Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads

Russo, Ethan B.; Marcu, Jahan P.

doi:10.1016/bs.apha.2017.03.004

Cited by 290 publications

(294 citation statements)

References 302 publications

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“…5 These varieties are called ''strains'' in the common vernacular, but should properly be referred to as chemovars as they do not meet the scientific definition of a strain such as that used for bacteria or viruses. 6,7 The vast majority of commercially cultivated Cannabis plants are produced through cloning. 5 Clonal propagation ensures that plants are genetically identical to the mother plant.…”

Section: Introductionmentioning

confidence: 99%

Cannabis Chemovar Nomenclature Misrepresents Chemical and Genetic Diversity; Survey of Variations in Chemical Profiles and Genetic Markers in Nevada Medical Cannabis Samples

Reimann‐Philipp¹,

Speck

Orser³

et al. 2020

Cannabis and Cannabinoid Research

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Introduction: Medical cannabis patients receive clinical benefits from the secondary metabolites of the plant, which contain a variety of cannabinoids and terpenoids in combinations that can be used to classify the chemovars. State-regulated medical cannabis programs rely on breeder-reported ''strain'' names both within diversion control systems and to describe the medical cannabis products that are sold to patients in medical cannabis dispensaries. In state-regulated medical cannabis programs, there is no conventional nomenclature system that correlates the breeder-reported names with their profiles of active ingredients, and these ''strain'' names are invalid as they refer to chemical differences properly referred to as to chemovars. Materials and Methods: To determine the actual levels of chemical diversity represented in 2662 samples of Cannabis flower collected between January 2016 and June of 2017 in Nevada, chemical profile data were measured from these samples by a state-qualified third-party testing laboratory. Principal component analysis (PCA) was used to define clusters in data sets representing both cannabinoids and terpenoids, cannabinoids only, or terpenoids only. Results: The PCA of the terpenoid only data set revealed three well-defined clusters. All three terpenoids only data clusters had high tetrahydrocannabinolic acid synthase, but the terpene profiles listed in reverse-order of abundance best defined these chemovars. The three chemovars in Nevada were labeled with 396 breederreported sample names, which overestimate the diversity and do not inform patients regarding chemical properties. Representative DNA samples were taken from each chemovar to determine whether the genetic diversity was greater than the chemical diversity. The limited genotyping experiment was based on DNA sequence polymorphisms. The genetic analysis revealed twelve distinct genetic clades, which still does not account for the entirety of the 396 reported sample names. The finite genotypes did not correlate with the chemotypes determined for the samples. This suggests that either the DNA-markers used were too narrowly restricted for factual separation or that environmental factors contributed more significantly to the chemical profiles of cannabis than genetics. Conclusion: The three chemovars and twelve genotypes reflect low medical diversity on the market in Nevada during its ''medical use only'' phase. Furthermore, the 396 breeder-reported sample names within this set imply a false sense of diversity of products in Nevada dispensaries.

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Section: Introductionmentioning

confidence: 99%

Cannabis Chemovar Nomenclature Misrepresents Chemical and Genetic Diversity; Survey of Variations in Chemical Profiles and Genetic Markers in Nevada Medical Cannabis Samples

Reimann‐Philipp¹,

Speck

Orser³

et al. 2020

Cannabis and Cannabinoid Research

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“…12,13 However, some terpenoids do have intrinsic psychoactive and physiological effects, and modulatory effects on ∆ 9 -THC actions is not farfetched. 1,14 For example, in studies with laboratory animals, limonene displayed anxiolytic effects, pinene increased gastrointestinal motility, linalool was sedative, anticonvulsant and anxiolytic, while myrcene produced sedation, analgesia and muscle relaxant effects (summarised in Russo and Marcu 14 ). However, compelling evidence for cannabinoid-terpenoid interactions or synergy does not yet exist, and it is also worth noting the relatively low concentrations of terpenoids present in herbal cannabis.…”

Section: Introductionmentioning

confidence: 99%

Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1and CB2 receptors

Santiago

Sachdev

Arnold

et al. 2019

Preprint

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IntroductionCompounds present in Cannabis sativa such as phytocannabinoids and terpenoids, may act in concert to elicit therapeutic effects. Cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) directly activate cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), however, it is not known if terpenoids present in Cannabis also affect cannabinoid receptor signalling. Therefore, we examined 6 common terpenoids alone, and in combination with cannabinoid receptor agonists, on CB1 and CB2 signalling in vitro.Materials and MethodsPotassium channel activity in AtT20 FlpIn cells transfected with human CB1 or CB2 receptors was measured in real-time using FLIPR® membrane potential dye in a FlexStation 3 plate reader. Terpenoids were tested individually and in combination for periods up to 30 minutes. Endogenous somatostatin receptors served as a control for direct effects of drugs on potassium channels.Resultsα-Pinene, β-pinene, β-caryophyllene, linalool, limonene and β-myrcene (up to 30-100 µM) did not change membrane potential in AtT20 cells expressing CB1 or CB2, or affect the response to a maximally effective concentration of the synthetic cannabinoid CP55,940. The presence of individual or a combination of terpenoids did not affect the hyperpolarization produced by Δ9-THC (10µM): (CB1: control, 59±7%; with terpenoids (10 µM each) 55±4%; CB2: Δ9-THC 16±5%, with terpenoids (10 µM each) 17±4%). To investigate possible effect on desensitization of CB1 responses, all six terpenoids were added together with Δ9-THC and signalling measured continuously over 30 min. Terpenoids did not affect desensitization, after 30 minutes the control hyperpolarization recovered by 63±6%, in the presence of the terpenoids recovery was 61±5%.DiscussionNone of the six of the most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signalling of the phytocannabinoid agonist Δ9-THC. These results suggest that if a phytocannabinoid-terpenoid entourage effect exists, it is not at the CB1 or CB2 receptor level. It remains possible that terpenoids activate CB1 and CB2 signalling pathways that do not involve potassium channels, however, it seems more likely that they may act at different molecular target(s) in the neuronal circuits important for the behavioural effect of Cannabis.

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“…Our work was inspired by the idea that terpenoids might influence the actions of endocannabinoids and phytocannabinoids at their receptor targets. 11,30 Terpenoid-cannabinoid synergy at cannabinoid drug targets may provide one mechanism for the ''entourage effect:'' the notion that the pharmacological effects of the cannabis plant, and its mixture of 500 bioactive molecules, are greater than the sum of its individual components. We have addressed this hypothesis recently by examining the interaction between terpenoids and D 9 -THC at CB 1 and CB 2 receptors but could not find any evidence of terpenoid modulation of the actions of D 9 -THC at these receptors.…”

Section: Discussionmentioning

confidence: 99%

Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Actions of Phytocannabinoids or Endocannabinoids on TRPA1 and TRPV1 Channels

Heblinski

Santiago

Fletcher

et al. 2020

Cannabis and Cannabinoid Research

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Introduction: Cannabis sativa produces hundreds of bioactive compounds, including cannabinoids and terpenoids. It has been proposed that cannabinoids act in synergy with terpenoids to produce the entourage effect, a concept used to explain the therapeutic benefits of medicinal cannabis. One molecular explanation for the entourage effect is that the terpenoids augment the actions of cannabinoids at their molecular drug targets in cells. We recently reported that terpenoids commonly found in cannabis do not influence the functional effects of D 9 -tetrahydrocannabinol (D 9 -THC) on cannabinoid 1 and cannabinoid 2 receptors. The present study aimed to extend on this research by examining whether terpenoids influence the effects of phytocannabinoids and endocannabinoids on human transient receptor potential ankyrin 1 (hTRPA1) and human transient receptor potential vanilloid 1 (hTRPV1) channels heterologously expressed in mammalian cells. Materials and Methods: The activity of terpenoids, phytocannabinoids, and endocannabinoids was assessed in inducible HEK Flp-In T-Rex cells transfected with hTRPA1 and hTRPV1 channels, respectively. Real-time changes in intracellular calcium ([Ca] i ) were measured using the Calcium 5 dye and a FlexStation 3 plate reader. Results: a-pinene, b-pinene, b-caryophyllene, linalool, limonene, b-myrcene or a-humulene did not affect [Ca] i in hTRPA1 and hTRPV1 overexpressing cells. Cinnamaldehyde (CA), D 9 -THC, and 2-arachidonoylglycerol (2-AG) activated TRPA1 receptors with high efficacy and similar potency (EC 50 s of *10 lM). Capsaicin and anandamide (AEA) activated TRPV1 receptors with an EC 50 of 61 nM and 4.3 lM, respectively, but TRPV1 showed no response to D 9 -THC, cannabidiol, and other minor cannabinoids. Terpenoids did not significantly affect the responses of TRPA1 and TRPV1 receptors to submaximal and maximal concentrations of CA and D 9 -THC or the endocannabinoids AEA and 2-AG. Discussion: We could not find any evidence that the terpenoids tested here activate TRPA1 and TRPV1 channels or modulate their activation by D 9 -THC and other agonists, including endocannabinoids.

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Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads

Cited by 290 publications

References 302 publications

Cannabis Chemovar Nomenclature Misrepresents Chemical and Genetic Diversity; Survey of Variations in Chemical Profiles and Genetic Markers in Nevada Medical Cannabis Samples

Cannabis Chemovar Nomenclature Misrepresents Chemical and Genetic Diversity; Survey of Variations in Chemical Profiles and Genetic Markers in Nevada Medical Cannabis Samples

Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1and CB2 receptors

Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Actions of Phytocannabinoids or Endocannabinoids on TRPA1 and TRPV1 Channels

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