Most clinical studies of Cannabis today focus on the contents of two phytocannabinoids: (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), regardless of the fact that the plant contains over 100 additional phytocannabinoids whose therapeutic effects and interplay have not yet been fully elucidated This narrow view of a complex Cannabis plant is insufficient to comprehend the medicinal and pharmacological effects of the whole plant In this study we suggest a new ESI-LC/MS/MS approach to identify phytocannabinoids from 10 different subclasses, and comprehensively profile the identified compounds in diverse medical Cannabis plants Overall, 94 phytocannabinoids were identified and used for profiling 36 of the most commonly used Cannabis plants prescribed to patients in Israel In order to demonstrate the importance of comprehensive phytocannabinoid analysis before and throughout medical Cannabis clinical trials, treatments, or experiments, we evaluated the anticonvulsant effects of several equally high-CBD Cannabis extracts (50% w/w) We found that despite the similarity in CBD contents, not all Cannabis extracts produced the same effects This study’s approach for phytocannabinoid profiling can enable researchers and physicians to analyze the effects of specific Cannabis compositions and is therefore critical when performing biological, medical and pharmacological-based research using Cannabis

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A new ESI-LC/MS approach for comprehensive metabolic profiling of phytocannabinoids in Cannabis

Background: β-Caryophyllene (BCP) is a natural bicyclic sesquiterpene abundantly found in essentialoils from various spices, fruits and medicinal as well as ornamental plants. It is approved by United States Foodand Drug Administration and European agencies as food additive, taste enhancer and flavoring agent and termed asa phytocannabinoid. Methods: All the available literature on BCP and its synonyms were collected through different literature databases.Results: BCP was found to elicit a full agonist action on cannabinoid type 2 (CB2) receptors, a G-protein coupled receptor representingimportant therapeutic target in several diseases. Activation of CB2 receptors notably appeared devoid of psychotropic adverse effect ofcannabinoids contrary to the CB1 receptors. In addition, it activates peroxisome proliferated activator receptors (PPARs) isoforms;PPAR-α &-γ and inhibits pathways triggered by the activation of toll like receptor complex; CD14/TLR4/MD2, reduce immuneinflammatoryprocesses and exhibit synergy with µ-opioid receptor dependent pathways. Additionally, it found as potent antagonist ofhomomeric nicotinic acetylcholine receptors (α7-nAChRs) and devoid of effects mediated by serotonergic and GABAergic receptors. Italso modulates numerous molecular targets by altering their gene expression, signaling pathways or through direct interaction. Variouspharmacological activities such as cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, antioxidant,anti-inflammatory, antimicrobial and immune-modulator have been reported in experimental studies. It has shown potent therapeuticpromise in neuropathic pain, neurodegenerative and metabolic diseases. Conclusion: The present review provides a comprehensive insightof pharmacological and therapeutic potential of BCP, its molecular mechanism and signaling pathways in different pathologicalconditions. The review also examines the possibility of its further development as a novel candidate for various pathologies consideringthe polypharmacological and multifaceted therapeutic properties potential along with favorable oral bioavailability, lipophilicity andphysicochemical properties.

Polypharmacological Properties and Therapeutic Potential of β-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise.

Review evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy. Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL). Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5–55 years). Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17). CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs. Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed. PROSPERO registration number CRD42017055412.

https://jnnp.bmj.com/content/jnnp/89/7/741.full.pdf

Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence

Targeting the endocannabinoid system: future therapeutic strategies

Recently, cannabis has been suggested as a potential alternative therapy for refractory epilepsy, which affects 30% of epilepsy, both adults and children, who do not respond to current medications. There is a large unmet medical need for new antiepileptics that would not interfere with normal function in patients with refractory epilepsy and conditions associated with refractory seizures. The two chief cannabinoids are Δ-9-tetrahyrdrocannabinol, the major psychoactive component of marijuana, and cannabidiol (CBD), the major nonpsychoactive component of marijuana. Claims of clinical efficacy in epilepsy of CBD-predominant cannabis or medical marijuana come mostly from limited studies, surveys, or case reports. However, the mechanisms underlying the antiepileptic efficacy of cannabis remain unclear. This article highlights the pharmacological basis of cannabis therapy, with an emphasis on the endocannabinoid mechanisms underlying the emerging neurotherapeutics of CBD in epilepsy. CBD is anticonvulsant, but it has a low affinity for the cannabinoid receptors CB1 and CB2; therefore the exact mechanism by which it affects seizures remains poorly understood. A rigorous clinical evaluation of pharmaceutical CBD products is needed to establish the safety and efficacy of their use in the treatment of epilepsy. Identification of mechanisms underlying the anticonvulsant efficacy of CBD is also critical for identifying other potential treatment options.

https://jpet.aspetjournals.org/content/jpet/357/1/45.full.pdf

The Pharmacological Basis of Cannabis Therapy for Epilepsy

SUMMARY What is known and objective: Antiepileptic drugs often produce serious adverse effects, and many patients do not respond to them properly. Phytocannabinoids produce anticonvulsant effects in preclinical and preliminary human studies, and appear to produce fewer adverse effects than available antiepileptic drugs. The present review summarizes studies on the anticonvulsant properties of phytocannabinoids. Methods: Literature search using the PubMed database to identify studies on phytocannabinoids and epilepsy. Results and discussion: Preclinical studies suggest that phytocannabinoids, especially cannabidiol and cannabidivarin, have potent anticonvulsant effects which are mediated by the endocannabinoid system. Human studies are limited in number and quality, but suggest that cannabidiol has anticonvulsant effects in adult and infantile epilepsy and is well tolerated after prolonged administration. What is new and conclusion: Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects. Cannabidiol and cannabidivarin should be tested in randomized, controlled clinical trials, especially in infantile epileptic syndromes.

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Phytocannabinoids and epilepsy

Pharmacological treatments are available for alcohol, nicotine, and opioid dependence,and several drugs for cannabis-related disorders are currently under investigation. On the otherhand, psychostimulant abuse and dependence lacks pharmacological treatment. Mesolimbicdopaminergic neurons mediate the motivation to use drugs and drug-induced euphoria, andpsychostimulants (cocaine, amphetamine, and methamphetamine) produce their effects in theseneurons, which may be modulated by the opioid system. Salvinorin A is a κ-opioid receptoragonist extracted from Salvia divinorum, a hallucinogenic plant used in magico-ritual contexts byMazateca Indians in Mexico. Salvinorin A and its analogues have demonstrated anti-addictioneffects in animal models using psychostimulants by attenuating dopamine release, sensitization,and other neurochemical and behavioral alterations associated with acute and prolongedadministration of these drugs. The objective of the present article is to present an overview of the preclinical evidencesuggesting anti-addictive effects of salvinorin A and its analogues.

http://xkapastora.org/wp-content/uploads/2015/08/CDAR_7.2.2014.pdf

Salvinorin A and Related Compounds as Therapeutic Drugs for Psychostimulant-Related Disorders

The problematic use of psychoactive substances like alcohol, cannabis, cocaine, amphetamines, heroin, and nicotine carry a series of health, economic, and social costs to individuals and society. Although pharmacological treatments for alcohol, heroin, and nicotine abuse or dependence are available, there is no approved medication for the treatment of cannabis and stimulant dependence. Cannabidiol (CBD), a nonpsychotomimetic cannabinoid present in the cannabis plant, has anxiolytic, antipsychotic, antiepileptic, and antiaddictive potentials, and is well tolerated after acute and prolonged administration. The objective of this chapter is to present an overview of the available preclinical and clinical evidence of potential antiaddictive effects of CBD. Preclinical evidence suggests that CBD has antiaddictive effects in animal models using opiates/opioids and stimulants, and preliminary studies in humans suggest that CBD reduces cigarette consumption and reduces symptoms of cannabis dependence/withdrawal. The antiaddictive effects of CBD should be investigated in randomized, place-controlled clinical trials.

R.G. dos Santos

Papers

Phytocannabinoids and epilepsy

Salvinorin A and Related Compounds as Therapeutic Drugs for Psychostimulant-Related Disorders

Cannabidiol for the Treatment of Drug Use Disorders