Tag Archives: THC

Endocannabinoid Signaling and the Hypothalamic-Pituitary-Adrenal Axis.

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“The elucidation of Δ9-tetrahydrocannabinol as the active principal of Cannabis sativa in 1963 initiated a fruitful half-century of scientific discovery, culminating in the identification of the endocannabinoid signaling system, a previously unknown neuromodulatory system.

A primary function of the endocannabinoid signaling system is to maintain or recover homeostasis following psychological and physiological threats. We provide a brief introduction to the endocannabinoid signaling system and its role in synaptic plasticity.

The majority of the article is devoted to a summary of current knowledge regarding the role of endocannabinoid signaling as both a regulator of endocrine responses to stress and as an effector of glucocorticoid and corticotrophin-releasing hormone signaling in the brain.

We summarize data demonstrating that cannabinoid receptor 1 (CB1R) signaling can both inhibit and potentiate the activation of the hypothalamic-pituitary-adrenal axis by stress.

We present a hypothesis that the inhibitory arm has high endocannabinoid tone and also serves to enhance recovery to baseline following stress, while the potentiating arm is not tonically active but can be activated by exogenous agonists.

We discuss recent findings that corticotropin-releasing hormone in the amygdala enables hypothalamic-pituitary-adrenal axis activation via an increase in the catabolism of the endocannabinoid N-arachidonylethanolamine.

We review data supporting the hypotheses that CB1R activation is required for many glucocorticoid effects, particularly feedback inhibition of hypothalamic-pituitary-adrenal axis activation, and that glucocorticoids mobilize the endocannabinoid 2-arachidonoylglycerol.

These features of endocannabinoid signaling make it a tantalizing therapeutic target for treatment of stress-related disorders but to date, this promise is largely unrealized.”

https://www.ncbi.nlm.nih.gov/pubmed/28134998

Topical application of THC containing products is not able to cause positive cannabinoid finding in blood or urine.

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“A male driver was checked during a traffic stop.

A blood sample was collected 35min later and contained 7.3ng/mL THC, 3.5ng/mL 11-hydroxy-THC and 44.6ng/mL 11-nor-9-carboxy-THC. The subject claimed to have used two commercially produced products topically that contained 1.7ng and 102ng THC per mg, respectively. In an experiment, three volunteers (25, 26 and 34 years) applied both types of salves over a period of 3days every 2-4h. The application was extensive (50-100cm2). Each volunteer applied the products to different parts of the body (neck, arm/leg and trunk, respectively). After the first application blood and urine samples of the participants were taken every 2-4h until 15h after the last application (overall n=10 urine and n=10 blood samples, respectively, for each participant).

All of these blood and urine samples were tested negative for THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC by a GC-MS method (LoD (THC)=0.40ng/mL; LoD (11-hydroxy-THC)=0.28ng/mL; LoD (THC-COOH)=1.6ng/mL;. LoD (THC-COOH in urine)=1.2ng/mL).

According to our studies and further literature research on in vitro testing of transdermal uptake of THC, the exclusive application of (these two) topically applied products did not produce cannabinoid findings in blood or urine.”

https://www.ncbi.nlm.nih.gov/pubmed/28122323

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

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

Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms.

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“This study assessed whether oral administration of delta-9-tetrahydrocannbinol (THC) effectively suppressed cannabis withdrawal in an outpatient environment.

The primary aims were to establish the pharmacological specificity of the withdrawal syndrome and to obtain information relevant to determining the potential use of THC to assist in the treatment of cannabis dependence.

METHOD:

Eight adult, daily cannabis users who were not seeking treatment participated in a 40-day, within-subject ABACAD study. Participants administered daily doses of placebo, 30 mg (10 mg/tid), or 90 mg (30 mg/tid) oral THC during three, 5-day periods of abstinence from cannabis use separated by 7-9 periods of smoking cannabis as usual.

RESULTS:

Comparison of withdrawal symptoms across conditions indicated that (1) the lower dose of THC reduced withdrawal discomfort, and (2) the higher dose produced additional suppression in withdrawal symptoms such that symptom ratings did not differ from the smoking-as-usual conditions. Minimal adverse effects were associated with either active dose of THC.

CONCLUSIONS:

This demonstration of dose-responsivity replicates and extends prior findings of the pharmacological specificity of the cannabis withdrawal syndrome. The efficacy of these doses for suppressing cannabis withdrawal suggests oral THC might be used as an intervention to aid cannabis cessation attempts.”  https://www.ncbi.nlm.nih.gov/pubmed/16769180

“The endocannabinoid system as a target for the treatment of cannabis dependence” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2647947/

“Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report. CBD can be effective for the treatment of cannabis withdrawal syndrome.” https://www.ncbi.nlm.nih.gov/pubmed/23095052

“Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms.” https://www.ncbi.nlm.nih.gov/pubmed/16769180

Cannabinoids – a new weapon against cancer?

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“Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent.

The isolation and characterization of the structure of one of the main active ingredients of cannabis – Δ9 – tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine.

Many scientific studies indicate the potential use of cannabinoids in the fight against cancer.

Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize.

The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors.

Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.”

 https://www.ncbi.nlm.nih.gov/pubmed/28100841

Pharmacology of cannabinoids in the treatment of epilepsy.

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“The use of cannabis products in the treatment of epilepsy has long been of interest to researchers and clinicians alike; however, until recently very little published data were available to support its use.

This article summarizes the available scientific data of pharmacology from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including ∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), ∆9-tetrahydrocannabivarin (∆9-THCV), cannabidivarin (CBDV), and ∆9-tetrahydrocannabinolic acid (Δ9-THCA).

It has long been known that ∆9-THC has partial agonist activity at the endocannabinoid receptors CB1 and CB2, though it also binds to other targets which may modulate neuronal excitability and neuroinflammation.

The actions of Δ9-THCV and Δ9-THCA are less well understood. In contrast to ∆9-THC, CBD has low affinity for CB1 and CB2 receptors and other targets have been investigated to explain its anticonvulsant properties including TRPV1, voltage gated potassium and sodium channels, and GPR55, among others.

We describe the absorption, distribution, metabolism, and excretion of each of the above mentioned compounds. Cannabinoids as a whole are very lipophilic, resulting in decreased bioavailability, which presents challenges in optimal drug delivery. Finally, we discuss the limited drug-drug interaction data available on THC and CBD.

As cannabinoids and cannabis-based products are studied for efficacy as anticonvulsants, more investigation is needed regarding the specific targets of action, optimal drug delivery, and potential drug-drug interactions.”

https://www.ncbi.nlm.nih.gov/pubmed/28087250

Diuretic effects of cannabinoid agonists in mice

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“Cannabinoids both increase urine output and decrease urinary frequency in human subjects. However, these effects have not been systematically evaluated in intact mice, a species commonly used to evaluate the effects of novel cannabinoids.

The present studies investigated whether cannabinoid agonists reliably produce diuresis in mice at doses comparable to those that produce other cannabinoid effects and, further, identified the receptors that may mediate these effects.

These findings suggest that mice may provide a model for understanding the mixed effects of marijuana on urine output, as described in clinical studies, and aid in the development of targeted cannabinoid based therapies for bladder dysfunction.

Clinical studies have reported beneficial effects of smoked or aerosolized cannabis on bladder dysfunction in patients with multiple sclerosis, primarily by decreasing urinary frequency in these subjects following marijuana use. These reports contrast with the earlier clinical reports demonstrating increase in urine output after cannabis administration.

Our findings in mice demonstrate a dose related increase or decrease in urine output, providing a platform for understanding the mixed effects on urine output observed with marijuana in various clinical studies. As noted earlier in a study with rats, the diuresis induced by THC in mice also is weakly naturetic compared to furosemide and further investigations in this area may yield a new, clinically beneficial diuretic.

In contrast, our data suggest that development of peripherally selective cannabinoid CB1 agonists may be beneficial for patients suffering from bladder dysfunction.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872476/

Tetrahydrocannabinol and endocannabinoids in feeding and appetite.

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“The physiological control of appetite and satiety, in which numerous neurotransmitters and neuropeptides play a role, is extremely complex. Here we describe the involvement of endocannabinoids in these processes.

These endogenous neuromodulators enhance appetite in animals.

The same effect is observed in animals and in humans with the psychotropic plant cannabinoid Delta(9)-tetrahydrocannabinol, which is an approved appetite-enhancing drug.

The CB(1) cannabinoid receptor antagonist SR141716A blocks the effects on feeding produced by the endocannabinoids. If administered to mice pups, this antagonist blocks suckling.

In obese humans, it causes weight reduction.

Very little is known about the physiological and biochemical mechanisms involved in the effects of Delta(9)-tetrahydrocannabinol and the cannabinoids in feeding and appetite.”

https://www.ncbi.nlm.nih.gov/pubmed/12182965