nutrition transition of Western high calorie diets. In this review the interplay between diet and the ECS is highlighted from an evolutionary perspective.

The emerging potential of cannabimimetic food as nutraceutical strategy is critically discussed.”