“To assess the impact of cannabis use as secondary drug on mortality of patients with other major substance use disorders.
Positive urinary cannabis did not confer an increased risk of death in patients with severe opiate, cocaine or alcohol dependence.”
“The endocannabinoid system comprises receptors (CB1 and CB2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT).
Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep.
For instance, SR141716A (the CB1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep.
Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20mg/Kg; ip; separately each one) to rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period.
Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, as well as adenosine while VDM-11 caused a decline in contents of these molecules.
These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking.
It can be concluded that elements of the endocannabinoid system, such as the CB1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking.”
“Cannabis is one of the earliest cultivated plants.
Cannabis of industrial utility and culinary value is generally termed as hemp.
Conversely, cannabis that is bred for medical, spiritual and recreational purposes is called marijuana.
The female marijuana plant produces a significant quantity of bio- and psychoactive phytocannabinoids, which regained the spotlight with the discovery of the endocannabinoid system of the animals in the early 90’s.
Nevertheless, marijuana is surrounded by controversies, debates and misconceptions related to its taxonomic classification, forensic identification, medical potential, legalization and its long-term health consequences.
In the first part, we provide an in-depth review of the botany and taxonomy of Cannabis. We then overview the biosynthesis of phytocannabinoids within the glandular trichomes with emphasis on the role of peculiar plastids in the production of the secreted material. We also compile the analytical methods used to determine the phytocannabinoid composition of glandular trichomes.
In the second part, we revisit the psychobiology and molecular medicine of marijuana. We summarize our current knowledge on the recreational use of cannabis with respect to the modes of consumption, short-term effects, chronic health consequences and cannabis use disorder.
Next, we overview the molecular targets of a dozen major and minor bioactive cannabinoids in the body. This helps us introduce the endocannabinoid system in an unprecedented detail: its up-to-date molecular biology, pharmacology, physiology and medical significance, and beyond.
In conclusion, we offer an unbiased survey about cannabis to help better weigh its medical value versus the associated risks.”
“There is an increasing recognition that the endocannabinoid system is the crucial cytokine-hormone system regulating early human pregnancy. The synchronous development of the fertilized embryo and the endometrium to ensure timely implantation has been shown to be one of the pivotal steps to successful implantation. This development is thought to be regulated by a finely balanced relationship between various components of the endocannabinoid system in the endometrium, the embryo and the Fallopian tube. In addition, this system has also been shown to be involved in the regulation of the development and maturation of the gametes prior to fertilization. In this review, we will examine the evidence from animal and human studies to support the role of the endocannabinoid system in gametogenesis, fertilization, implantation, early pregnancy maintenance, and in immunomodulation of pregnancy. We will discuss the role of the cannabinoid receptors and the enzymes involved in the synthesis and degradation of the key endocannabinoid ligands (e.g., anandamide and 2-arachinoylglycerol) in early reproduction.”
“Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects.
Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC) and the non-psychotropic cannabidiol (CBD) modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC).
The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO), suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system.
Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling.
We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC.”
“Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized.
Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes.
In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord.
Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation.
We hypothesized that CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling.
We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking).
Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord.
MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630.
Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.”
“Allosteric modulators of G-protein coupled receptors (GPCRs) hold the promise of improved pharmacology and safety over typical orthosteric GPCR ligands.
These features are particularly relevant to the cannabinoid receptor 1 (CB1R) GPCR, since typical orthosteric CB1R ligands are associated with adverse events that limit their translational potential.
Areas covered: The contextual basis for applying allostery to CB1R is considered from pharmacological, drug-discovery, and medicinal standpoints.
Rational design of small-molecule CB1R allosteric modulators as potential pharmacotherapeutics would be greatly facilitated by direct experimental characterization of structure-function correlates underlying the biological activity of chemically-diverse CB1R allosteric modulators, CB1R allosteric ligand-binding binding pockets, and amino acid contact residues critical to allosteric ligand engagement and activity.
In these regards, designer covalent probes exhibiting well-characterized molecular pharmacology as CB1R allosteric modulators are emerging as valuable molecular reporters enabling experimental interrogation of CB1R allosteric site(s) and informing the design of new CB1R agents as drugs.
Expert opinion: Synthesis and pharmacological profiling of CB1R allosteric ligands will continue to provide valuable insights into CB1R structure-function correlates. The resulting data should expand the repertoire of novel agents capable of exerting therapeutic benefit by modulating CB1R-dependent signaling.”
“Cannabisol (1), a unique dimer of Δ9-tetrahydrocannabinol (Δ9-THC) with a methylene bridge, was isolated from Cannabis sativa.
This is the first example of a C-bridged dimeric cannabinoid.
The structure of 1 was unambiguously deduced by HRESIMS, GCMS, and NMR spectroscopy.
A plausible biogenesis of 1 is described.”
“Recent clinical and preclinical research has suggested that cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have interactive effects on measures of cognition; however, the nature of these interactions is not yet fully characterized.
To address this, we investigated the effects of Δ9-THC and CBD independently and in combination with proposed therapeutic dose ratios of 1:1 and 1:3 Δ9-THC:CBD in adult rhesus monkeys performing a stop signal task (SST).
These results indicate that CBD, when combined with Δ9-THC in clinically available dose ratios, does not exacerbate and, under restricted conditions may even attenuate, Δ9-THC’s behavioral effects.”
“The endocannabinoid system (ECS) has emerged as an important regulator of both physiological and pathological processes. Notably, this endogenous system plays a key role in the modulation of pain and inflammation in a number of tissues.
The components of the ECS, including endocannabinoids, their cognate enzymes and cannabinoid receptors, are localized in the eye, and evidence indicates that ECS modulation plays a role in ocular disease states.
Of these diseases, ocular inflammation presents a significant medical problem, given that current clinical treatments can be ineffective or are associated with intolerable side-effects. Furthermore, a prominent comorbidity of ocular inflammation is pain, including neuropathic pain, for which therapeutic options remain limited.
Recent evidence supports the use of drugs targeting the ECS for the treatment of ocular inflammation and pain in animal models; however, the potential for therapeutic use of cannabinoid drugs in the eye has not been thoroughly investigated at this time.
This review will highlight evidence from experimental studies identifying components of the ocular ECS and discuss the functional role of the ECS during different ocular inflammatory disease states, including uveitis and corneal keratitis.
Candidate ECS targeted therapies will be discussed, drawing on experimental results obtained from both ocular and non-ocular tissue(s), together with their potential application for the treatment of ocular inflammation and pain.”
