Tag Archives: THC

Beyond THC and Endocannabinoids.

Posted on by

Image result for AR Annual Reviews“Research in the cannabinoid field, namely on phytocannabinoids, the endogenous cannabinoids anandamide and 2-arachidonoyl glycerol and their metabolizing and synthetic enzymes, the cannabinoid receptors, and anandamide-like cannabinoid compounds, has expanded tremendously over the last few years. Numerous endocannabinoid-like compounds have been discovered. The Cannabis plant constituent cannabidiol (CBD) was found to exert beneficial effects in many preclinical disease models ranging from epilepsy, cardiovascular disease, inflammation, and autoimmunity to neurodegenerative and kidney diseases and cancer. CBD was recently approved in the United States for the treatment of rare forms of childhood epilepsy. This has triggered the development of many CBD-based products for human use, often with overstated claims regarding their therapeutic effects. In this article, the recently published research on the chemistry and biological effects of plant cannabinoids (specifically CBD), endocannabinoids, certain long-chain fatty acid amides, and the variety of relevant receptors is critically reviewed. ”

https://www.ncbi.nlm.nih.gov/pubmed/31580774

https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-010818-021441

Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus Through Bi-Directional Control of ERK1-2 Phosphorylation

Posted on by

Journal of Neuroscience“Evidence suggests that the phytocannabinoids Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) differentially regulate salience attribution and psychiatric risk. The ventral hippocampus (vHipp) relays emotional salience via control of dopamine (DA) neuronal activity states, which are dysregulated in psychosis and schizophrenia. Using in-vivo electrophysiology in male Sprague Dawley rats, we demonstrate that intra-vHipp THC strongly increases ventral tegmental area (VTA) DA neuronal frequency and bursting rates, decreases GABA frequency, and amplifies VTA beta, gamma and epsilon oscillatory magnitudes via modulation of local extracellular signal-regulated kinase phosphorylation (pERK1-2). Remarkably, whereas intra-vHipp THC also potentiates salience attribution in morphine place-preference and fear conditioning assays, CBD co-administration reverses these changes by down-regulating pERK1-2 signaling, as pharmacological re-activation of pERK1-2 blocked the inhibitory properties of CBD. These results identify vHipp pERK1-2 signaling as a critical neural nexus point mediating THC-induced affective disturbances and suggest a potential mechanism by which CBD may counteract the psychotomimetic and psychotropic side-effects of THC.

SIGNIFICANCE STATEMENT

Strains of marijuana with high levels of delta-9-tetrahydrocannabinol (THC) and low levels of cannabidiol (CBD) have been shown to underlie neuropsychiatric risks associated with high potency cannabis use. However, the mechanisms by which CBD mitigates the side effects of THC have not been identified. We demonstrate that THC induces cognitive and affective abnormalities resembling neuropsychiatric symptoms directly in the hippocampus, while dysregulating dopamine activity states and amplifying oscillatory frequencies in the ventral tegmental area via modulation of the extracellular signal-regulated kinase (ERK) signaling pathway. In contrast, CBD co-administration blocked THC-induced ERK phosphorylation, and prevented THC-induced behavioural and neural abnormalities. These findings identify a novel molecular mechanism that may account for how CBD functionally mitigates the neuropsychiatric side-effects of THC.”

https://www.ncbi.nlm.nih.gov/pubmed/31570536

https://www.jneurosci.org/content/early/2019/09/27/JNEUROSCI.0708-19.2019

“Western University researchers show how CBD blocks side-effects of THC in cannabis. Research out of Western University is showing for the first time how cannabidiol (CBD) helps to lessen negative psychiatric side effects of tetrahydrocannabinol (THC) in cannabis.”  https://globalnews.ca/news/5970908/western-university-research-cbd-thc-cannabis/

“Cannabis study reveals how CBD offsets the psychiatric side-effects of THC”  https://neurosciencenews.com/cbd-thc-psychosis-15002/

Absence of Entourage: Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Functional Activity of Δ9-THC at Human CB1 and CB2 Receptors.

Posted on by

 View details for Cannabis and Cannabinoid Research cover image“Compounds present in Cannabis sativa such as phytocannabinoids and terpenoids may act in concert to elicit therapeutic effects. Cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) directly activate cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2); however, it is not known if terpenoids present in Cannabis also affect cannabinoid receptor signaling. Therefore, we examined six common terpenoids alone, and in combination with cannabinoid receptor agonists, on CB1 and CB2 signaling in vitro.

Results: α-Pinene, β-pinene, β-caryophyllene, linalool, limonene, and β-myrcene (up to 30-100 μM) did not change membrane potential in AtT20 cells expressing CB1 or CB2, or affect the response to a maximally effective concentration of the synthetic cannabinoid CP55,940. The presence of individual or a combination of terpenoids did not affect the hyperpolarization produced by Δ9-THC (10 μM): (CB1: control, 59%±7%; with terpenoids (10 μM each) 55%±4%; CB2: Δ9-THC 16%±5%, with terpenoids (10 μM each) 17%±4%). To investigate possible effect on desensitization of CB1 responses, all six terpenoids were added together with Δ9-THC and signaling measured continuously over 30 min. Terpenoids did not affect desensitization, after 30 min the control hyperpolarization recovered by 63%±6% in the presence of the terpenoids recovery was 61%±5%.

Discussion: None of the six of the most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signaling of the phytocannabinoid agonist Δ9-THC. These results suggest that if a phytocannabinoid-terpenoid entourage effect exists, it is not at the CB1 or CB2 receptor level. It remains possible that terpenoids activate CB1 and CB2 signaling pathways that do not involve potassium channels; however, it seems more likely that they may act at different molecular target(s) in the neuronal circuits important for the behavioral effect of Cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/31559333

https://www.liebertpub.com/doi/10.1089/can.2019.0016

“Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity. We found that in “high THC” or “high CBD” strains, phytocannabinoids are produced alongside certain sets of terpenoids. Only co-related terpenoids enhanced the cytotoxic activity of phytocannabinoids on MDA-MB-231 and HCT-116 cell lines. This was found to be most effective in natural ratios found in extracts of cannabis inflorescence.”  https://www.ncbi.nlm.nih.gov/pubmed/31438532

Medical cannabis for inflammatory bowel disease: real-life experience of mode of consumption and assessment of side-effects.

Posted on by

 

Image result for ovid journal“Use of medical cannabis for improving symptoms of inflammatory bowel disease is increasing. However, reports on long-term outcomes are lacking. This prospective, observational study assessed the effects of licensed cannabis use among patients with inflammatory bowel disease.

METHODS:

Dose and mode of consumption, adverse events, use of other medications, and long-term effects were evaluated among 127 patients with inflammatory bowel disease using legalized medical cannabis. Blood count, albumin, and C-reactive protein were assessed before, 1 month, and at least 1 year after medical cannabis therapy was initiated. Questionnaires on disease activity, patient function, and signs of addiction were completed by patients and by a significant family member to assess its effects.

RESULTS:

The average dose used was 31 ± 15 g/month. The average Harvey-Bradshaw index improved from 14 ± 6.7 to 7 ± 4.7 (P < 0.001) during a median follow-up of 44 months (interquartile range, 24-56 months). There was a slight, but statistically significant, average weight gain of 2 kg within 1 year of cannabis use. The need for other medications was significantly reduced. Employment among patients increased from 65 to 74% (P < 0.05). We conclude that the majority of inflammatory bowel disease patients using cannabis are satisfied with a dose of 30 g/month. We did not observe negative effects of cannabis use on the patients’ social or occupational status.

CONCLUSIONS:

Cannabis use by inflammatory bowel disease patients can induce clinical improvement and is associated with reduced use of medication and slight weight gain. Most patients respond well to a dose of 30 g/month, or 21 mg Δ9-tetra- hydrocannabinol (THC) and 170 mg Cannabidiol (CBD) per day.”

 https://www.ncbi.nlm.nih.gov/pubmed/31567639
https://insights.ovid.com/crossref?an=00042737-900000000-97736

Δ9-Tetrahydrocannabinol During Adolescence Attenuates Disruption of Dopamine Function Induced in Rats by Maternal Immune Activation.

Posted on by

Image result for frontiers in behavioral neuroscience“Here, we hypothesized that adolescent Δ9-tetrahydrocannabinol (THC) worsens the impact of prenatal maternal immune activation (MIA) on ventral tegmental area (VTA) dopamine cells in rat offspring.

Adolescent THC attenuated several MIA-induced effects.

Contrary to our expectations, adolescent THC did not worsen MIA-induced deficits.”

https://www.ncbi.nlm.nih.gov/pubmed/31551729

https://www.frontiersin.org/articles/10.3389/fnbeh.2019.00202/full

Potential of Cannabinoid Receptor Ligands as Treatment for Substance Use Disorders.

Posted on by

 “Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited.

During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids.

Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008.

Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs.

In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs.

As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆9-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals.

Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.”

https://www.ncbi.nlm.nih.gov/pubmed/31549358

https://link.springer.com/article/10.1007%2Fs40263-019-00664-w

Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation.

Posted on by

 Image result for journal of geriatric psychiatry and neurology

“The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation.

We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38).

These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.”

https://www.ncbi.nlm.nih.gov/pubmed/31547752

https://journals.sagepub.com/doi/abs/10.1177/0891988719874118?journalCode=jgpb

Medical cannabis for chronic pain: can it make a difference in pain management?

Posted on by

 “Globally, chronic pain is a major therapeutic challenge and affects more than 15% of the population. As patients with painful terminal diseases may face unbearable pain, there is a need for more potent analgesics.

Although opioid-based therapeutic agents received attention to manage severe pain, their adverse drug effects and mortality rate associated with opioids overdose are the major concerns.

Evidences from clinical trials showed therapeutic benefits of cannabis, especially delta-9-tetrahydrocannabinol and cannabinoids reduced neuropathic pain intensity in various conditions. Also, there are reports on using combination cannabinoid therapies for chronic pain management.

The association of cannabis dependence and addiction has been discussed much and the reports mentioned that it can be comparatively lower than other substances such as nicotine and alcohol.

More countries have decided to legalise the medicinal use of cannabis and marijuana.

Healthcare professionals should keep themselves updated with the changing state of medical cannabis and its applications.”

https://www.ncbi.nlm.nih.gov/pubmed/31535218

https://link.springer.com/article/10.1007%2Fs00540-019-02680-y

Modulation of the endocannabinoid system: vulnerability factor and new treatment target for stimulant addiction

Posted on by

Image result for frontiers in psychiatry“Interestingly, increasing recent evidence points toward the involvement of the endocannabinoid system (ECBS) in the neurobiological processes related to stimulant addiction.

This article presents an up-to-date review with deep insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. This article aims to: (1) review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and (2) evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction.

A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoids in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants.

Interestingly, emerging human data supports a role for ECBS modulation in vulnerability to psychostimulant addiction, and more significantly in addictive behaviors among dependent individuals. Accumulating evidence thus points to the ECBS as a critical target for the development of pharmacotherapies for the treatment of addiction to psychostimulants.

Given the various neuropharmacological actions of exogenous cannabinoids, and their ability to modulate the acute reinforcing effects of drugs, data on Δ9-THC and CBD is particularly promising as to the potential use of cannabinoids in relapse prevention strategies for psychostimulant-dependent individuals.”

https://www.frontiersin.org/articles/10.3389/fpsyt.2013.00109/full

The effects of cannabis, cannabinoids, and their administration routes on pain control efficacy and safety: A systematic review and network meta-analysis.

Posted on by

“To determine the effects of cannabis, cannabinoids, and their administration routes on pain and adverse euphoria events.

Randomized controlled trials investigating the effects of cannabis or cannabinoids on pain reduction.

RESULTS:

A total of 25 studies involving 2270 patients were included. We found that delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) (oromucosal route), THC (oromucosal route), and standardized dried cannabis (with THC; SCT; inhalation route) could reduce neuropathic pain score (SMD -0.41, 95% CI -0.7 to -0.1; -0.61, 95% CI -1.2 to -0.02; and -0.77, 95% CI -1.4 to -0.2; respectively). For nociceptive pain, only standardized cannabis extract (with THC; SCET) via oral route could reduce pain score (SMD -1.8, 95% C; -2.4 to -1.2). In cancer pain, THC/CBD via oromucosal route and THC via oral or oromucosal route could reduce pain score (SMD -0.7, 95% CI -1.2 to -0.2; and -2.1, 95% CI -2.8 to -1.4; respectively). No study was observed for THC/CBD via oral route or inhalation or THC via inhalation for cancer and nociceptive pain, SCET via oromucosal route or inhalation for neuropathic and cancer pain, THC via oromucosal route for nociceptive pain, and SCT via oromucosal or oral route for neuropathic, cancer, and nociceptive pain. Statistically significant increased risks of euphoria were observed in THC/CBD (oromucosal), THC (oromucosal), and SCT (inhalation).

CONCLUSION:

The use of cannabis and cannabinoids via certain administration routes could reduce different types of pain. Product developers could consider our findings as part of their product design so that the effective route of cannabis and cannabinoids for pain control can be achieved.”

https://www.ncbi.nlm.nih.gov/pubmed/31495691

https://www.japha.org/article/S1544-3191(19)30353-X/fulltext