Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age.

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“Among the many cannabinoids in the cannabis plant, cannabidiol (CBD) is a compound that does not produce the typical subjective effects of marijuana.

The aim of the present review is to describe the main advances in the development of the experimental and clinical use of cannabidiol CBD in neuropsychiatry.

CBD was shown to have anxiolytic, antipsychotic and neuroprotective properties. In addition, basic and clinical investigations on the effects of CBD have been carried out in the context of many other health conditions, including its potential use in epilepsy, substance abuse and dependence, schizophrenia, social phobia, post-traumatic stress, depression, bipolar disorder, sleep disorders, and Parkinson.

CBD is an useful and promising molecule that may help patients with a number of clinical conditions. Controlled clinical trials with different neuropsychiatric populations that are currently under investigation should bring important answers in the near future and support the translation of research findings to clinical settings.”

https://www.ncbi.nlm.nih.gov/pubmed/30298064

https://www.frontiersin.org/articles/10.3389/fimmu.2018.02009/full

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Avidekel Cannabis extracts and cannabidiol are as efficient as Copaxone in suppressing EAE in SJL/J mice.

“Multiple sclerosis (MS) is an autoimmune disease leading to the destruction of myelin with consequent axonal degeneration and severe physical debilitation. The disease can be treated with immunosuppressive drugs that alleviate the symptoms and retard disease aggravation. One such drug in clinical use is glatiramer acetate (Copaxone).

The non-psychotropic immunosuppressive cannabinoid compound cannabidiol (CBD) has recently been shown to have beneficial effects on experimental autoimmune encephalomyelitis (EAE). The aim of our study was to compare the efficacy of CBD and standardized extracts from a CBD-rich, ∆9-THClow Cannabis indica subspecies (Avidekel) with that of Copaxone.

Our data show that CBD and purified Avidekel extracts are as efficient as Copaxone to alleviate the symptoms of proteolipid protein (PLP)-induced EAE in SJL/J mice. No synergistic effect was observed by combining CBD or Avidekel extracts with Copaxone.

Our data support the use of Avidekel extracts in the treatment of MS symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/30291491

https://link.springer.com/article/10.1007%2Fs10787-018-0536-3

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Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial.

“Treatment with a highly purified oral solution of cannabidiol (CBD), derived from the plant Cannabis sativa L., demonstrated some evidence of central nervous system (CNS)-related adverse events in patients enrolled in phase 3 trials for treatment of childhood-onset epilepsy. Cannabidiol was categorized as a Schedule 1 substance by the United States Drug Enforcement Administration; therefore, it was important to test CBD for human abuse potential.

Administration of a therapeutic dose of CBD (750 mg) showed significantly low abuse potential in a highly sensitive population of polydrug users. Although high and supratherapeutic doses of CBD (1500 mg and 4500 mg, respectively) had detectable subjective effects compared with placebo; the effects were significantly lower than those observed with alprazolam and dronabinol.

The majority of adverse events reported during the trial were of mild or moderate severity; no serious adverse events or deaths were reported.”

https://www.ncbi.nlm.nih.gov/pubmed/30286443

https://www.epilepsybehavior.com/article/S1525-5050(18)30483-9/fulltext

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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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Report of Objective Clinical Responses of Cancer Patients to Pharmaceutical-grade Synthetic Cannabidiol.

“Cannabinoids are widely used in the management of pain, nausea and cachexia in cancer patients. However, there has been no objective clinical evidence of any anticancer activity yet.

The aim of this study was to assess the effects of pharmaceutical-grade synthetic cannabidiol on a range of cancer patients.

RESULTS:

Clinical responses were seen in 92% of the 119 cases with solid tumours including a reduction in circulating tumour cells in many cases and in other cases, a reduction in tumour size, as shown by repeat scans. No side-effects of any kind were observed when using pharmaceutical grade synthetic cannabidiol.

CONCLUSION:

Pharmaceutical-grade synthetic cannabidiol is a candidate for treating breast cancer and glioma patients.”

https://www.ncbi.nlm.nih.gov/pubmed/30275207

http://ar.iiarjournals.org/content/38/10/5831

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Repeated Cannabidiol treatment reduces cocaine intake and modulates neural proliferation and CB1R expression in the mouse hippocampus.

Neuropharmacology

“Cannabinoid derivatives have shown promising results for treating neuropsychiatric disorders, including drug addiction.

Recent studies on the therapeutic effects of Cannabidiol (CBD) on drug abuse showed mixed results, especially with psychostimulant substances such as cocaine. To determine whether CBD can attenuate cocaine reinforcement, we assessed behavioural responses induced by cocaine in mice, using the behavioural sensitization, conditioned place preference and intravenous self-administration paradigms.

We show that repeated CBD treatment produces anxiolytic effects in the elevated plus maze test, increases the discrimination index of the novel object recognition task and attenuates cocaine-induced conditioned place preference but does not affect behavioural sensitization.

CBD reduced cocaine voluntary consumption and progressive ratio breaking point in the self-administration paradigm, but not drug-induced reinstatement. In parallel, CBD increased expression of type 1 cannabinoid receptor, MAPK-CREB phosphorylation, BDNF expression, and neural cell proliferation in the hippocampus, and reduced the GluA1/2 AMPA subunit receptor ratio in the striatum.

In summary, we show that CBD can modulate some behavioural and molecular manifestations of cocaine reinforcement. Moreover, our findings show that CBD has pro-neurogenic effects also in cocaine consuming animals.

Overall, this novel evidence provides new perspectives to use CBD as a therapeutic tool.”

https://www.ncbi.nlm.nih.gov/pubmed/30273593

https://www.sciencedirect.com/science/article/pii/S0028390818307135?via%3Dihub

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Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.

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“This meta-analysis paper describes the analysis of observational clinical studies on the treatment of refractory epilepsy with cannabidiol (CBD)-based products. Beyond attempting to establish the safety and efficacy of such products, we also investigated if there is enough evidence to assume any difference in efficacy between CBD-rich extracts compared to purified CBD products.

The systematic search took place in February/2017 and updated in December/2017 using the keywords “epilepsy” or “Dravet” or “Lennox-Gastaut” or “CDKL5” combined with “Cannabis,” “cannabinoid,” “cannabidiol,” or “CBD” resulting in 199 papers.

The qualitative assessment resulted in 11 valid references, with an average impact factor of 8.1 (ranging from 1.4 to 47.8). The categorical data of a total of 670 patients were analyzed by Fischer test. The average daily dose ranged between 1 and 50 mg/kg, with treatment length from 3 to 12 months (mean 6.2 months).

Two thirds of patients reported improvement in the frequency of seizures (399/622, 64%). There were more reports of improvement from patients treated with CBD-rich extracts (318/447, 71%) than patients treated with purified CBD (81/223, 36%), with statistical significance (p < 0.0001).

Nevertheless, when the standard clinical threshold of a “50% reduction or more in the frequency of seizures” was applied, only 39% of the individuals were considered “responders,” and there was no difference (p = 0.56) between treatments with CBD-rich extracts (97/255, 38%) and purified CBD (94/223, 42%).

Patients treated with CBD-rich extracts reported lower average dose (6.1 mg/kg/day) than those using purified CBD (27.1 mg/kg/day). The reports of mild (109/285 vs. 291/346, p < 0.0001) and severe (23/285 vs. 77/346, p < 0.0001) adverse effects were more frequent in products containing purified CBD than in CBD-rich extracts.

CBD-rich extracts seem to present a better therapeutic profile than purified CBD, at least in this population of patients with refractory epilepsy. The roots of this difference is likely due to synergistic effects of CBD with other phytocompounds (aka Entourage effect), but this remains to be confirmed in controlled clinical studies.”

https://www.ncbi.nlm.nih.gov/pubmed/30258398

https://www.frontiersin.org/articles/10.3389/fneur.2018.00759/full

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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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Cannabidiol treatment reduces the motivation to self-administer methamphetamine and methamphetamine-primed relapse in rats.

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“Methamphetamine is an addictive stimulant that can cause many adverse physical, psychological and psychosocial effects.

Preliminary evidence shows cannabidiol, a non-intoxicating constituent of the cannabis plant, may have efficacy in treating opioid and nicotine dependence. However, no study has yet examined whether cannabidiol treatment might impact on methamphetamine addiction.

AIMS:

The current study investigated whether cannabidiol administration reduces the motivation to self-administer methamphetamine and relapse to methamphetamine-seeking behavior following abstinence.

RESULTS:

Cannabidiol (80 mg/kg, but not 40 mg/kg, or 20 mg/kg) reduced the motivation to self-administer methamphetamine and attenuated methamphetamine-primed relapse to methamphetamine-seeking behavior after extinction.

CONCLUSION:

This is the first demonstration that cannabidiol can reduce the motivation to seek and consume methamphetamine, and suggests that cannabidiol might be worth trialing as a novel pharmacotherapy for methamphetamine dependence.”

https://www.ncbi.nlm.nih.gov/pubmed/30260267

http://journals.sagepub.com/doi/abs/10.1177/0269881118799954?journalCode=jopa

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Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle.

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“Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders. Recently, CBD has also been explored for potential in treating drug addiction.

Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control.

Here, we evaluated the “anti-relapse” potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity.

The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment.

The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.”

https://www.ncbi.nlm.nih.gov/pubmed/29686308

https://www.nature.com/articles/s41386-018-0050-8

“Unique treatment potential of cannabidiol for the prevention of relapse to drug use” https://www.nature.com/articles/s41386-018-0218-2

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