Cannabinoids for the pharmaceutical industry

Summary Cannabis sativa, is a rich source of a variety of compounds, including cannabinoids, terpenoids and flavonoids. Their content depends upon the plant genetics, growth conditions, time of harvest and drying conditions. To date, more than 60 different cannabinoids have been identified in the plant. Cannabis has been used medicinally for 4000 years and remained in the British pharmacopaeia until 1932, and in the British Pharmaceutical Codex until 1949. Medical use has been prohibited in the UK since 1973. The principal cannabinoid, delta-9-tetrahydrocannabinol (THC) was first isolated in 1964; the first cannabinoid pharmaceutical product Marinol® (a synthetic THC product) was approved in the USA in 1985. The discovery of specific cannabinoid receptors in the early 1990s and subsequent identification of the endocannabinoids anandamide and 2-arachadonoylglycerol, led to a resurgence of interest in the field of cannabinoid medicine, especially within the pharmaceutical industry. Cannabidiol (CBD), as a non-psychoactive, cannabinoid is currently a cannabinoid of significant interest, showing a wide range of pharmacological activity. The other classes of compounds present in cannabis also have their own pharmacology (e.g. terpenoids, flavonoids). The potential for interaction and synergy between compounds within the plant, may play a role in the therapeutic potential of cannabis. This may explain why a cannabis-based medicine using extracts containing multiple cannabinoids, in defined ratios, and other non-cannabinoid fractions, may provide better therapeutic success and be better tolerated than the single synthetic cannabinoid medicines currently available. The development and employment of one of these medicines, Sativex®, is described.     

Pharmacological and therapeutic targets for Δ9 tetrahydrocannabinol and cannabidiol

Summary Cannabis is the unique source of a set of at least 66 compounds known collectively as cannabinoids. Of these, most is known about the pharmacology of ⁹-tetrahydrocannabinol (⁹-THC), the main psychoactive constituent of cannabis, and about cannabidiol (CBD), which lacks psychoactivity. Accordingly, this paper focuses on the pharmacological and therapeutic targets of these two cannabinoids. Many of the effects of ⁹-THC are mediated by cannabinoid receptors of which at least two types, CB₁ and CB₂, are present in mammalian tissues. Endogenous agonists for cannabinoid receptors have also been discovered. CB₁ receptors are present at the terminals of central and peripheral neurones, where they modulate transmitter release. They also exist in some non-neuronal cells. CB₂ receptors are expressed mainly by immune cells, one of their roles being to alter cytokine release. ⁹-THC also appears to have non-CB₁, non-CB₂ pharmacological targets. It is already licensed for clinical use in the U.S.A. as an anti-emetic and appetite stimulant and both ⁹-THC and ⁹-THC-rich cannabis extracts show therapeutic potential as neuroprotective and anticancer agents and for the management of glaucoma, pain and various kinds of motor dysfunction associated, for example, with multiple sclerosis and spinal cord injury. CBD has much less affinity for CB₁ and CB₂ receptors than ⁹-THC and its pharmacological actions have been less well characterized. Potential clinical applications of CBD and CBD-rich cannabis extracts include the production of anti-inflammatory and neuroprotective effects, the management of epilepsy, anxiety disorders, glaucoma and nausea, and the modulation of some effects of ⁹-THC.     

The inheritance of chemical phenotype in Cannabis sativa L. (II): Cannabigerol predominant plants

This paper aims to clarify the genetic mechanism that is responsible for the accumulation of cannabigerol (CBG) in certain phenotypes of Cannabis sativa L. CBG is the direct precursor of the cannabinoids CBD, THC and CBC. Plants strongly predominant in CBG have been found in different fibre hemp accessions. Inbred offspring derived from one such individual were crossed with true breeding THC predominant- and CBD predominant plants, respectively. The segregations in the cross progenies indicate that CBG accumulation is due to the homozygous presence of a minimally functional allele, tentatively called B₀, at the single locus B that normally controls the conversion of CBG into THC (allele B_T) and/or CBD (allele B_D). The fact that CBG accumulating plants have so far been found in European fibre hemp populations that are generally composed of B_D/B_D plants, and the observation that the here investigated B₀ allele possesses a residual ability to convert small amounts of CBG into CBD, make it plausible that this B₀ is a mutation of normally functional B_D. Therefore, B₀ is considered as a member of the B_D allelic series encoding a CBD synthase isoform with greatly weakened substrate affinity and/or catalytic capacity.     

Role of endoplasmic reticulum stress and autophagy mediated by endocannabinoid N-arachidonic acid aminoethanol in ovarian cancer cells

AIM To study the effect of endocannabinoid N-arachidonic acid aminoethanol （AEA） on ovarian cancer and its mechanism. METHODS The serum levels of AEA in healthy control group and ovarian cancer group were analyzed by ELISA, and the diagnostic value of AEA in ovarian cancer patients was evaluated by ROC curve. The effects of AEA on the viability, migration and invasion abilities of the ovarian cancer cells were detected by CCK-8 assay, Transwell cell invasion test and Scratch test. The effect of AEA on ovarian cancer was further verified by the measurement of tumor volume, tumor weight and visual map of tumor tissue. Meanwhile, flow cytometry and Western blot were used to determine the effect of AEA on the apoptosis of ovarian cancer cells, so as to explore the mechanism of AEA promoting the apoptosis of ovarian cancer cells through detecting the endoplasmic reticulum stress and autophagy related proteins by Western blot. RESULTS The serum levels of N-arachidonic aminoethanol in the patients with ovarian cancer were significantly decreased. ROC results suggested that AEA was a sensitive biological marker to distinguish the patients with ovarian cancer from healthy dedividuals. In addition, AEA inhibited the cell viability, migration and invasion abilities of ovarian cancer cells, and inhibited the growth of ovarian cancer tissues. CONCLUSION By promoting endoplasmic reticulum stress and affecting autophagy of ovarian cancer cells, AEA promotes apoptosis of ovarian cancer cells.     

Characterisation of Cannabis accessions with regard to cannabinoid content in relation to other plant characters

Summary Ninety seven Cannabis accessions were evaluated for cannabinoid content and non-chemical plant characters. Variation within populations for cannabinoid content, and consistency of chemical characters at the population level were investigated. The relationship between chemical and other plant characters was very limited. Leaflet width and phenological data can be used for a rough prediction of the chemical phenotype on a population level. Various combinations of cannabinoid content and other economic plant characters were observed, thus a breeding programme will not be hampered by strict linkage. For a selection programme a direct analysis of cannabinoids will be inevitable.