New Perspectives on the Use of Cannabis in the Treatment of Psychiatric Disorders.

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“Following the discovery of the endocannabinoid system and its potential as a therapeutic target for various pathological conditions, growing interest led researchers to investigate the role of cannabis and its derivatives for medical purposes. The compounds Δ9-tetrahydrocannabinol and cannabidiol are the most abundant phytocannabinoids found in cannabis extracts, as well as the most studied. The present review aims to provide an overview of the current evidence for their beneficial effects in treating psychiatric disorders, including schizophrenia, anxiety, and depression. Nevertheless, further investigations are required to clarify many pending issues, especially those relative to the assessment of benefits and risks when using cannabis for therapeutic purposes, thereby also helping national and federal jurisdictions to remain updated.”

https://www.ncbi.nlm.nih.gov/pubmed/30279403

https://www.mdpi.com/2305-6320/5/4/107

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Cannabidiol for Treatment of Childhood Epilepsy-A Cross-Sectional Survey.

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“The interest in cannabidiol (CBD) for treatment of epilepsy has been increasing over the last years. However, practitioner’s attitudes concerning the use of CBD for epilepsy treatment appears to be divided and data about its clinical use in daily practice are not available.

Objective: To improve the knowledge about the current use of CBD amongst European practitioners treating children and adolescents for epilepsy.

Methods: Cross-sectional survey using an open-access online questionnaire for physicians treating children or adolescents for epilepsy within eight European countries from December 2017 to March 2018.

Results: One-hundred fifty-five physicians participated in the survey. CBD is increasingly used by 45% (69/155) of participants, treating a mean (range) number of 3 (1-35) with CBD. Only 48% of the participants prescribing CBD are exclusively using purified CBD to treat children and adolescents with epilepsy, the remainder also applies preparations containing delta9-tetrahydrocannabinol (THC). Reported daily CBD doses range from < 10 to 50 mg/kg body weight. Management of CBD therapy in regard of monitoring side effects and adjusting concomitant therapy differs widely amongst participants. Their primary objective for commencing CBD is improving patient’s quality of life. Participants frequently receive inquiries about CBD treatment but only 40% may actively suggest CBD as a treatment option. Of the 85 participants currently not using CBD for epilepsy treatment, 70% would consider using CBD if available in their country of practice or given the opportunity to become familiar with this treatment option.

Conclusions: CBD is increasingly used by participating physicians but individual experience remains limited. There are very diverse opinions about the use of CBD to treat epilepsy in children and adolescents and widely differing views on how to manage the CBD treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30258395

https://www.frontiersin.org/articles/10.3389/fneur.2018.00731/full

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A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

 Annals of Clinical and Translational Neurology banner

“Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects.

Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy.

Primary objective was to establish dosing and tolerability of TIL-TC150 – a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life.

RESULTS:

Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%.

CONCLUSIONS:

TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.”

https://www.ncbi.nlm.nih.gov/pubmed/30250864

https://onlinelibrary.wiley.com/doi/abs/10.1002/acn3.621

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A review of the effects of baclofen and of THC:CBD oromucosal spray on spasticity-related walking impairment in multiple sclerosis.

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“Multiple sclerosis (MS) is a complex disease with a heterogeneous and unpredictable clinical course. Mobility impairment after progressive paralyses and muscle tone spasticity is common.

Areas covered: The prevalence, assessment, and pharmacological management of gait impairment and spasticity in MS and their effects on health-related quality of life (HRQoL) are discussed.

The roles of oral and intrathecal baclofen and of delta-9-tetrahydrocannabinol/cannabidiol (THC:CBD) oromucosal spray in treating MS spasticity-related gait impairment are reviewed.

Expert commentary: Mobility impairment and spasticity are experienced by approximately 90% and 80% of MS patients, respectively, during the disease course. Prevalence and severity of gait impairment and spasticity increase as disease progresses. The symptoms are related and both impact negatively on HRQoL.

Oral baclofen and tizanidine are generally used for first-line treatment of MS spasticity but are ineffective in approximately 40% of cases.

Second-line therapy includes add-on THC:CBD spray for patients with resistant MS spasticity. Results of studies evaluating baclofen for treating MS spasticity gait impairment are equivocal.

In studies of patients with resistant MS spasticity, THC:CBD spray consistently improved the timed 10-meter walk test and significantly improved multiple spatial-temporal and kinematic gait parameters.

THC:CBD oromucosal spray warrants further investigation as a treatment for MS spasticity-related gait impairment.”

https://www.ncbi.nlm.nih.gov/pubmed/30235965

https://www.tandfonline.com/doi/abs/10.1080/14737175.2018.1510772?journalCode=iern20

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Cannabinoids and spinal cord stimulation for the treatment of failed back surgery syndrome refractory pain

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“This study aimed to evaluate pain and its symptoms in patients with failed back surgery syndrome (FBSS) refractory to other therapies, treated with a combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), in association with spinal cord stimulation (SCS).

Results: Effective pain management as compared to baseline result was achieved in all the cases studied. The positive effect of cannabinoid agonists on refractory pain was maintained during the entire duration of treatment with minimal dosage titration. Pain perception, evaluated through numeric rating scale, decreased from a baseline mean value of 8.18±1.07–4.72±0.9 by the end of the study duration (12 months) (P<0.001).

Conclusion: The results indicate that cannabinoid agonists (THC/CBD) can have remarkable analgesic capabilities, as adjuvant of SCS, for the treatment of chronic refractory pain of FBSS patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30233233

https://www.dovepress.com/cannabinoids-and-spinal-cord-stimulation-for-the-treatment-of-failed-b-peer-reviewed-article-JPR

“Outcomes indicate remarkable analgesic capabilities of cannabinoid agonists (THC/CBD) as an adjuvant to SCS for treating chronic refractory pain in FBSS patients, since all the cases studied achieved effective pain management compared to baseline.”

https://www.mdlinx.com/journal-summaries/cannabinoids-delta-9-tetrahydrocannabinol-thc-cannabidiol/2018/09/13/7544234/

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Effect of cannabidiolic acid and ∆9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain.

“Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ9-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties.

OBJECTIVES:

The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD’s potent acidic precursor, cannabidiolic acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically (intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we compare the efficacy of CBD and CBDA.

RESULTS:

CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a cannabinoid 1 receptor antagonist), while CBDA’s effects were blocked by AMG9810 (a transient receptor potential cation channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation.

CONCLUSION:

CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia effects in this animal model of acute inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/30225659

https://link.springer.com/article/10.1007%2Fs00213-018-5034-1

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Benefits and Risks of Therapeutic Cannabinoids for Neurologic Disorders

Clinical Therapeutics Home

“The Cannabis genus originated in Central Asia and is probably one of the most ancient nonfood crops to be cultivated by humans. Its medicinal properties have been recognized for centuries. Isolation of the psychoactive compound, Δ9-tetrahydrocannabinol, followed by the identification of cannabidiol, led to increased focus on the therapeutic potential of the plant. One of the prominent species, Cannabis sativa, may produce more than 100 different cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/30224192

https://www.clinicaltherapeutics.com/article/S0149-2918(18)30331-X/fulltext

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Oral cannabinoid-rich THC/CBD cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting: a study protocol for a pilot and definitive randomised double-blind placebo-controlled trial (CannabisCINV).

BMJ Journals

“Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV.

METHODS AND ANALYSIS:

The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day -1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day -1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients.

ETHICS AND DISSEMINATION:

The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.”

https://www.ncbi.nlm.nih.gov/pubmed/30209152

https://bmjopen.bmj.com/content/8/9/e020745

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Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history.

Journal of Ethnopharmacology

“Cannabis sativa L. (C. sativa) is an annual dioecious plant, which shares its origins with the inception of the first agricultural human societies in Asia. Over the course of time different parts of the plant have been utilized for therapeutic and recreational purposes, for instance, extraction of healing oils from seed, or the use of inflorescences for their psychoactive effects. The key psychoactive constituent in C. sativa is called Δ-9-tetrahydrocannabinol (D9-THC). The endocannabinoid system seems to be phylogenetically ancient, as it was present in the most primitive vertebrates with a neuronal network. N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG) are the main endocannabinoids ligands present in the animal kingdom, and the main endocannabinoid receptors are cannabinoid type-1 (CB1) receptor and cannabinoid type-2 (CB2) receptor.

AIM OF THE STUDY:

The review aims to provide a critical and comprehensive evaluation, from the ancient times to our days, of the ethnological, botanical, chemical and pharmacological aspects of C. sativa, with a vision for promoting further pharmaceutical research to explore its complete potential as a therapeutic agent.

RESULTS AND CONCLUSIONS:

A detailed comparative analysis of the available resources for C. sativa confirmed its origin and traditional spiritual, household and therapeutic uses and most importantly its popularity as a recreational drug. The result of several studies suggested a deeper involvement of phytocannabinoids (the key compounds in C. sativa) in several others central and peripheral pathophysiological mechanisms such as food intake, inflammation, pain, colitis, sleep disorders, neurological and psychiatric illness. However, despite their numerous medicinal benefits, they are still considered as a menace to the society and banned throughout the world, except for few countries. We believe that this review will help lay the foundation for promoting exhaustive pharmacological and pharmaceutical studies in order to better understand the clinical relevance and applications of non-psychoactive cannabinoids in the prevention and treatment of life-threatening diseases and help to improve the legal status of C. sativa.”

https://www.ncbi.nlm.nih.gov/pubmed/30205181

https://www.sciencedirect.com/science/article/pii/S0378874118316611?via%3Dihub

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Targeting Glioma Initiating Cells With A Combined Therapy Of Cannabinoids And Temozolomide.

Biochemical Pharmacology

“Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve the survival of the patients suffering this devastating disease.

Previous observations by our group and others have shown that Δ9-Tetrahydrocannabinol (THC, the main active ingredient of marijuana) and other cannabinoids including cannabidiol (CBD) exert antitumoral actions in several animal models of cancer, including gliomas.

We also found that the administration of THC (or of THC + CBD at a 1:1 ratio) in combination with temozolomide, the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts.

In this work we investigated the effect of the combination of TMZ and THC:CBD mixtures containing different ratios of the two cannabinoids in preclinical glioma models, including those derived from GICs.

Our findings show that TMZ + THC:CBD combinations containing a higher proportion of CDB (but not TMZ + CBD alone) produce a similar antitumoral effect as the administration of TMZ together with THC and CBD at a 1:1 ratio in xenografts generated with glioma cell lines. In addition, we also found that the administration of TMZ + THC:CBD at a 1:1 ratio reduced the growth of orthotopic xenografts generated with GICs derived from GBM patients and enhanced the survival of the animals bearing these intracranial xenografts.

Remarkably, the antitumoral effect observed in GICs-derived xenografts was stronger when TMZ was administered together with cannabinoid combinations containing a higher proportion of CBD. These findings support the notion that the administration of TMZ together with THC:CBD combinations – and specifically those containing a higher proportion of CBD – may be therapeutically explored to target the population of GICs in GBM.”

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