Tag Archives: phytocannabinoids

Cannabinoids for drug-resistant seizures in a critically ill patient-Case report and literature review.

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Publication cover image“Drug-resistant seizures are life-threatening and contribute to sustained hospitalization.

We present the case of a critically ill 28-year-old male with Lennox-Gastaut syndrome who had approximately 30 seizures/day in the intensive care unit.

CASE DESCRIPTION:

Patient required mechanical ventilation and pharmacologically induced thiopentone coma.

He was commenced on cannabidiol and subsequently extubated.

He remained seizure-free thereafter on a combination of cannabidiol and anti-epileptic medication that predated his critical illness.

WHAT IS NEW AND CONCLUSION:

Our case report provides a unique perspective on the role of cannabidiol in achieving remission from drug-resistant seizures in critically ill patients.”

https://www.ncbi.nlm.nih.gov/pubmed/31770462

https://onlinelibrary.wiley.com/doi/abs/10.1111/jcpt.13082

Experimental Cannabinoid 2 Receptor Activation by Phyto-Derived and Synthetic Cannabinoid Ligands in LPS-Induced Interstitial Cystitis in Mice.

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molecules-logo“Interstitial cystitis (IC) is a chronic bladder disorder with unclear etiology.

The endocannabinoid system has been identified as a key regulator of immune function, with experimental evidence for the involvement of cannabinoid receptors in bladder inflammation.

This study used intravital microscopy (IVM) and behavioral testing in lipopolysaccharide-induced IC, to investigate the anti-inflammatory analgesic effects of a natural dietary sesquiterpenoid, beta-caryophyllene (BCP), which is present in cannabis among other plants, and has reported agonist actions at the cannabinoid 2 receptor (CB2R).

BCP’s anti-inflammatory actions were compared to the synthetic CB2R-selective cannabinoid, HU308, and to an FDA-approved clinical treatment (dimethyl sulfoxide: DMSO). IVM data revealed that intravesical instillation of BCP and/or HU308 significantly reduces the number of adhering leukocytes in submucosal bladder venules and improves bladder capillary perfusion.

The effects of BCP were found to be comparable to that of the selective CB2R synthetic cannabinoid, HU308, and superior to intravesical DMSO treatment. Oral treatment with BCP was also able to reduce bladder inflammation and significantly reduced mechanical allodynia in experimental IC.

Based on our findings, we believe that CB2R activation may represent a viable therapeutic target for IC, and that drugs that activate CB2R, such as the generally regarded as safe (GRAS) dietary sesquiterpenoid, BCP, may serve as an adjunct and/or alternative treatment option for alleviating symptoms of inflammation and pain in the management of IC.”

https://www.ncbi.nlm.nih.gov/pubmed/31766439

https://www.mdpi.com/1420-3049/24/23/4239

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

Could the Combination of Two Non-Psychotropic Cannabinoids Counteract Neuroinflammation? Effectiveness of Cannabidiol Associated with Cannabigerol.

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medicina-logo“Neuroinflammation is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this study, we investigate the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of two non-psychoactive phytocannabinoids, cannabigerol (CBG) and cannabidiol (CBD).

Results: Pre-treatment with CBG (at 2.5 and 5 µM doses) alone and in combination with CBD (at 2.5 and 5 µM doses) was able to reduce neuroinflammation induced by a culture medium of LPS-stimulated macrophages. In particular, the pre-treatment with CBD at a 5 µM dose decreased TNF-α levels and increased IL10 and IL-37 expression. CBG-CBD association at a 5 µM dose also reduced NF-kB nuclear factor activation with low degradation of the inhibitor of kappaB alpha (IkBα). CBG and CBD co-administered at a 5 µM dose decreased iNOS expression and increased Nrf2 levels. Furthermore, the pre-treatment with the association of two non-psychoactive cannabinoids downregulated Bax protein expression and upregulated Bcl-2 expression. Our data show the anti-inflammatory, anti-oxidant, and anti-apoptotic effects PPARγ-mediated.

Conclusions: Our results provide preliminary support on the potential therapeutic application of a CBG-CBD combination for further preclinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31752240

https://www.mdpi.com/1010-660X/55/11/747

Cannabidiol as a potential treatment for psychosis

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Image result for therapeutic advances in psychopharmacology“Accumulating evidence implicates the endocannabinoid system in the pathophysiology of psychosis.

If the endocannabinoid system plays a role in psychosis pathophysiology, it raises the interesting possibility that pharmacological compounds that modulate this system may have therapeutic value.

Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa, has been heralded as one such potential treatment.

Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has emerged as a potential novel class of antipsychotic with a unique mechanism of action.

In this review, we set out the prospects of CBD as a potential novel treatment for psychotic disorders.

In sum, CBD currently represents a promising potential novel treatment for patients with psychosis.”

https://journals.sagepub.com/doi/10.1177/2045125319881916

https://www.ncbi.nlm.nih.gov/pubmed/31741731

Pharmacokinetics of Phytocannabinoid Acids and Anticonvulsant Effect of Cannabidiolic Acid in a Mouse Model of Dravet Syndrome.

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 Go to Volume 0, Issue 0“Cannabis sativa produces a complex mixture of many bioactive molecules including terpenophenolic compounds known as phytocannabinoids. Phytocannabinoids come in neutral forms (e.g., Δ9-tetrahydrocannabinol, THC; cannabidiol, CBD; etc.) or as acid precursors, which are dominant in the plant (e.g., Δ9-tetrahydrocannabinolic acid, THCA; cannabidiolic acid, CBDA; etc.).

There is increasing interest in unlocking the therapeutic applications of the phytocannabinoid acids; however, the present understanding of the basic pharmacology of phytocannabinoid acids is limited. Herein the brain and plasma pharmacokinetic profiles of CBDA, THCA, cannabichromenic acid (CBCA), cannabidivarinic acid (CBDVA), cannabigerolic acid (CBGA), and cannabigerovarinic acid (CBGVA) were examined following intraperitoneal administration in mice.

Next it was examined whether CBDA was anticonvulsant in a mouse model of Dravet syndrome (Scn1aRX/+ mice). All the phytocannabinoid acids investigated were rapidly absorbed with plasma tmax values of between 15 and 45 min and had relatively short half-lives (<4 h). The brain-plasma ratios for the acids were very low at ≤0.04. However, when CBDA was administered in an alternate Tween 80-based vehicle, it exhibited a brain-plasma ratio of 1.9. The anticonvulsant potential of CBDA was examined using this vehicle, and it was found that CBDA significantly increased the temperature threshold at which the Scn1aRX/+ mice had a generalized tonic-clonic seizure.”

https://www.ncbi.nlm.nih.gov/pubmed/31686510

https://pubs.acs.org/doi/abs/10.1021/acs.jnatprod.9b00600

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Cannabidiol and Cannabinoid Compounds as Potential Strategies for Treating Parkinson’s Disease and L-DOPA-Induced Dyskinesia.

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 “Parkinson’s disease (PD) and L-DOPA-induced dyskinesia (LID) are motor disorders with significant impact on the patient’s quality of life. Unfortunately, pharmacological treatments that improve these disorders without causing severe side effects are not yet available. Delay in initiating L-DOPA is no longer recommended as LID development is a function of disease duration rather than cumulative L-DOPA exposure.

Manipulation of the endocannabinoid system could be a promising therapy to control PD and LID symptoms.

In this way, phytocannabinoids and synthetic cannabinoids, such as cannabidiol (CBD), the principal non-psychotomimetic constituent of the Cannabis sativa plant, have received considerable attention in the last decade.

In this review, we present clinical and preclinical evidence suggesting CBD and other cannabinoids have therapeutic effects in PD and LID. Here, we discuss CBD pharmacology, as well as its neuroprotective effects and those of other cannabinoids.

Finally, we discuss the modulation of several pro- or anti-inflammatory factors as possible mechanisms responsible for the therapeutic/neuroprotective potential of Cannabis-derived/cannabinoid synthetic compounds in motor disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31637586

https://link.springer.com/article/10.1007%2Fs12640-019-00109-8

Modulation of the Endocannabinoid and Oxytocinergic Systems as a Potential Treatment Approach for Social Anxiety Disorder.

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 “Social anxiety disorder (SAD), or social phobia, is one of the most common types of anxiety disorder, with a lifetime prevalence that can reach 15%.

Pharmacological treatments for SAD have moderate efficacy and are associated with significant adverse reactions. Therefore, recent studies have focused on searching for new treatments for this disorder.

Preclinical studies and preliminary evidence in humans suggest that the phytocannabinoid cannabidiol and the neuropeptide oxytocin have anxiolytic effects. In the present text, we review this evidence and its implications for pharmacological treatment.

We conclude that although current available studies show promising results regarding both the safety and efficacy of cannabidiol and oxytocin for the treatment of SAD, most studies were performed using single or few doses of these compounds, with small sample sizes.

Therefore, future studies should explore the anxiolytic potential of these compounds using long-term, placebo-controlled designs with larger samples to elucidate the possible use of these compounds in the treatment of SAD.”

https://www.ncbi.nlm.nih.gov/pubmed/31617149

https://link.springer.com/article/10.1007%2Fs40263-019-00669-5

Beyond THC and Endocannabinoids.

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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

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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.

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 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