From “Azalla” to Anandamide: Distilling the Therapeutic Potential of Cannabinoids

Biological Psychiatry Home

“Cannabis has held a unique place in the hearts and minds of people since time immemorial: some have exalted its properties and considered it to be sacred; others have reviled it, considering it a root cause of social evil.

The Assyrians, who lived about 3000 years ago, documented the effects of cannabis on clay tablets. They referred to the plant according to its various uses: as “azalla,” when used as a medical agent; as hemp; and as “gan-zi-gun-nu”—“the drug that takes away the mind”   These seemingly contradictory properties—a substance that can be both a therapeutic agent and a corrupting psychoactive drug—have continued to puzzle us over the ensuing centuries.

As early as the 11th century, excessive cannabis use was suggested to be a cause of “moral degeneracy.”  On the other hand, the ostensible therapeutic value of cannabis was documented extensively in the early 19th century by Sir William B. O’Shaughnessy, an Irish physician working in Calcutta, India.

Given the critical role of the endocannabinoid system in modulating anxiety, it is clear that compounds that can modulate this system offer great promise as therapeutic agents for psychiatric disorders. It is therefore not surprising that the concept of medical marijuana is compelling to laypersons, clinicians, and researchers alike.

While there is not yet a robust body of literature supporting any specific psychiatric indication (despite the regulatory approval in some states of medical marijuana for specific psychiatric disorders), active lines of investigation of therapeutic targets within the endocannabinoid system offer hope for better treatment options.

The evidence at present suggests that the question of whether cannabinoids are good or bad is not dichotomous—it is likely both good and bad depending on the context of use, including dose, duration of exposure, and an individual’s genetic vulnerabilities. Therefore, the challenge that remains is to distill the good therapeutic effects of cannabinoids and thus weed out “gan-zi-gun-nu” from “azalla.””

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(17)32207-2/fulltext

 

Analysis of cannabinoids in commercial hemp seed oil and decarboxylation kinetics studies of cannabidiolic acid (CBDA).

Journal of Pharmaceutical and Biomedical Analysis

“Hemp seed oil from Cannabis sativa L. is a very rich natural source of important nutrients, not only polyunsaturated fatty acids and proteins, but also terpenes and cannabinoids, which contribute to the overall beneficial effects of the oil.

Hence, it is important to have an analytical method for the determination of these components in commercial samples. At the same time, it is also important to assess the safety of the product in terms of amount of any psychoactive cannabinoid present therein.

This work presents the development and validation of a highly sensitive, selective and rapid HPLC-UV method for the qualitative and quantitative determination of the main cannabinoids, namely cannabidiolic acid (CBDA), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN), cannabigerol (CBG) and cannabidivarin (CBDV), present in 13 commercial hemp seed oils.

Moreover, since decomposition of cannabinoid acids generally occurs with light, air and heat, decarboxylation studies of the most abundant acid (CBDA) were carried out in both open and closed reactor and the kinetics parameters were evaluated at different temperatures in order to evaluate the stability of hemp seed oil in different storage conditions.”

New ACE inhibitory peptides from hemp seed (Cannabis sativa L.) proteins.

Journal of Agricultural and Food Chemistry

“An hemp seed protein isolate, prepared from defatted hemp seed meals by alkaline solubilization/acid precipitation, was subjected to extensive chemical hydrolysis under acid conditions (6 M HCl). The resulting hydrolysate was fractionated by semipreparative RP-HPLC and the purified fractions were tested as inhibitors of angiotensin converting enzyme (ACE). Mono- and bi-dimensional NMR experiments and LC-MS/MS analyses led to the identification of four potentially bioactive peptides, i.e. GVLY, IEE, LGV, and RVR. They were prepared by solid-phase synthesis, and tested for ACE-inhibitory activity. The IC50 values were GVLY 16 ± 1.5 µM, LGV 145 ± 13 µM, and RVR 526 ± 33 µM, confirming that hemp seed may be a valuable source of hypotensive peptides.”

Bioactivities of alternative protein sources and their potential health benefits.

“Increasing the utilisation of plant proteins is needed to support the production of protein-rich foods that could replace animal proteins in the human diet so as to reduce the strain that intensive animal husbandry poses to the environment. Lupins, quinoa and hempseed are significant sources of energy, high quality proteins, fibre, vitamins and minerals. In addition, they contain compounds such as polyphenols and bioactive peptides that can increase the nutritional value of these plants. From the nutritional standpoint, the right combination of plant proteins can supply sufficient amounts of essential amino acids for human requirements. This review aims at providing an overview of the current knowledge of the nutritional properties, beneficial and non-nutritive compounds, storage proteins, and potential health benefits of lupins, quinoa and hempseed.”

https://www.ncbi.nlm.nih.gov/pubmed/28804797

Hempseed Peptides Exert Hypocholesterolemic Effects with a Statin-Like Mechanism.

Journal of Agricultural and Food Chemistry

“This study had the objective of preparing a hempseed protein hydrolysate and investigating its hypocholesterolemic properties. The hydrolysate was prepared treating a total protein extract with pepsin. Nano HPLC-ESI-MS/MS analysis permitted identifying in total 90 peptides belonging to 33 proteins. In the range 0.1-1.0 mg/mL, it inhibited the catalytic activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) in a dose-dependent manner. HepG2 cells were treated with 0.25, 0.5, and 1.0 mg/mL of the hydrolysate. Immunoblotting detection showed increments in the protein levels of regulatory element binding proteins 2 (SREBP2), low-density lipoprotein receptor (LDLR), and HMGCoAR. However, the parallel activation of the phospho-5′-adenosine monophosphate-activated protein kinase (AMPK) pathway, produced an inactivation of HMGCoAR by phosphorylation. The functional ability of HepG2 cells to uptake extracellular LDL was raised by 50.5 ± 2.7%, 221.5 ± 1.6%, and 109 ± 3.5%, respectively, versus the control at 0.25, 0.5, and 1.0 mg/mL concentrations. Finally, also a raise of the protein level of proprotein convertase subtilisin/kexintype 9 was observed. All of these data suggest that the mechanism of action has some similarity with that of statins.”

https://www.ncbi.nlm.nih.gov/pubmed/28931275

http://pubs.acs.org/doi/abs/10.1021/acs.jafc.7b02742

Challenges towards Revitalizing Hemp: A Multifaceted Crop.

“Hemp has been an important crop throughout human history for food, fiber, and medicine. Despite significant progress made by the international research community, the basic biology of hemp plants remains insufficiently understood. Clear objectives are needed to guide future research. As a semi-domesticated plant, hemp has many desirable traits that require improvement, including eliminating seed shattering, enhancing the quantity and quality of stem fiber, and increasing the accumulation of phytocannabinoids. Methods to manipulate the sex of hemp plants will also be important for optimizing yields of seed, fiber, and cannabinoids. Currently, research into trait improvement is hindered by the lack of molecular techniques adapted to hemp. Here we review how addressing these limitations will help advance our knowledge of plant biology and enable us to fully domesticate and maximize the agronomic potential of this promising crop.” https://www.ncbi.nlm.nih.gov/pubmed/28886910 http://www.cell.com/trends/plant-science/fulltext/S1360-1385(17)30177-2?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1360138517301772%3Fshowall%3Dtrue]]>

The Name of Cannabis: A Short Guide for Nonbotanists.

Mary Ann Liebert, Inc. publishers “The genus Cannabis (Family Cannabaceae) is probably indigenous to wet habitats of Asiatic continent. The long coexistence between mankind and Cannabis led to an early domestication of the plant, which soon showed an amazing spectrum of possible utilizations, as a source of textile fibers, as well as narcotic and psychoactive compounds. Nowadays, the specie(s) belonging to the genus Cannabis are represented by myriads of cultivated varieties, often with unstable taxonomic foundations. The nomenclature of Cannabis has been the object of numerous nomenclatural treatments. Linnaeus in Species Plantarum (1753) described a single species of hemp, Cannabis sativa, whereas Lamarck (1785) proposed two species of CannabisC. sativa, the species largely cultivated in Western Continent, and Cannabis indica, a wild species growing in India and neighboring countries. The dilemma about the existence of the species C. indica considered distinct from C. sativa continues up to present days. Due to their prevalent economic interest, the nomenclatural treatment is particularly important as far as it concerns the cultivated varieties of Cannabis. In this context, we propose to avoid the distinction between sativa and indica, suggesting a bimodal approach: when a cultivar has been correctly established. It could be advisable to apply a nomenclature system based on the International Code of Nomenclature for Cultivated Plants (ICNCP): it is not necessary to use the species epithets, sativa or indica, and a combination of the genus name and a cultivar epithet in any language and bounded by single quotation marks define an exclusive name for each Cannabis cultivar. In contrast, Cannabis varieties named with vernacular names by medical patients and recreational users, and lacking an adequate description as required by ICNCP, should be named as Cannabis strain, followed by their popularized name and without single quotation marks, having in mind that their names have no taxonomical validity.” https://www.ncbi.nlm.nih.gov/pubmed/28861494 http://online.liebertpub.com/doi/10.1089/can.2016.0027
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