Tag Archives: treatment

A peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain.

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“Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain.

Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients’ quality of life.

In contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP.

Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP.

Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects.

Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP.”

 https://www.ncbi.nlm.nih.gov/pubmed/29781960
https://insights.ovid.com/crossref?an=00006396-900000000-98957

Review of the neurological benefits of phytocannabinoids.

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“Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.

METHODS:

In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.

RESULTS:

Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.

CONCLUSIONS:

In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/29770251

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/

Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation.

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The Journal of Lipid Research “Phytocannabinoids, such as Δ9–tetrahydrocannabinol (THC), bind and activate cannabinoid (CB) receptors, thereby “piggy-backing” on the same pathway’s endogenous endocannabinoids (ECs).

The recent discovery that liver fatty acid binding protein-1 (FABP1) is the major cytosolic “chaperone” protein with high affinity for both Δ9-THC and ECs suggests that Δ9-THC may alter hepatic EC levels.

Therefore, the impact of Δ9-THC or EC treatment on the levels of endogenous ECs, such as N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), was examined in cultured primary mouse hepatocytes from WT and Fabp1 gene-ablated (LKO) mice. Δ9-THC alone or 2-AG alone significantly increased AEA and especially 2-AG levels in WT hepatocytes. LKO alone markedly increased AEA and 2-AG levels. However, LKO blocked/diminished the ability of Δ9-THC to further increase both AEA and 2-AG. In contrast, LKO potentiated the ability of exogenous 2-AG to increase the hepatocyte level of AEA and 2-AG.

These and other data suggest that Δ9-THC increases hepatocyte EC levels, at least in part, by upregulating endogenous AEA and 2-AG levels.

This may arise from Δ9-THC competing with AEA and 2-AG binding to FABP1, thereby decreasing targeting of bound AEA and 2-AG to the degradative enzymes, fatty acid amide hydrolase and monoacylglyceride lipase, to decrease hydrolysis within hepatocytes.”

https://www.ncbi.nlm.nih.gov/pubmed/29414765

http://www.jlr.org/content/59/4/646

Anandamide and endocannabinoid system: an attractive therapeutic approach for cardiovascular disease.

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SAGE Journals

“Cardiovascular disease is currently not adequately managed and has become one of the main causes of morbidity and mortality worldwide. Current therapies are inadequate in terms of preventing its progression. There are several limitations, such as poor oral bioavailability, side effects, low adherence to treatment, and high dosage frequency of formulations due to the short half-life of the active ingredients used, among others.

This review aims to highlight the most relevant aspects of the relationship between the cardiovascular system and the endocannabinoid system, with special attention to the possible translational effect of the use of anandamide in cardiovascular health. The deep and detailed knowledge of this interaction, not always beneficial, and that for years has gone unnoticed, is essential for the development of new therapies.

We discuss the most recent and representative results obtained in the field of basic research, referring to the aforementioned subject, emphasizing fundamentally the main role of nitric oxide, renal physiology and its deregulation in pathological processes.”

 https://www.ncbi.nlm.nih.gov/pubmed/29764302
http://journals.sagepub.com/doi/10.1177/1753944718773690

Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

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“Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy.

We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.

Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo.”

https://www.ncbi.nlm.nih.gov/pubmed/29768152

https://www.nejm.org/doi/10.1056/NEJMoa1714631

Medication overuse headache following repeated morphine, but not [INCREMENT]9-tetrahydrocannabinol administration in the female rat.

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“The potential of [INCREMENT]-tetrahydrocannabinol (THC) as a treatment for migraine depends on antinociceptive efficacy with repeated administration.

Although morphine has good antinociceptive efficacy, repeated administration causes medication overuse headache (MOH) – a condition in which the intensity/frequency of migraine increases.

The present study compared the effect of repeated morphine or THC administration on the magnitude and duration of migraine-like pain induced by a microinjection of allyl isothiocyanate (AITC) onto the dura mater of female rats.

Acute administration of THC or morphine prevented AITC-induced depression of wheel running. This antinociception was maintained in rats treated repeatedly with THC, but not following repeated administration of morphine. Moreover, repeated morphine, but not THC administration, extended the duration of AITC-induced depression of wheel running.

These data indicate that tolerance and MOH develop rapidly to morphine administration. The lack of tolerance and MOH to THC indicates that THC may be an especially effective long-term treatment against migraine.”

 https://www.ncbi.nlm.nih.gov/pubmed/29462111
https://insights.ovid.com/crossref?an=00008877-900000000-99334

Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol

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“Cannabidiol (CBD), a major constituent of Cannabis, has been shown to be a powerful anti-inflammatory and anti-anxiety drug, without exerting a psychotropic effect. However, when given either intraperitoneally or orally as a purified product, a bell-shaped dose-response was observed, which limits its clinical use.
In the present study, we have studied in mice the anti-inflammatory and anti-nociceptive activities of standardized plant extracts derived from the Cannabis sativa L., clone 202, which is highly enriched in CBD and hardly contains any psychoactive ingredients.
In stark contrast to purified CBD, the clone 202 extract, when given either intraperitoneally or orally, provided a clear correlation between the anti-inflammatory and anti-nociceptive responses and the dose, with increasing responses upon increasing doses, which makes this plant medicine ideal for clinical uses.
The clone 202 extract reduced zymosan-induced paw swelling and pain in mice, and prevented TNFα production in vivo. It is likely that other components in the extract synergize with CBD to achieve the desired anti-inflammatory action that may contribute to overcoming the bell-shaped dose-response of purified CBD.
We therefore propose that Cannabis clone 202 (Avidekel) extract is superior over CBD for the treatment of inflammatory conditions.”  https://www.scirp.org/journal/PaperInformation.aspx?paperID=53912
“In conclusion, we recommend standardized plant extract of the Cannabis clone 202 for treatment of various inflammatory conditions.” https://file.scirp.org/Html/5-2500582_53912.htm

The influence of THC:CBD oromucosal spray on driving ability in patients with multiple sclerosis-related spasticity.

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“Driving ability is a key function for the majority of patients with multiple sclerosis (MS) to help maintain daily interactions. Both physical and cognitive disability, as well as treatments, may affect the ability to drive. Spasticity is a common symptom associated with MS, and it may affect driving performance either directly or via the medications used to treat it.

In this article, we review the evidence relating the antispasticity medicine, Δ9-tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®), and its potential impact on driving performance.

The results from THC:CBD oromucosal spray driving studies and real-world registries did not show any evidence of an increase in motor vehicle accidents associated with THC:CBD oromucosal spray. The majority of patients reported an improvement in driving ability after starting THC:CBD oromucosal spray, and it was speculated that this may be related to reduced spasticity and/or better cognitive function.

THC:CBD oromucosal spray was shown not to impair driving performance.”

https://www.ncbi.nlm.nih.gov/pubmed/29761015

https://onlinelibrary.wiley.com/doi/abs/10.1002/brb3.962

Possible mechanisms of cannabinoid-induced antinociception in the spinal cord.

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European Journal of Pharmacology

“Anandamide is an endogenous ligand at both the inhibitory cannabinoid CB(1) receptor and the excitatory vanilloid receptor 1 (VR1). The CB(1) receptor and vanilloid VR1 receptor are expressed in about 50% and 40% of dorsal root ganglion neurons, respectively. While all vanilloid VR1 receptor-expressing cells belong to the calcitonin gene-related peptide-containing and isolectin B4-binding sub-populations of nociceptive primary sensory neurons, about 80% of the cannabinoid CB(1) receptor-expressing cells belong to those sub-populations. Furthermore, all vanilloid VR1 receptor-expressing cells co-express the cannabinoid CB(1) receptor.

In agreement with these findings, neonatal capsaicin treatment that induces degeneration of capsaicin-sensitive, vanilloid VR1 receptor-expressing, thin, unmyelinated, nociceptive primary afferent fibres significantly reduced the cannabinoid CB(1) receptor immunostaining in the superficial spinal dorsal horn.

Synthetic cannabinoid CB(1) receptor agonists, which do not have affinity at the vanilloid VR1 receptor, and low concentrations of anandamide both reduce the frequency of miniature excitatory postsynaptic currents and electrical stimulation-evoked or capsaicin-induced excitatory postsynaptic currents in substantia gelatinosa cells in the spinal cord without any effect on their amplitude. These effects are blocked by selective cannabinoid CB(1) receptor antagonists. Furthermore, the paired-pulse ratio is increased while the postsynaptic response of substantia gelatinosa neurons induced by alpha-amino-3-hydroxy-5-methylisoxasole-propionic acid (AMPA) in the presence of tetrodotoxin is unchanged following cannabinoid CB(1) receptor activation.

These results strongly suggest that the cannabinoid CB(1) receptor is expressed presynaptically and that the activation of these receptors by synthetic cannabinoid CB(1) receptor agonists or low concentration of anandamide results in inhibition of transmitter release from nociceptive primary sensory neurons. High concentrations of anandamide, on the other hand, increase the frequency of miniature excitatory postsynaptic currents recorded from substantia gelatinosa neurons. This increase is blocked by ruthenium red, suggesting that this effect is mediated through the vanilloid VR1 receptor.

Thus, anandamide at high concentrations can activate the VR1 and produce an opposite, excitatory effect to its inhibitory action produced at low concentrations through cannabinoid CB(1) receptor activation. This “dual”, concentration-dependent effect of anandamide could be an important presynaptic modulatory mechanism in the spinal nociceptive system.”

https://www.ncbi.nlm.nih.gov/pubmed/11698030

https://www.sciencedirect.com/science/article/pii/S0014299901013097?via%3Dihub

A Critical Systematic Review of Evidence for Cannabinoids in the Treatment of Schizophrenia

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Psychiatric Annals

“Cannabinoids have an emerging evidence base as an effective treatment option in a number of medical conditions, including anorexia and intractable vomiting.

It is well known that patients with schizophrenia are more likely to use cannabis; it has also been argued that this could be a way of self-treating adverse side effects (secondary to antipsychotics) in a group of people with schizophrenia. Therefore, studies have attempted to examine the use of cannabinoids in schizophrenia.

Given the recent interest in the use of cannabinoids in general and the ensuing ethical debates, we systematically review the available literature on the use of four cannabinoids, namely delta-9-tetrahydrocannabinol, dronabinol, rimonabant, and cannabidiol, in the management of schizophrenia. We also offer suggestions for future research in this area.”

https://www.healio.com/psychiatry/journals/psycann/2018-5-48-5/%7B04639e36-7fd1-4e31-aff2-7cea85ea3bc3%7D/a-critical-systematic-review-of-evidence-for-cannabinoids-in-the-treatment-of-schizophrenia