Effectiveness of Raw, Natural Medical Cannabis Flower for Treating Insomnia under Naturalistic Conditions.

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“Background: We use a mobile software application (app) to measure for the first time, which fundamental characteristics of raw, natural medical Cannabis flower are associated with changes in perceived insomnia under naturalistic conditions.

Methods: Four hundred and nine people with a specified condition of insomnia completed 1056 medical cannabis administration sessions using the Releaf AppTM educational software during which they recorded real-time ratings of self-perceived insomnia severity levels prior to and following consumption, experienced side effects, and product characteristics, including combustion method, cannabis subtypes, and/or major cannabinoid contents of cannabis consumed. Within-user effects of different flower characteristics were modeled using a fixed effects panel regression approach with standard errors clustered at the user level.

Results: Releaf AppTM users showed an average symptom severity reduction of -4.5 points on a 0⁻10 point visual analogue scale (SD = 2.7, d = 2.10, p < 0.001). Use of pipes and vaporizers was associated with greater symptom relief and more positive and context-specific side effects as compared to the use of joints, while vaporization was also associated with lower negative effects. Cannabidiol (CBD) was associated with greater statistically significant symptom relief than tetrahydrocannabinol (THC), but the cannabinoid levels generally were not associated with differential side effects. Flower from C. sativa plants was associated with more negative side effects than flower from C. indica or hybrid plant subtypes.

Conclusions: Consumption of medical Cannabis flower is associated with significant improvements in perceived insomnia with differential effectiveness and side effect profiles, depending on the product characteristics.”

https://www.ncbi.nlm.nih.gov/pubmed/29997343

http://www.mdpi.com/2305-6320/5/3/75

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Evidence for the use of “medical marijuana” in psychiatric and neurologic disorders.

College of Psychiatric and Neurologic Pharmacists

“Cannabis is listed as a Schedule I substance under the Controlled Substances Act of 1970, meaning the US federal government defines it as an illegal drug that has high potential for abuse and no established medical use; however, half of the states in the nation have enacted “medical marijuana” (MM) laws. Clinicians must be aware of the evidence for and against the use of MM in their patients who may consider using this substance.

RESULTS:

Publications were identified that included patients with dementia, multiple sclerosis, Parkinson disease, Huntington disease, schizophrenia, social anxiety disorder, depression, tobacco use disorder, and neuropathic pain.

DISCUSSION:

There is great variety concerning which medical conditions are approved for treatment with MM for either palliative or therapeutic benefit, depending on the state law. It is important to keep an evidence-based approach in mind, even with substances considered to be illegal under US federal law. Clinicians must weigh risks and benefits of the use of MM in their patients and should ensure that patients have tried other treatment modalities with higher levels of evidence for use when available and appropriate.”

https://www.ncbi.nlm.nih.gov/pubmed/29955495

““Medical marijuana” encompasses everything from whole-plant cannabis to synthetic cannabinoids available for commercial use approved by regulatory agencies. In determining whether MM is of clinical utility to our patients, it is important to keep in mind chemical constituents, dose, delivery, and indication. Selection of the patient appropriate for MM must be carefully considered because clinical guidelines and treatment options with stronger levels of evidence should be exhausted first in most cases. There seems to be strongest evidence for the use of MM in patients with MS and in patients with neuropathic pain; moderate evidence exists to support further research in social anxiety disorder, schizophrenia, PD, and tobacco use disorder; evidence is limited for use in patients with dementia, Huntington disease, depression, and anorexia.”

http://mhc.cpnp.org/doi/10.9740/mhc.2017.01.029?code=cpnp-site

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Appraising the “entourage effect”: antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer.

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“Breast cancer is the second leading cause of death among women. Although early diagnosis and development of new treatments have improved their prognosis, many patients present innate or acquired resistance to current therapies. New therapeutic approaches are therefore warranted for the management of this disease.

Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer. Most of these studies have been conducted with pure compounds, mainly Δ9-tetrahydrocannabinol (THC).

The cannabis plant, however, produces hundreds of other compounds with their own therapeutic potential and the capability to induce synergic responses when combined, the so-called “entourage effect”.

Here, we compared the antitumor efficacy of pure THC with that of a botanical drug preparation (BDP). The BDP was more potent than pure THC in producing antitumor responses in cell culture and animal models of ER+/PR+, HER2+ and triple-negative breast cancer. This increased potency was not due to the presence of the 5 most abundant terpenes in the preparation.

While pure THC acted by activating cannabinoid CB2 receptors and generating reactive oxygen species, the BDP modulated different targets and mechanisms of action. The combination of cannabinoids with estrogen receptor- or HER2-targeted therapies (tamoxifen and lapatinib, respectively) or with cisplatin, produced additive antiproliferative responses in cell cultures. Combinations of these treatments in vivo showed no interactions, either positive or negative.

Together, our results suggest that standardized cannabis drug preparations, rather than pure cannabinoids, could be considered as part of the therapeutic armamentarium to manage breast cancer.”

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Localization of cannabinoid receptors CB1, CB2, GPR55, and PPARα in the canine gastrointestinal tract.

Histochemistry and Cell Biology

“The endocannabinoid system (ECS) is composed of cannabinoid receptors, their endogenous ligands, and the enzymes involved in endocannabinoid turnover.

Modulating the activity of the ECS may influence a variety of physiological and pathophysiological processes.

A growing body of evidence indicates that activation of cannabinoid receptors by endogenous, plant-derived, or synthetic cannabinoids may exert beneficial effects on gastrointestinal inflammation and visceral pain.

The present ex vivo study aimed to investigate immunohistochemically the distribution of cannabinoid receptors CB1, CB2, G protein-coupled receptor 55 (GPR55), and peroxisome proliferation activation receptor alpha (PPARα) in the canine gastrointestinal tract.

Cannabinoid receptors showed a wide distribution in the gastrointestinal tract of the dog.

Since cannabinoid receptors have a protective role in inflammatory bowel disease, the present research provides an anatomical basis supporting the therapeutic use of cannabinoid receptor agonists in relieving motility disorders and visceral hypersensitivity in canine acute or chronic enteropathies.”

https://www.ncbi.nlm.nih.gov/pubmed/29882158

https://link.springer.com/article/10.1007%2Fs00418-018-1684-7

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Systemic Injections of Cannabidiol Enhance Acetylcholine Levels from Basal Forebrain in Rats.

Neurochemical Research

Cannabis sativa is a plant that contains more than 500 components, of which the most studied are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Several studies have indicated that CBD displays neurobiological effects, including wake promotion.

Moreover, experimental evidence has shown that injections of CBD enhance wake-related compounds, such as monoamines (dopamine, serotonin, epinephrine, and norepinephrine). However, no clear evidence is available regarding the effects of CBD on additional wake-related neurochemicals such as acetylcholine (ACh).

Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means. Moreover, the time course effects on the contents of ACh were present 5 h post-injection of CBD.

Altogether, these data demonstrate that CBD increases ACh levels in a brain region related to wake control. This study is the first to show the effects of ACh levels in CBD-treated rats and suggests that the basal forebrain might be a site of action of CBD for wakefulness modulation.”

https://www.ncbi.nlm.nih.gov/pubmed/29876791

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Medicinal cannabis: presenting possible treatment modalities for the future

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“Cannabis is the most popular recreational drug used in the world. It is estimated that 178 million people aged 15–64 years used cannabis at least once in 2012.

Cannabis or cannabinoids used to manage medical conditions is referred to as medicinal cannabis. There are various formulations of cannabis available on the market.

Cannabis can be administered orally, sublingually, or topically; it can be smoked, inhaled, mixed with food, or made into tea. It can be taken in herbal form, extracted naturally from the plant, gained by isomerization of cannabidiol (CBD), or manufactured synthetically.

The commercially available prescribed cannabinoids include dronabinol capsules, nabilone capsules, and the oromucosal spray nabiximols.

Canada and the Netherlands have government-run programs in which dedicated companies supply quality-controlled herbal cannabis. In the United States, 23 states and Washington, DC (May 2015) have introduced laws permitting the medical use of cannabis; other countries have similar laws.”

https://www.ncbi.nlm.nih.gov/pubmed/29870436

https://insights.ovid.com/crossref?an=01787381-201806000-00001

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Is Cannabidiol a Promising Substance for New Drug Development? A Review of its Potential Therapeutic Applications.

Critical Reviews™ in Eukaryotic Gene Expression

“The pharmacological importance of cannabidiol (CBD) has been in study for several years.

CBD is the major nonpsychoactive constituent of plant Cannabis sativa and its administration is associated with reduced side effects.

Currently, CBD is undergoing a lot of research which suggests that it has no addictive effects, good safety profile and has exhibited powerful therapeutic potential in several vital areas.

It has wide spectrum of action because it acts through endocannabinoid receptors; CB1 and CB2 and it also acts on other receptors, such as GPR18, GPR55, GPR 119, 5HT1A, and TRPV2.

This indicates its therapeutic value for numerous medical conditions because of its neuroprotective and immunomodulatory properties.

Potential therapeutic applications of CBD include, analgesic, anti-inflammatory, anxiolytic, anti-arthritic, anti-depressant, anti-Alzheimer disease, anti-ischemic, neuroprotective, and anti-fibrotic.

More promising areas appear to include diabetes and cancer where CBD exhibits lesser side effects and more therapeutic benefits as compared to recent available medical therapies.

Hence, CBD is a promising substance for the development of new drug. However further research and clinical studies are required to explore its complete potential.”

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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/

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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
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The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function.

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“Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine.

Cannabidiol is a nonpsychotropic plant constituent of Cannabis sativa.

As we hypothesized that non-CB receptor mechanisms of cannabidiol might contribute to its anti-inflammatory and neuroprotective effects, we investigated the interaction of cannabidiol with strychnine-sensitive alpha(1 )and alpha(1)beta glycine receptors by using the whole-cell patch clamp technique.

Cannabidiol showed a positive allosteric modulating effect in a low micromolar concentration range (EC(50) values: alpha(1) = 12.3 +/- 3.8 micromol/l and alpha(1)beta = 18.1 +/- 6.2 micromol/l). Direct activation of glycine receptors was observed at higher concentrations above 100 micromol/l (EC(50) values: alpha(1) = 132.4 +/- 12.3 micromol/l and alpha(1)beta = 144.3 +/- 22.7 micromol/l).

These in vitro results suggest that strychnine-sensitive glycine receptors may be a target for cannabidiol mediating some of its anti-inflammatory and neuroprotective properties.”

https://www.ncbi.nlm.nih.gov/pubmed/19204413

https://www.karger.com/Article/Abstract/201556

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