Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine.

“Cannabis sativa L. has been utilized for treatment of pain and sleep disorders since ancient times.

This review examines modern studies on effects of Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on sleep. It goes on to report new information on the effects on sleep in the context of medical treatment of neuropathic pain and symptoms of multiple sclerosis, employing standardized oromucosal cannabis-based medicines containing primarily THC, CBD, or a 1 : 1 combination of the two (Sativex).

Sleep-laboratory results indicate a mild activating effect of CBD, and slight residual sedation with THC-predominant extracts. Experience to date with Sativex in numerous Phase I-III studies in 2000 subjects with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile.

No tolerance to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety extension studies of up to four years, wherein 40-50% of subjects attained good or very good sleep quality, a key source of disability in chronic pain syndromes that may contribute to patients’ quality of life.”

http://www.ncbi.nlm.nih.gov/pubmed/17712817

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Therapeutic Satisfaction and Subjective Effects of Different Strains of Pharmaceutical-Grade Cannabis.

“The aims of this study are to assess the therapeutic satisfaction within a group of patients using prescribed pharmaceutical-grade cannabis and to compare the subjective effects among the available strains with special focus on their delta-9-tetrahydrocannabinol and cannabidiol content…

One hundred two patients were included; their average age was 53 years and 76% used it for more than a year preceding this study. Chronic pain (53%; n = 54) was the most common medical indication for using cannabis followed by multiple sclerosis (23%; n = 23), and 86% (n = 88) of patients (almost) always experienced therapeutic satisfaction when using pharmaceutical cannabis.

These results show that patients report therapeutic satisfaction with pharmaceutical cannabis, mainly pain alleviation. Some subjective effects were found to differ among the available strains of cannabis, which is discussed in relation to their different tetrahydrocannabinol/cannabidiol content. These results may aid in further research and critical appraisal for medicinally prescribed cannabis products.”

http://www.ncbi.nlm.nih.gov/pubmed/24747979

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The detection of THC, CBD and CBN in the oral fluid of Sativex® patients using two on-site screening tests and LC-MS/MS.

“Sativex® is an oromucosal spray used to treat spasticity in multiple sclerosis sufferers in some European countries, the United Kingdom, Canada and New Zealand. The drug has also recently been registered by the Therapeutic Goods Administration (TGA) in Australia for treatment of multiple sclerosis.

Sativex® contains high concentrations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with the former being the subject of random roadside drug tests across Australia to detect cannabis use.

This pilot study aims to determine whether or not patients taking Sativex® will test positive to THC using these roadside screening tests. Detectable levels of THC, CBD and cannabinol (CBN) in their oral fluid were also confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study was a double-blind, placebo controlled design.

In conclusion, Sativex® users may test positive for THC by roadside drug testing within 2-3h of use. Confirmatory analysis can identify Sativex® treatment through use of THC/CBD ratios, however, these ratios would unlikely be sufficient to differentiate non-medicinal cannabis use from Sativex® use if both are taken concurrently.”

http://www.ncbi.nlm.nih.gov/pubmed/24699310

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Delta-9-Tetrahydrocannabinol/Cannabidiol (Sativex®): A Review of Its Use in Patients with Moderate to Severe Spasticity Due to Multiple Sclerosis.

“Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) [Sativex®] is an oromucosal spray formulation that contains principally THC and CBD at an approximately 1:1 fixed ratio, derived from cloned Cannabis sativa L. plants.

The main active substance, THC, acts as a partial agonist at human cannabinoid receptors (CB1 and CB2)…

THC/CBD is approved in a number of countries, including Germany and the UK, as an add-on treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

In the largest multinational clinical trial that evaluated the approved THC/CBD regimen in this population, 12 weeks’ double-blind treatment with THC/CBD significantly reduced spasticity severity (primary endpoint) compared with placebo in patients who achieved a clinically significant improvement in spasticity after 4 weeks’ single-blind THC/CBD treatment, as assessed by a patient-rated numerical rating scale.

A significantly greater proportion of THC/CBD than placebo recipients achieved a ≥30 % reduction (a clinically relevant reduction) in spasticity severity. The efficacy of THC/CBD has been also shown in at least one everyday clinical practice study (MOVE 2). THC/CBD was generally well tolerated in clinical trials. Dizziness and fatigue were reported most frequently during the first 4 weeks of treatment and resolved within a few days even with continued treatment.

Thus, add-on THC/CBD is a useful symptomatic treatment option for its approved indication.”

http://www.ncbi.nlm.nih.gov/pubmed/24671907

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Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety.

“Our recent work has shown that cannabidiol (CBD) exhibits the most potent direct inhibition of human cytochrome P450 1A1 (CYP1A1)…

These results suggest that the pentylresorcinol structure in CBD may have structurally important roles in direct CYP1A1 inhibition, although the whole structure of CBD is required for overall inhibition.”

http://www.ncbi.nlm.nih.gov/pubmed/23811569

“CYP1A1 regulates breast cancer proliferation and survival. This study supports the notion that CYP1A1 promotes breast cancer proliferation and survival… reduction of CYP1A1 levels is a potential strategy for breast cancer therapeutics.”  http://www.ncbi.nlm.nih.gov/pubmed/23576571

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Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes.

“Inhibitory effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabidiol (CBD), and cannabinol (CBN), the three major constituents in marijuana, on catalytic activities of human cytochrome P450 (CYP) 1 enzymes were investigated.

These results indicated that CBD and CBN showed CYP1 isoform-selective direct inhibition and that CBD was characterized as a potent mechanism-based inhibitor of human CYP1 enzymes, especially CYP1A1.”

http://www.ncbi.nlm.nih.gov/pubmed/20117100

“CYP1A1 regulates breast cancer proliferation and survival. This study supports the notion that CYP1A1 promotes breast cancer proliferation and survival… reduction of CYP1A1 levels is a potential strategy for breast cancer therapeutics.”  http://www.ncbi.nlm.nih.gov/pubmed/23576571

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The yin and yang of cannabis-induced psychosis: the actions of Δ(9)-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia.

“There is substantial epidemiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms.

…propsychotic actions of THC… antipsychotic actions of CBD.

…animal studies… showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD potentiates the actions of THC.

Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors…”

…the present study suggests a beneficial property of a direct cannabinoid receptor agonist… and of CBD…”

http://www.ncbi.nlm.nih.gov/pubmed/22716133

http://www.thctotalhealthcare.com/category/schizophrenia/

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Can Cannabis Cure Schizophrenia? GWPH Thinks So

 ”GW Pharmaceuticals (GWPH)… touted the extended breadth of its cannabinoid drugs: beyond treating pediatric epilepsy and cancer pain, GWPH says it has the capabilities to treat Type 2 diabetes and schizophrenia. This would position GWPH as a fantastic pharma stock play,..

“As GW continues to progress its clinical work with cannabinoids, our pipeline has the potential to yield, as it did with Epidiolex, a flow of exciting new product candidates in a wide variety of therapeutic areas,” said Dr. Stephen Wright, GW’s Director of Research and Development.

GW has started Phase 2a trial using to treat schizophrenia featuring purified CBD as its active ingredient.”

http://www.mainstreet.com/article/family/family-health/can-cannabis-cure-schizophrenia-gwph-thinks-so

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A drug discovery case history of ‘delta-9-tetrahydrocannabinol, cannabidiol’.

“…the Cannabis sativa herb has been known for its therapeutic benefit for centuries… interest in the clinical potential of cannabinoid-based drugs escalated after the discovery of the endocannabinoid system… therapeutic applications of cannabinoids (plant-derived or synthetic)… may constitute a useful addition to the pharmacotherapeutic armamentarium in chronic conditions insufficiently alleviated by existing drugs.”  http://www.ncbi.nlm.nih.gov/pubmed/22646020

“The endocannabinoid system and its therapeutic exploitation.” http://www.ncbi.nlm.nih.gov/pubmed/15340387

“Cannabinoid receptors as therapeutic targets.” http://www.ncbi.nlm.nih.gov/pubmed/16402900

“Cannabinoids.” http://www.ncbi.nlm.nih.gov/pubmed/16266285

“Plant, synthetic, and endogenous cannabinoids in medicine.” http://www.ncbi.nlm.nih.gov/pubmed/16409166

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Cannabidiol-2′,6′-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor.

“Cannabidiol (CBD), one of the major components of marijuana, is known to inhibit LOX activity…

15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.”

http://dmd.aspetjournals.org/content/37/8/1733.long

“15-lipoxygenase inhibitors as anti-atherosclerosis agents.”  http://www.ncbi.nlm.nih.gov/pubmed/18465533

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