Monthly Archives: July 2017

Identification of Terpenoid Chemotypes Among High (−)-trans-Δ9- Tetrahydrocannabinol-Producing Cannabis sativa L. Cultivars

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“Cannabis sativa L. (cannabis) is an annual diecious member of the Cannabaceae family. Since ancient times cannabis has been used by humans for its fiber, seed, as well as its psychoactive and medicinal resin. Despite a long history of use, the legal status of cannabis in modern times often depends on its intended use. Cannabis grown for its fiber or seed, commonly known as hemp, is legally cultivated in many nations. Cannabis used for its psychoactive properties, in North American commonly known as “marijuana,” has been illegal in most nations worldwide since the 1961 United Nations Single Convention on Narcotic Drugs. Recently however, laws concerning the legal status of cannabis are changing around the world. In the United States of America, many states have legalized cannabis for medical use, whereas some have even legalized cannabis for adult consumption. Uruguay recently legalized cannabis and laws in various countries within the European Union (EU) are also changing regarding cannabis. Due to its many and controversial uses, the taxonomic classification of cannabis has been the subject of both legal and scientific debate.

From a morphological perspective, three main types of cannabis have been described sativa, indica, and ruderalis. Generally sativa plants are described as taller and loosely branched, whereas indica is typically shorter, more densely branched, and conical in shape. Ruderalis is described as short (≤2 feet) at maturity and sparsely if at all branched.7Whether the genus Cannabis is monotypic and composed of just a single species (C. sativa) or polytypic and composed of multiple species is an old taxonomic debate. A more recent taxonomic classification dividing cannabis into seven putative taxa based on morphological, geographical, and genetic traits has been proposed.

Cannabinoids are a group of terpenophenolic compounds found in cannabis. Today over 100 cannabinoids from cannabis have been characterized. (−)-Trans-Δ9-tetrahydrocannabinol (THC) is considered the primary active ingredient responsible for the intoxicating and medical effects attributed to cannabis. THC has antiemetic, neuroprotectant, and anti-inflammatory properties as well as the ability to reduce certain forms of neuropathic and chronic pain. Another important cannabinoid, cannabidiol (CBD), has neuroprotective, anti-inflammatory, antipsychotic, and antiseizure properties without the intoxicating effects of THC. Other minor cannabinoids, such as cannabigerol (CBG), cannabichromene (CBC), and tetrahydrocannabivarin (THCV), also exhibit interesting pharmacological properties.

Since cannabinoids are the major active ingredients found in cannabis, it makes sense to classify cannabis from a chemotaxonomic perspective according to cannabinoid levels for both medical and legal purposes. Early studies noted that cannabis used for fiber tended to have higher levels of CBD, whereas cannabis used for drug purposes had higher levels of THC

Terpenoids represent another interesting group of biologically active compounds found in cannabis. Due to their volatile nature, the mono- and sesquiterpenoids found in cannabis contribute to the plants’ aroma and flavor. About 100 terpenoids have been identified in cannabis, many of which are found in other plants. Both cannabinoids and terpenoids are produced in the trichomes of cannabis, which are found at highest density on female flower buds.Terpenoids are usually present in cannabis flower buds in the 0.5–3.5% range and are found at significant levels in cannabis smoke and vapor. As biologically active compounds, terpenoids may play a role in the overall effects of herbal cannabis.

The popularly understood distinctions between indica and sativa may have more to do with aroma and subjective effects than plant morphology. Recent studies have shown that terpenoids are useful in distinguishing cannabis cultivars that have similar cannabinoid content. A study of cannabinoid and terpenoid profiles among medical cannabis samples analyzed by a cannabis testing laboratory in California found a continuum of terpenoid profiles among the wide variety of sample names.Another study found that cannabis samples described as indica contained more myrcene and hydroxylated terpenoids, whereas those described as sativa tended to contain more terpinolene, 3-carene, and a few specified sesquiterpenes.” http://online.liebertpub.com/doi/full/10.1089/can.2016.0040

“Due to its astonishing efficacy, nowadays cannabis is prescribed by physicians for the treatment of neurological, psychiatric, immunological, cardiovascular, gastrointestinal, and oncological conditions. The active principles inside plants have been exploited by humans for centuries, with Cannabis sativa being one of the oldest ever used for medicinal purposes. Surprisingly, contrary to whole plant extracts, medicinal products containing exclusively THC have been found to lack efficacy and lead to unbearable side effects. These results arise from the fact that these products lack other important co-factors typically found in the Phyto-complex, such as terpenoids and other cannabinoids that contribute to the synergistic effects seen with whole plant extracts.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482328/

“In silico discovery of terpenoid metabolism in Cannabis sativa. Due to their efficacy, cannabis based therapies are currently being prescribed for the treatment of many different medical conditions. Interestingly, treatments based on the use of cannabis flowers or their derivatives have been shown to be very effective, while therapies based on drugs containing THC alone lack therapeutic value and lead to increased side effects, likely resulting from the absence of other pivotal entourage compounds found in the Phyto-complex. Among these compounds are terpenoids,” https://www.ncbi.nlm.nih.gov/pubmed/28690830

 

“Terpenoids: natural products for cancer therapy.”  https://www.ncbi.nlm.nih.gov/pubmed/23092199

“Inhibition of tumor progression by naturally occurring terpenoids.”  https://www.ncbi.nlm.nih.gov/pubmed/21936626

“Terpenoids as anti-colon cancer agents – A comprehensive review on its mechanistic perspectives.” https://www.ncbi.nlm.nih.gov/pubmed/27940056

 

A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans

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“Cannabidiol (CBD), a major cannabinoid of hemp, does not bind to CB1 receptors and is therefore devoid of psychotomimetic properties. Under acidic conditions, CBD can be transformed to delta9-tetrahydrocannabinol (THC) and other cannabinoids. It has been argued that this may occur also after oral administration in humans. However, the experimental conversion of CBD to THC and delta8-THC in simulated gastric fluid (SGF) is a highly artificial approach that deviates significantly from physiological conditions in the stomach; therefore, SGF does not allow an extrapolation to in vivo conditions.

Unsurprisingly, the conversion of oral CBD to THC and its metabolites has not been observed to occur in vivo, even after high doses of oral CBD. In addition, the typical spectrum of side effects of THC, or of the very similar synthetic cannabinoid nabilone, as listed in the official Summary of Product Characteristics (e.g., dizziness, euphoria/high, thinking abnormal/concentration difficulties, nausea, tachycardia) has not been observed after treatment with CBD in double-blind, randomized, controlled clinical trials. In conclusion, the conversion of CBD to THC in SGF seems to be an in vitro artifact.

Over 40 years of research on CBD does not suggest a conversion of CBD to delta9-THC and/or other cannabinoids in vivo after oral administration. Such transformation occurs under artificial conditions, but is without any relevance for an oral therapy with CBD.”  http://online.liebertpub.com/doi/full/10.1089/can.2017.0009?_ga=2.206725530.884504339.1500032065-2115951543.1500032065#

“Cannabidiol Does Not Convert to THC In Vivo. Although CBD Can Be Transformed to THC Under Acidic Conditions, the Conversion of Oral CBD Doesn’t Occur In Vivo” http://www.genengnews.com/gen-exclusives/cannabidiol-does-not-convert-to-thc-iin-vivoi/77900938

An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol.

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“Cannabidiol (CBD) has been traditionally used in Cannabis-based preparation, however historically, it has received far less interest as a single drug than the other components of Cannabis. Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging.”  https://www.ncbi.nlm.nih.gov/pubmed/28701957

http://journal.frontiersin.org/article/10.3389/fphar.2017.00422/full

Engineering yeasts as platform organisms for cannabinoid biosynthesis.

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“Δ9-tetrahydrocannabinolic acid (THCA) is a plant derived secondary natural product from the plant Cannabis sativa l. The discovery of the human endocannabinoid system in the late 1980s resulted in a growing number of known physiological functions of both synthetic and plant derived cannabinoids. Thus, manifold therapeutic indications of cannabinoids currently comprise a significant area of research. Here we reconstituted the final biosynthetic cannabinoid pathway in yeasts. The use of the soluble prenyltransferase NphB from Streptomyces sp. strain CL190 enables the replacement of the native transmembrane prenyltransferase cannabigerolic acid synthase from C. sativa. In addition to the desired product cannabigerolic acid, NphB catalyzes an O-prenylation leading to 2-O-geranyl olivetolic acid. We show for the first time that the bacterial prenyltransferase and the final enzyme of the cannabinoid pathway tetrahydrocannabinolic acid synthase can both be actively expressed in the yeasts Saccharomyces cerevisiae and Komagataella phaffii simultaneously. While enzyme activities in S. cerevisiae were insufficient to produce THCA from olivetolic acid and geranyl diphosphate, genomic multi-copy integrations of the enzyme’s coding sequences in K. phaffii resulted in successful synthesis of THCA from olivetolic acid and geranyl diphosphate. This study is an important step toward total biosynthesis of valuable cannabinoids and derivatives and demonstrates the potential for developing a sustainable and secure yeast bio-manufacturing platform.” https://www.ncbi.nlm.nih.gov/pubmed/28694184  http://www.sciencedirect.com/science/article/pii/S0168165617315201

“Production of Δ9-tetrahydrocannabinolic acid from cannabigerolic acid by whole cells of Pichia (Komagataella) pastoris expressing Δ9-tetrahydrocannabinolic acid synthase from Cannabis sativa L.” https://www.ncbi.nlm.nih.gov/pubmed/25994576

“Scientists Engineer Yeast to Produce Active Marijuana Compound, THC”  https://www.sciencealert.com/scientists-engineer-yeast-to-produce-active-marijuana-compound-thc

Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats.

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Epilepsia

“Although drugs targeting the cannabinoid system (e.g., CB1 receptor agonists) display anticonvulsant efficacy in adult animal models of seizures/epilepsy, they remain unexplored in developing animal models. However, cannabinoid system functions emerge early in development, providing a rationale for targeting this system in neonates.

We examined the therapeutic potential of drugs targeting the cannabinoid system in three seizure models in developing rats.

The mixed CB1/2 agonist and the CB1-specific agonist, but no other drugs, displayed anticonvulsant effects against clonic seizures in the DMCM model. By contrast, both CB1 and CB2 antagonism increased seizure severity. Similarly, we found that the CB1/2 agonist displayed antiseizure efficacy against acute hypoxia-induced seizures (automatisms, clonic and tonic-clonic seizures) and tonic-clonic seizures evoked by PTZ.

Early life seizures represent a significant cause of morbidity, with 30-40% of infants and children with epilepsy failing to achieve seizure remission with current pharmacotherapy. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority.

These data indicate that the anticonvulsant action of the CB system is specific to CB1 receptor activation during early development and provide justification for further examination of CB1 receptor agonists as novel antiepileptic drugs targeting epilepsy in infants and children.” https://www.ncbi.nlm.nih.gov/pubmed/28691158

http://onlinelibrary.wiley.com/doi/10.1111/epi.13842/abstract

Anti-inflammatory ω-3 endocannabinoid epoxides.

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“Clinical studies suggest that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) provide beneficial anti-inflammatory effects, in part through their conversion to bioactive metabolites. Here we report on the endogenous production of a previously unknown class of ω-3 PUFA-derived lipid metabolites that originate from the crosstalk between endocannabinoid and cytochrome P450 (CYP) epoxygenase metabolic pathways. The ω-3 endocannabinoid epoxides are derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to form epoxyeicosatetraenoic acid-ethanolamide (EEQ-EA) and epoxydocosapentaenoic acid-ethanolamide (EDP-EA), respectively. Both EEQ-EAs and EDP-EAs are endogenously present in rat brain and peripheral organs as determined via targeted lipidomics methods. These metabolites were directly produced by direct epoxygenation of the ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by activated BV-2 microglial cells, and by human CYP2J2. Neuroinflammation studies revealed that the terminal epoxides 17,18-EEQ-EA and 19,20-EDP-EA dose-dependently abated proinflammatory IL-6 cytokines while increasing anti-inflammatory IL-10 cytokines, in part through cannabinoid receptor-2 activation. Furthermore the ω-3 endocannabinoid epoxides 17,18-EEQ-EA and 19,20-EDP-EA exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides’ physiological effects are mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo; thus their identification may aid in the development of therapeutics for neuroinflammatory and cerebrovascular diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/28687674

http://www.pnas.org/content/early/2017/07/06/1610325114

“Omega-3 fatty acids fight inflammation via cannabinoids”  https://www.sciencedaily.com/releases/2017/07/170718142909.htm

Polyunsaturated fatty acids and endocannabinoids in health and disease.

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“Polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) or of omega-6 (arachidonic acid, ARA) synthesized from membrane phospholipids and used as a precursor for endocannabinoids (ECs). They mediate significant effects in the fine-tune adjustment of body homeostasis. Phyto- and synthetic cannabinoids also rule the daily life of billions worldwide, as they are involved in obesity, depression and drug addiction. Consequently, there is growing interest to reveal novel active compounds in this field. Cloning of cannabinoid receptors in the 90s and the identification of the endogenous mediators arachidonylethanolamide (anandamide, AEA) and 2-arachidonyglycerol (2-AG), led to the characterization of the endocannabinoid system (ECS), together with their metabolizing enzymes and membrane transporters. Today, the ECS is known to be involved in diverse functions such as appetite control, food intake, energy balance, neuroprotection, neurodegenerative diseases, stroke, mood disorders, emesis, modulation of pain, inflammatory responses, as well as in cancer therapy. Western diet as well as restriction of micronutrients and fatty acids, such as DHA, could be related to altered production of pro-inflammatory mediators (e.g. eicosanoids) and ECs, contributing to the progression of cardiovascular diseases, diabetes, obesity, depression or impairing conditions, such as Alzheimer’ s disease. Here we review how diets based in PUFAs might be linked to ECS and to the maintenance of central and peripheral metabolism, brain plasticity, memory and learning, blood flow, and genesis of neural cells.”

https://www.ncbi.nlm.nih.gov/pubmed/28686542

http://www.tandfonline.com/doi/abs/10.1080/1028415X.2017.1347373?journalCode=ynns20

Neuroprotective Effects of β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson’s Disease Induced by MPTP.

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“Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the cannabinoid signalling system in PD. β-caryophyllene (BCP) is a natural bicyclic sesquiterpene that is an agonist of the cannabinoid type 2 receptor (CB2R). Previous studies have suggested that BCP exerts prophylactic and/or curative effects against inflammatory bowel disease through its antioxidative and/or anti-inflammatory action. The present study describes the neuroprotective effects of BCP in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine model of PD, and we report the results of our investigation of its neuroprotective mechanism in neurons and glial cells. In the murine model, BCP pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in the SN and striatum, and alleviated MPTP-induced glia activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. The observed neuroprotection and inhibited glia activation were reversed upon treatment with the CB2R selective antagonist AM630, confirming the involvement of the CB2R. These results indicate that BCP acts via multiple neuroprotective mechanisms in our murine model and suggest that BCP may be viewed as a potential treatment and/or preventative agent for PD.”  https://www.ncbi.nlm.nih.gov/pubmed/28684694

http://www.mdpi.com/1424-8247/10/3/60
“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats.

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“Drugs that interfere with the endocannabinoid system are alternatives for the management of clinical pain. Cannabidiol (CBD), a phytocannabinoid found in Cannabis sativa, has been utilized in preclinical and clinical studies for the treatment of pain. Herein, we evaluate the effects of CBD. The study provides evidence that CBD influences different dimensions of the response of rats to a surgical incision, and the results establish the rostral anterior cingulate cortex (rACC) as a brain area from which CBD evokes antinociceptive effects in a manner similar to the systemic administration of CBD. The present study has shown for the first time that CBD injected either systemically or into the rACC induces a long-lasting anti-allodynic effect with a bell-shaped dose-response curve in a rat model of incision pain.” https://www.ncbi.nlm.nih.gov/pubmed/28680401

Efficacy, tolerability, and safety of non-pharmacological therapies for chronic pain: An umbrella review on various CAM approaches.

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“Complementary and alternative medicine (CAM) therapies may be used as a non-pharmacological approach to chronic pain management. Twenty-six reviews (207 clinical trials, >12,000 participants) about 18 CAM modalities, falling under natural products, mind and body practices or other complementary health approaches were included. Inhaled cannabis, graded motor imagery, and Compound Kushen injection (a form of Chinese medicine) were found the most efficient and tolerable for chronic pain relief. When reported, adverse effects related to these CAM were minor.” https://www.ncbi.nlm.nih.gov/pubmed/28669581