Tag Archives: Delta-9-Tetrahydrocannabinol

The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism.

Posted on by
Reply

pharmaceuticals-logo

“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.”

 https://www.ncbi.nlm.nih.gov/pubmed/27713369

Acute and chronic effects of cannabidiol on Δ⁹-tetrahydrocannabinol (Δ⁹-THC)-induced disruption in stop signal task performance.

Posted on by
Reply

Image result for Exp Clin Psychopharmacol

“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.”

https://www.ncbi.nlm.nih.gov/pubmed/27690502

THC (Δ9-Tetrahydrocannabinol) Exerts Neuroprotective Effect in Glutamate-affected Murine Primary Mesencephalic Cultures Through Restoring Mitochondrial Membrane Potential and Anti-apoptosis Involving CB1 Receptor-dependent Mechanism.

Posted on by
Reply

Phytotherapy Research

“Aging-related neurodegenerative diseases, such as Parkinson’s disease (PD) or related disorders, are an increasing societal and economic burden worldwide.

Δ9-Tetrahydrocannabinol (THC) is discussed as a neuroprotective agent in several in vitro and in vivo models of brain injury. However, the mechanisms by which THC exhibits neuroprotective properties are not completely understood.

In the present study, we investigated neuroprotective mechanisms of THC in glutamate-induced neurotoxicity in primary murine mesencephalic cultures, as a culture model for PD.

THC protected dopaminergic neurons and other cell types of primary dissociated cultures from glutamate-induced neurotoxicity.

Moreover, THC significantly counteracted the glutamate-induced mitochondrial membrane depolarization and apoptosis.

In conclusion, THC exerts anti-apoptotic and restores mitochondrial membrane potential via a mechanism dependent on CB1 receptor.

It strengthens the fact that THC has a benefit on degenerative cellular processes occurring, among others, in PD and other neurodegenerative diseases by slowing down the progression of neuronal cell death.”

https://www.ncbi.nlm.nih.gov/pubmed/27654887

http://onlinelibrary.wiley.com/wol1/doi/10.1002/ptr.5712/full

Gonadal hormone modulation of ∆9-tetrahydrocannabinol-induced antinociception and metabolism in female versus male rats.

Posted on by
Reply

Image result for Pharmacol Biochem Behav

“The gonadal hormones testosterone (T) in adult males and estradiol (E2) in adult females have been reported to modulate behavioral effects of ∆9-tetrahydrocannabinol (THC). This study determined whether activational effects of T and E2 are sex-specific, and whether hormones modulate production of the active metabolite 11-hydroxy-THC (11-OH-THC) and the inactive metabolite 11-nor-9-carboxy-THC (THC-COOH). Adult male and female rats were gonadectomized (GDX) and treated with nothing (0), T (10-mm Silastic capsule/100g body weight), or E2 (1-mm Silastic capsule/rat). Three weeks later, saline or the cytochrome P450 inhibitor proadifen (25mg/kg; to block THC metabolism and boost THC’s effects) was injected i.p.; 1h later, vehicle or THC (3mg/kg females, 5mg/kg males) was injected i.p., and rats were tested for antinociceptive and motoric effects 15-240min post-injection. T did not consistently alter THC-induced antinociception in males, but decreased it in females (tail withdrawal test). Conversely, T decreased THC-induced catalepsy in males, but had no effect in females. E2 did not alter THC-induced antinociception in females, but enhanced it in males. The discrepant effects of T and E2 on males’ and females’ behavioral responses to THC suggests that sexual differentiation of THC sensitivity is not simply due to activational effects of hormones, but also occurs via organizational hormone or sex chromosome effects. Analysis of serum showed that proadifen increased THC levels, E2 increased 11-OH-THC in GDX males, and T decreased 11-OH-THC (and to a lesser extent, THC) in GDX females. Thus, hormone modulation of THC’s behavioral effects is caused in part by hormone modulation of THC oxidation to its active metabolite. However, the fact that hormone modulation of metabolism did not alter THC sensitivity similarly on all behavioral measures within each sex suggests that other mechanisms also play a role in gonadal hormone modulation of THC sensitivity in adult rats.”

https://www.ncbi.nlm.nih.gov/pubmed/27670094

Endocannabinoid signaling in social functioning: an RDoC perspective.

Posted on by
Reply

Image result for Transl Psychiatry.

“Core deficits in social functioning are associated with various neuropsychiatric and neurodevelopmental disorders, yet biomarker identification and the development of effective pharmacological interventions has been limited.

Recent data suggest the intriguing possibility that endogenous cannabinoids, a class of lipid neuromodulators generally implicated in the regulation of neurotransmitter release, may contribute to species-typical social functioning.

Systematic study of the endogenous cannabinoid signaling could, therefore, yield novel approaches to understand the neurobiological underpinnings of atypical social functioning.

This article provides a critical review of the major components of the endogenous cannabinoid system (for example, primary receptors and effectors-Δ9-tetrahydrocannabinol, cannabidiol, anandamide and 2-arachidonoylglycerol) and the contributions of cannabinoid signaling to social functioning.

Data are evaluated in the context of Research Domain Criteria constructs (for example, anxiety, chronic stress, reward learning, motivation, declarative and working memory, affiliation and attachment, and social communication) to enable interrogation of endogenous cannabinoid signaling in social functioning across diagnostic categories.

The empirical evidence reviewed strongly supports the role for dysregulated cannabinoid signaling in the pathophysiology of social functioning deficits observed in brain disorders, such as autism spectrum disorder, schizophrenia, major depressive disorder, posttraumatic stress disorder and bipolar disorder.

Moreover, these findings indicate that the endogenous cannabinoid system holds exceptional promise as a biological marker of, and potential treatment target for, neuropsychiatric and neurodevelopmental disorders characterized by impairments in social functioning.”

https://www.ncbi.nlm.nih.gov/pubmed/27676446

Medical Marijuana: Just the Beginning of a Long, Strange Trip?

Posted on by
Reply

Physical Therapy Journal

“Medical marijuana continues to gain acceptance and become legalized in many states. Various species of the marijuana plant have been cultivated, and this plant can contain up to 100 active compounds known as cannabinoids.

Two cannabinoids seem the most clinically relevant: Δ9-tetrahydrocannabinol (THC), which tends to produce the psychotropic effects commonly associated with marijuana, and cannabidiol (CBD), which may produce therapeutic effects without appreciable psychoactive properties.

Smoking marijuana, or ingesting extracts from the whole plant orally (in baked goods, teas, and so forth), introduces variable amounts of THC, CBD, and other minor cannabinoids into the systemic circulation where they ultimately reach the central and peripheral nervous systems.

Alternatively, products containing THC, CBD, or a combination of both compounds, can also be ingested as oral tablets, or via sprays applied to the oral mucosal membranes. These products may provide a more predictable method for delivering a known amount of specific cannabinoids into the body.

Although there is still a need for randomized controlled clinical trials, preliminary studies have suggested that medical marijuana and related cannabinoids may be beneficial in treating chronic pain, inflammation, spasticity, and other conditions seen commonly in physical therapist practice.

Physical therapists should therefore be aware of the options that are available for patients considering medical marijuana, and be ready to provide information for these patients.”

http://www.ncbi.nlm.nih.gov/pubmed/27660328

Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines

Posted on by
Reply

Logo of amjtr

“Cannabis sativa, commonly called hemp, has thousands of years-long history of medical use. Cannabis extracts were widely used in Europe and North America for their therapeutic value as sedatives, hypnotics, analgesics, muscle relaxants, and anticonvulsant agents. However, cannabis was removed from British and American Pharmacopoeias in 20th century, partially due to politic bias. Although prohibited, many patients were nevertheless self-medicating to obtain therapeutic benefits from cannabis for various conditions, including AIDS wasting syndrome, multiple sclerosis (MS) and spinal injuries. More recently, a growing interest in the therapeutic effects of cannabis has developed following the isolation of cannabinoids, the principal chemical compounds of cannabis, as well as the discovery of endocannabinoids and their cognate receptors in humans. These advances supported legalisation and wide-spread use of cannabis for therapeutic purposes in many countries.

There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009397/

Δ9-Tetrahydrocannabinol Reverses TNFα-induced Increase in Airway Epithelial Cell Permeability through CB2 Receptors.

Posted on by
Reply

Image result for Biochem Pharmacol

“Despite pharmacological treatment, bronchial hyperresponsiveness continues to deteriorate as airway remodelling persists in airway inflammation.

Previous studies have demonstrated that the phytocannabinoid Δ9-tetrahydrocannabinol (THC) reverses bronchoconstriction with an anti-inflammatory action.

The aim of this study was to investigate the effects of THC on bronchial epithelial cell permeability after exposure to the pro-inflammatory cytokine, TNFα. Calu-3 bronchial epithelial cells were cultured at air-liquid interface.

These data indicate that THC prevents cytokine-induced increase in airway epithelial permeability through CB2 receptor activation.

This highlights that THC, or other cannabinoid receptor ligands, could be beneficial in the prevention of inflammation-induced changes in airway epithelial cell permeability, an important feature of airways diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27641813

Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization.

Posted on by
Reply

Image result for autophagy journal

“Autophagy is considered primarily a cell survival process, although it can also lead to cell death. However, the factors that dictate the shift between these 2 opposite outcomes remain largely unknown. In this work, we used Δ9-tetrahydrocannabinol (THC, the main active component of marijuana, a compound that triggers autophagy-mediated cancer cell death) and nutrient deprivation (an autophagic stimulus that triggers cytoprotective autophagy) to investigate the precise molecular mechanisms responsible for the activation of cytotoxic autophagy in cancer cells. By using a wide array of experimental approaches we show that THC (but not nutrient deprivation) increases the dihydroceramide:ceramide ratio in the endoplasmic reticulum of glioma cells, and this alteration is directed to autophagosomes and autolysosomes to promote lysosomal membrane permeabilization, cathepsin release and the subsequent activation of apoptotic cell death. These findings pave the way to clarify the regulatory mechanisms that determine the selective activation of autophagy-mediated cancer cell death.”

http://www.ncbi.nlm.nih.gov/pubmed/27635674

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology.

Posted on by
Reply

Image result for Physiol Rev.

“Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS).

This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one Δ9-tetrahydrocannabinol, and 2) the adaptive pro-homeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs.

In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.”

http://www.ncbi.nlm.nih.gov/pubmed/27630175