Tag Archives: THC

Can we make cannabis safer?

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“Cannabis use and related problems are on the rise globally alongside an increase in the potency of cannabis sold on both black and legal markets. Additionally, there has been a shift towards abandoning prohibition for a less punitive and more permissive legal stance on cannabis, such as decriminalisation and legalisation. It is therefore crucial that we explore new and innovative ways to reduce harm.

Research has found cannabis with high concentrations of its main active ingredient, δ-9-tetrahydrocannabinol (THC), to be more harmful (in terms of causing the main risks associated with cannabis use, such as addiction, psychosis, and cognitive impairment) than cannabis with lower concentrations of THC. By contrast, cannabidiol, which is a non-intoxicating and potentially therapeutic component of cannabis, has been found to reduce the negative effects of cannabis use.

Here, we briefly review findings from studies investigating various types of cannabis and discuss how future research can help to better understand and reduce the risks of cannabis use.”  https://www.ncbi.nlm.nih.gov/pubmed/28259650

“Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/

“CBD may also potentiate some of Δ9-THC’s beneficial effects as it reduces Δ9-THC’s psychoactivity to enhance its tolerability and widen its therapeutic window.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707667/

The current status of artisanal cannabis for the treatment of epilepsy in the United States.

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“The widespread patient use of artisanal cannabis preparations has preceded quality validation of cannabis use for epilepsy. Neurologists and cannabinoid specialists are increasingly in a position to monitor and guide the use of herbal cannabis in epilepsy patients. We report the retrospective data on efficacy and adverse effects of artisanal cannabis in Patients with medically refractory epilepsy with mixed etiologies in Washington State, California, and Maine. Clinical considerations, including potential risks and benefits, challenges related to artisanal preparations, and cannabinoid dosing, are discussed.

RESULTS:

Of 272 combined patients from Washington State and California, 37 (14%) found cannabis ineffective at reducing seizures, 29 (15%) experienced a 1-25% reduction in seizures, 60 (18%) experienced a 26-50% reduction in seizures, 45 (17%) experienced a 51-75% reduction in seizures, 75 (28%) experienced a 76-99% reduction in seizures, and 26 (10%) experienced a complete clinical response. Overall, adverse effects were mild and infrequent, and beneficial side effects such as increased alertness were reported. The majority of patients used cannabidiol (CBD)-enriched artisanal formulas, some with the addition of delta-9-tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA). Four case reports are included that illustrate clinical responses at doses <0.1mg/kg/day, biphasic dose-response effects, the use of THCA for seizure prevention, the use of THC for seizure rescue, and the synergy of cannabinoids and terpenoids in artisanal preparations. This article is part of a Special Issue entitled “Cannabinoids and Epilepsy”.”

https://www.ncbi.nlm.nih.gov/pubmed/28254350

The endocannabinoid system modulating levels of consciousness, emotions and likely dream contents.

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“Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is ∆9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors.

These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named as the CB1 and CB2 cannabinoid receptors.

Later, an endogenous molecule that exerts pharmacological effects similar to those described by ∆9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG).

Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2-AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT).

To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various diseases, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity.

Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams.

Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences.”

https://www.ncbi.nlm.nih.gov/pubmed/28240187

Concise review of the management of iatrogenic emesis using cannabinoids: emphasis on nabilone for chemotherapy-induced nausea and vomiting.

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“Chemotherapy-induced nausea and vomiting (CINV) is a prevalent, distressing, and burdensome side effect of cancer chemotherapy. It is estimated to affect the majority of patients receiving certain anti-cancer drug regimens and can be treatment-limiting, even for life-saving medications. Despite seemingly numerous options, such as antimuscarinic anticholinergics, antihistamines, 5-HT3 receptor antagonists, dopamine receptor antagonists, and neurokinin-1 receptor antagonists, preventative therapies are often inadequately effective, particularly for “delayed CINV”-leaving an important unmet clinical need.

Cannabinoid receptor agonists, by virtue of their unique mechanism of action and efficacy and safety data reported in clinical trials, appear to offer a useful additional option.

The mechanistic value of cannabinoids has been well known for many years, but these agents may have been underutilized in the past because of the notoriety and legal status of marijuana. While botanical marijuana contains nearly 500 components, including the psychoactive tetrahydrocannabinol (THC), nabilone is an established, single-entity synthetic cannabinoid receptor agonist that has become the focus of renewed interest. We review the basic pharmacology and clinical trial data of nabilone for use in prophylaxis and treatment of CINV.”

 https://www.ncbi.nlm.nih.gov/pubmed/28235999

Cannabidiol: State of the art and new challenges for therapeutic applications.

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“Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ9-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ9-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in nuerological diseases and cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/28232276

Cannabinoid HU210 Protects Isolated Rat Stomach against Impairment Caused by Serum of Rats with Experimental Acute Pancreatitis

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“Acute pancreatitis (AP), especially severe AP, is a potentially lethal inflammatory disease of pancreas which often leads to extra-pancreatic complications, even multiple systemic organ dysfunctions. It has been reported that 52% of patients with acute pancreatitis develop acute gastrointestinal mucosal lesion (AGML) or stress ulcer.

For centuries, Cannabis plant and its extracts have been used to alleviate symptoms of gastrointestinal inflammatory diseases.

It has been established that D9-tetrahydrocannabinol, the major psychoactive component of Cannabis, exerts its primary cellular actions though two G protein-coupled receptors, cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors.

Since then, these two receptors have been recognized as the major regulators of physiological and pathological processes. Cannabinoids can reduce gastrointestinal secretion, and the activation of CB1 receptor exhibits protective role against stress-induced AGML, but the mechanisms of their action remain elusive.

The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis.

Therefore, our experimental results suggest a novel mechanism in the onset of AGML and new therapeutic values of cannabinoids as supplement of anti-inflammatory therapy in acute pancreatitis.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532296/

Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells

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“While cannabinoids have been shown to ameliorate liver fibrosis, their effects in chronic pancreatitis and on pancreatic stellate cells (PSC) are unknown.

The activity of the endocannabinoid system was evaluated in human chronic pancreatitis (CP) tissues.

Augmentation of the endocannabinoid system via exogenously administered cannabinoid receptor agonists specifically induces a functionally and metabolically quiescent pancreatic stellate cell phenotype and may thus constitute an option to treat inflammation and fibrosis in chronic pancreatitis.

Because drugs for the treatment of chronic pancreatitis should ideally exert anti-fibrotic and anti-inflammatory properties, their bimodal effects rather contradict a therapeutic use of CB-receptor antagonists and promote the hypothesis that (re-)activation of the (endo-)cannabinoid system in chronic pancreatitis may be beneficial for suppressing disease progress.

In conclusion, we show that the endocannabinoid system is downregulated in chronic pancreatitis and that its augmentation via exogenously administered cannabinoids specifically reduces activation of pancreatic stellate cells.

These experiments lay a basis for testing the value of synthetic cannabinoids in the treatment of chronic pancreatitis.”

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001701

Cannabinoids and Cystic Fibrosis

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“Cannabis stimulates appetite and food intake. This property has been exploited to benefit AIDS and cancer patients suffering from wasting disease, by administering the whole plant or its major active ingredient ?-tetrahydrocannabinol (THC). Endogenous cannabinoids (“endocannabinoids”) are found in maternal milk. We have recently shown that endocannabinoids are critical for milk ingestion and survival of newborns because blocking CB1 receptors resulted in death from malnutrition. Lack of appetite resulting in malnutrition is a contributing factor to mortality in many Cystic Fibrosis (CF) patients. It is proposed here for the first time, to administer THC to CF patients. It is hoped that the cannabinoid will alleviate malnutrition and thus help prevent wasting in CF patients. Recent findings suggest that a lipid imbalance (high arachidonic acid/low DHA) is a primary factor in the etiology of CF and that defective CFTR (CF transmembrane conductor regulator) that characterizes the CF condition is responsible for the dysregulation. Endocannabinoids are all fatty acid derivatives. Therefore, it is further proposed here that the CFTR gene product also modulates endocannabinoid synthesis, through regulation of fatty acid biosynthesis. According to this hypothesis, CF patients display decreased levels of endocannabinoids and by elevating these levels, symptoms may improve. Indeed, a number of physiological mechanisms of cannabinoids and endocannabinoids coincide with the pathology of CF. Thus it is suggested that potential benefits from THC treatment, in addition to appetite stimulation, will include antiemetic, bronchodilating, anti-inflammatory, anti-diarrheal and hypo-algesic effects.” https://www.researchgate.net/publication/233294071_Cannabinoids_and_Cystic_Fibrosis

“Cannabinoids and Cystic Fibrosis. A Novel Approach to Etiology and Therapy”  http://www.tandfonline.com/doi/abs/10.1300/J175v02n01_03

Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice.

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“Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood.

The use of antipsychotics and benzodiazepines against CIAPS is limited by side effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed.

Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy.

The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis.

We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS.”  https://www.ncbi.nlm.nih.gov/pubmed/28220044

“Pregnenolone can protect the brain from cannabis intoxication. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057431/

Effects of tetrahydrocannabinol on glucose uptake in the rat brain.

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“Δ9-Tetrahydrocannabinol (THC) is the psychoactive component of the plant Cannabis sativa and acts as a partial agonist at cannabinoid type 1 and type 2 receptors in the brain.

The goal of this study was to assess the effect of THC on the cerebral glucose uptake in the rat brain.

Low blood THC levels of <1 ng/ml corresponded to an increased glucose uptake while blood THC levels > 10 ng/ml coincided with a decreased glucose uptake. The effective concentration in this region was estimated 2.4 ng/ml.

This glucose PET study showed that stimulation of CB1 receptors by THC affects the glucose uptake in the rat brain, whereby the effect of THC is regionally different and dependent on dose – an effect that may be of relevance in behavioural studies.”

https://www.ncbi.nlm.nih.gov/pubmed/28219717