A Cannabis Factoid

According to a 2016 article in Wired Magazine, in 1993, the average THC content in commercially available cannabis was roughly 3 percent by weight. By 2008, through traditional breeding programs, the THC content (potency) had nearly  tripled.  In 2017, analyses suggested that the world wide THC content of some strains of cannabis may be 12-16 percent or as high as 37 percent by weight (1-5). Recent genetic analysis suggest that this increase may be a  result of gene amplification with high THC-producing plants having multiple copies of THC biosynthetic genes.

Many cannabis  industry experts contend that the exponential increases in THC levels  can be directly attributed to the so-called “war on drugs” that forced illegal growers to abandon outdoor cultivation in favor of indoor growing operations. Unlike outdoor growing operations, indoor cultivation permits more controlled growing environments, less need for pesticides  and a reduced likelihood of theft of mature plants.  However, as the concentration of THC increased, so did prevailing market prices of cannabis. These price increases helped growers to absorb the higher cost  of indoor climate control and artificial lighting without cutting into profit margins. Ironically, however, the legal use of cannabis for medical and recreational use in many US States, has allowed growers to move their illicit indoor growing operations into legal, full scale greenhouse cultivation.  This, in turn, is currently causing the the price of cannabis to plunge in many states.

While THC concentration are at all time highs (pun intended), less attention has been paid to genetic manipulation of cannabis plants for medicinal use that contain high levels of cannabinoids other than THC. This area represents the next era of genetic manipulation of the Cannabis genome.

Stay tuned…..

References

  1. Radwan MM, Elsohly MA, Slade D, Radwan MM et al. Cannabinoid ester constituents from high-potency Cannabis sativa Phytochemistry 2008 69:2627-26-33
  2. Niesink RJ, Rigter S, Koeter NW, Brunt TM, Potency trends of delta=(9)-tetrahydrocannabinol, cannabidiol and cannbinol in cannabis in the Netherlands 2005-2015. Addiction 2015; Aug1 [Epub ahead of print]
  3. Swift W, Wong A, Li KM, Arnold JC, McGregor I Analysis of cannabis seizures in NSW Australia: cannabis potency and cannabinoid profile. PLoS one 2013; 8: e70052
  4. Zamengo L, Frison G, Bettin C, Sciarrone R, Variability of cannabis potency  in the Venice area (Italy): a survey over the period 2010-2012. Drug Test Anal 2014:6:46-51
  5. Bruci Z, Papoutsis I, Athanaselis S, Nikolaou P, et al. First systematic evaluation of the potency of Cannabis sativa plants grown in Albania Forensic Sci In 2012; 222:40-46.

 

 

 

Cannabis By Any Other Name

The number of species that compose the genus Cannabis is often debated. Some experts’ claim that the genus is composed of three distinct species designated Cannabis sativa, Cannabis indica and Cannabis ruderalis (1, 2). Others contend that the genus is composed of a single species—C. sativa L—which exhibits high degrees of variations and heterogeneity within different subpopulations.

According to most current scientific conventions, the plant is usually classified as a single species C. sativa.  Historically, most of the groupings or subdivisions in the genus have been made on physical characteristics or uses of the plant. For example, hemp plants are described as tall and skinny do not produce cannabinoids or terpenes (3) are not psychoactive when consumed and are mainly used for the extraction of fiber and oil (4).  Indica plants are typically short with broad leafs and generally are associated with sedative effects after consumption. Sativa plants are tall and skinny with narrow leafs, produce high levels of cannabinoids and terpenes and mediate psychoactive effects after consumption. (4). In addition, a large number of so-called Cannabis hybrids (crosses between the three Cannabis types) also exist.

Recent genomic and molecular biological analyses are beginning to provide new insights into the actual classification of the Cannabis genus. At present, there are six whole-genomes assemblies (two each) of three different strains of C. sativa. (4) These include Purple Kush (5, 6); Chemdawg (4) and LA confidential (4). In addition, there are two sativa transcriptomes (whole genome RNA analyses) [5], four mitochondrial genome assemblies (three sativa and one hemp) [4, 5, 7, 8], 6 chloroplast genome assemblies (5, 7, 9) and over 393 additional genomic resources that are being used to learn more about Cannabis classification (4).

Result of studies using the above mentioned genetic tools suggest that hemp is a distinct group and that two marijuana-type groups may also exist (5, 10, 11). To interpret their results, researchers suggested a naming convention based on leaf phenotypes: narrow-leaf drug type (NLDT) aka sativa, broad-leaf drug type (BLDT) aka indica and hemp (11). While 86% of plants classified as hemp fell into the hemp category, only 19% of popular sativa cultivar/brands fell into the NLDT category (sativa) and 27% of indica strains clustered within the BLDT (indica) group. Interestingly, 36% of so-called hybrid strains fell into the BLDT (indica) group and 62% were placed in the NLDT (sativa) category (4). Further, cultivars/brands that are most popularly reported as 100% sativa can be more closely related to be 100% indica (4).

Thanks to these genomic analyses it appears that the colloquial classifications given to individual Cannabis plants are not accurate. That said, it is important to note that the current genomic classification scheme is based on a small sample size and may not represent the actual genetic variation that exists in the Cannabis genus. To confirm or refute this possibility, more genomic analyses of existing Cannabis cultivars/brands must be performed before the genus can be accurately classified.

While current genomic studies may appear to be a purely academic exercise to some, accurate classification of Cannabis plants will be vitally important as Cannabis growers attempt to validate the identity, quality and properties of the cultivars/brands that they sell for medical or recreational purposes.

References 

  1. Hillig, K. W., and Mahlberg, P. G. A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae) Am. J. 2004; Bot. 91:966–975
  2. Hillig, K. W. Genetic evidence for speciation in Cannabis (Cannabaceae). Genet. Resources Crop Evol 2005; 52: 161–180
  3. Small, E, and Cronquist, A. A practical and natural taxonomy for Cannabis. Taxon. 1976; 25:405–435
  4. Vergara D,  Baker, H, Clancy K,  Keepers KG, Mendieta JP, Pauli CS,  Tittes SB, White KH, Kane,NC  Genetic and Genomic Tools for Cannabis sativa, Critical Reviews in Plant Sciences, 2016; 35:5-6, 364-377, DOI:10.1080/07352689.2016.1267496
  5. van Bakel,H., Stout, J. M., Cote, A. G., Tallon, C. M., Sharpe, A. G., Hughes, T. R., and Page, J. E. The draft genome and transcriptome of Cannabis sativa. Genome Biol. 2011;   12:1241–1250
  6. Li, R., Zhu, H., Ruan, J., Qian, W., Fang, X., Shi, Z., Li, Y., Li, S., Shan, G., and Kristiansen, K. De novo assembly of human genomes with massively parallel short read sequencing. Genome Res. 2010; 20: 265–272
  7. Vergara, D.,White, K. H., Keepers, K. G., and Kane, N. C. The complete chloroplast genomes of Cannabis sativa and Humulus lupulus. Mitochondrial DNA Part A 2015; 27: 3793–3794
  8. White, K. H., Vergara, D., Keepers, K. G., and Kane, N. C. The complete mitochondrial genome for Cannabis sativa. Mitochondrial DNA Part B 2016; 1: 715–716
  9. Oh, H., Seo, B., Lee, S., Ahn, D.-H., Jo, E., Park, J.-K., and Min,G.-S. Two complete chloroplast genome sequences of Cannabis sativa varieties. Mitochondrial DNA Part A. 2015; 27:2835–2837
  10. Sawler, J., Stout, J. M., Gardner, K. M., Hudson, D., Vidmar, J., Butler, L., Page, J. E., and Myles, S. The genetic structure of marijuana and hemp. PloS One 2015; 10: e0133292
  11. Lynch, R. C., Vergara, D., Tittes, S., White, K., Schwartz, C. J., Gibbs, M. J., Ruthenburg, T. C., Land, D. P., and Kane, N.C. Genomic and Chemical Diversity in Cannabis. Crit. Rev. Plant Sci. 2016: 35: 349–363

Educating and Training Workers for Jobs in the Legal Cannabis Industry

Clark College, a private two year college of nearly 14,000 students located in Vancouver Washington, has begun offering specialized cannabis education and training courses through its Clark College Economic and Community Development (ECD) program. ECD’s mission is to provide the residents of Southwestern Washington State with certificates programs and technical/workforce training.

Recognizing the, health implications, workforce development needs and economic upside of the legal recreational and medicinal cannabis industry in Washington, Clark offered its first cannabis course this past May.  The course entitled “Cannabis and Your Health” is a five week course that showcased topics such as current industry research, the medical benefits of cannabis and the regulatory and tax laws of recreational/medical cannabis in Washington State.  Not surprisingly, the first course offering was full and there is a waiting list to register.

Another course being offered this summer is more focused on work force development and job training. This offering which is geared toward professional Cannabis growers (not home gardeners) explores topics that include growing cannabis, difference between indoor and outdoor growing operations, and the therapeutic benefits offered by different strains/varieties of cannabis.  Like ECD’s first offering the class size for the second course is small (24 persons maximum).

While Clark College’s efforts are modest, it is becoming increasingly evident that cannabis education and job training will be necessary in states where cannabis use is legal. These efforts will help to provide state residents with science-based Cannabis information as well as to help develop the workforces that will be necessary support the development of Cannabis industries in those states.

 

 

Cannabis Genomics, Terpenes and the “Entourage Effect”

In addition to pharmacologically active cannabinoids, cannabis resins also contain a variety of terpenes (monoterpenes and sesquiterpenes) that are responsible for the scent of cannabis flowers and contribute to the unique, characteristic flavor qualities of cannabis-derived products. (1)  Over 200 terpenes have been reported in Cannabis sativa (2)

Differences in the medicinal properties of different cannabis strains have been attributed to interactions (or entourage effect) between cannabinoids and various terpenes (2, 3). For example, several cannabis terpenes (most notably, β-Caryophyllene (BCP) have been reported to interact with human cannabinoid receptors (4).  Put simply, terpenes plus cannabinoids—not cannabinoids alone—may be responsible for some of the medicinal benefits attributed to cannabis.  Consequently, it has been proposed that blends of cannabinoids and terpenes could be used in medicinal cannabis preparations to maximize therapeutic benefits via the so-called entourage effect (5). Finally, other research shows that terpenes may contribute to the anxiolytic, antibacterial, anti-inflammatory and sedative effects of Cannabis (2).

While much is known about the phytochemical composition of terpenes for forensic analysis and cannabis breeding, little is know about the molecular biology of terpene biosynthesis in cannabis.  In a recent paper, Booth et al (1) successfully identified nine terpene genes that appear to be involved in all stages of cannabis terpene biosynthesis. The authors suggested that knowledge of the genomics and gene functions of terpene biosynthesis may allow genetic manipulation of cannabis for desirable terpene profiles.  Further, genetic manipulation of terpene biosynthesis may help to scientifically unravel the so-called entourage effect and maximize the medicinal benefits of individual cannabinoids and cannabis-derived pharmaceuticals.

References

  1. Booth JK, Page JE, Bohlmann J. Terpene synthases from Cannabis sativa. PLoSOne 2017; 12:e0173911
  2. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects. British Journal of Pharmacology. 2011; 163: 1344–64
  3. ElSohly MA, editor. Marijuana and the cannabinoids. Springer Science & Business Media; 2007. November 15.
  4. ElSohly MA, editor. Marijuana and the cannabinoids. Springer Science & Business Media; 2007. November 15.
  5. Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009; 16: 97–110

Who’s Who In the World of Publicly Traded Cannabis Stocks

While the number of publicly traded Cannabis companies is relatively small, the so-called  US Marijuana Index has been created so that people who invest in the stock market know which companies are worth investing in.  The US Marijuana index is complied by the Marijuana International Corporation.

Unlike high flying biotechnology, tech and healthcare company stocks that trade on major stock indices like NASDAQ and the New York Stock exchange, most of the stock issued by companies that comprise the Marijuana Index is traded on the over-the-counter or OTC market.

At present, the marijuana index has a market cap over $5 billion and is equally weight among 20 companies that have at least 50% of their revenues generated from the cannabis or hemp industries.  A list of the companies and their market caps that comprise the US Marijuana Index can be found here.

As of April 2017, the US Marijuana Index delivered an annual return of 35.6% as compared with the 12.47% returns of the S&P 500 index.  This suggests that investment in Cannabis company stocks may be a good bet.  That said, the uncertainty of the Trump administration’s stand on the legal US recreation and medical Cannabis industries should also be considered (at least for long term investing strategies).

Given the chaos of the Trump administration and Jeff Sessions tenuous job security, many people remain high (pun intended) on investing in the Cannabis industry.  However, like any other stock investment, investment in companies that comprise the US Marijuana Index can be risky and not for the feint of heart!

Editorial: Are Cannabis-derived Pharmaceuticals a Possibility in the US?

Surveys conducted in the 1990s (1) and 2000s (2) found that between 30% and 54% of internists and oncologists were in offering cannabis as a therapeutic option for their patients. Yet, despite this, the willingness of many physicians to prescribe medical cannabis for their patients has been less than enthusiastic. Many physicians are concerned about the legality of making medical cannabis recommendations or writing prescriptions regardless of state laws that make medical cannabis legal (3).

Because cannabis and its products are illegal at the Federal level, many physicians believe that they may find themselves in legal jeopardy even though medical cannabis is legal in the states where they practice medicine.  Further, because medical cannabis has not be test or evaluated like other medicinal products, physicians have little or no scientific data to convince them that anecdotal claims about the there therapeutic benefits of cannabis are true. Finally, physicians make recommendations to patients about specific prescription drugs because they are educated about the safety and efficacy of those products.  In the absence of this vital information, physicians will not write prescriptions.

The existing confusion about the legality/criminality of cannabis-derived products has also had an effect on the behavior of insurers and third party payers. To that point, medical cannabis is not on the formularies of almost all insurers in states where medical cannabis is legal and, because of this, they do not reimburse patients for out-of-pocket medical cannabis costs.  While payers currently do not reimburse patients for the use of medical cannabis, it is possible that insurers may reimburse patients who use US Food and Drug administration (FDA)-approved cannabis products but continue to not reimburse patients who use unapproved medical cannabis treatments. Regardless of the outcome, medical cannabis costs continue to rise and its access and use by patients who might benefit from it may be in jeopardy unless payers place it on their formularies.

Because of the legal patchwork for Cannabis that has evolved over time in the US, it is likely that cannabis-derived pharmaceuticals may only be available in the states that have legalized their use. This would force companies developing cannabis-derived pharmaceuticals to duplicate commercial operations in states where medical cannabis is legal and underwrite multiple product launches in individual states because interstate transport of these products is currently illegal. This would be extremely costly (driving up product price) and also decrease patient access to these products to address unmet medical needs. To that point, most companies developing cannabis-derived pharmaceuticals believe that rescheduling of these products from Schedule I drugs to Schedule 2 or 3 would obviate most of these concerns and allow the US Cannabis market to grow to its full potential.  Alternatively, FDA may reschedule cannabis-derived pharmaceuticals on a case-by-case basis upon approval of individual products.

Finally, because Cannabis-derived pharmaceuticals represent a new class of therapeutics, patient and healthcare provider education will be vital to successfully commercialize these products. Put simply, if physicians don’t understand cannabis-derived pharmaceuticals, and they are not convinced they are safe and effective, then, they are not   going to write prescriptions for their patients. Therefore medical cannabis and cannabis-derived pharmaceutical companies must invest in public outreach activities as well as continuing medical education workshops and courses for healthcare professionals to ensure product success.

Despite all of these challenges, there is growing popular demand for cannabis-derived pharmaceuticals in the US. And, it is likely that inclusion of these products in the American pharmacopoeia will begin to address growing unmet medical needs in the US healthcare system and improve patient access to possibly life-changing therapeutic treatments.

References

  1. Doblin RE, Kleiman MA. Marijuana as antiemetic medicine: a survey of oncologists’ experiences and attitudes. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 1991; 9:1314-1319. 
  2. Charuvastra A, Friedmann PD, Stein MD. Physician attitudes regarding the prescription of medical marijuana. Journal of Addictive Diseases 2005; 24: 87-93.
  3. Bowles DW, O’Bryant CL, Camidge DR, Jimeno A. The intersection between cannabis and cancer in the United States. Critical Reviews in Oncology/Hematology 2012l; 83:1-10.

Commercializing Cannabis-Derived Pharmaceuticals: Manufacturing, Quality and Healthcare Challenges

While overcoming the legal and regulatory challenges for commercializing cannabis- derived pharmaceuticals is essential, there are a variety of technical, manufacturing and healthcare obstacles that must be addressed before this class of molecules can be successful.

First, substantial financial investment must be made in infrastructure and production facilities to breed and grow different cannabis strains to obtain appropriate chemical compositions and extracts to treat specific therapeutic indications (1). Industry experts contend that this investment must include research on strain construction, cannabinoid concentrations at different stages of plant growth/harvest times and yield improvements. Interestingly, crop failure (not having a redundancy of supply) is a serious issue that all commercial entities in the medical cannabis industry must address and contend with to meet commercial demand.

Second, plant growth (use of insecticides, herbicides etc), extraction processes, and product formulation of cannabis-derived pharmaceuticals must be conducted according to Current Good Manufacturing Practices (CGMP) and rigorous quality standards (1). After all, the primary reason for seeking regulatory approval for these drugs is to demonstrate to patients and healthcare providers that cannabis-derived pharmaceuticals have been thoroughly reviewed, are well characterized and determined to be safe and effective. Implementation of pharmaceutical CGMPs (2) will ensure cannabis-derived pharmaceutical product safety, efficacy and quality over time.

Third, the route of delivery and dosing regimens for cannabis-based pharmaceuticals for specific indications will be vitally important. While smoking/vaporizing cannabis is currently the most obvious method to deliver desired therapeutic effects, it may not be the most effective to maximize its therapeutic benefits for different indications and individual patients (3). Over the past few years, there has been a growing interest in exploring oral, oromucosal, topical and sustained release delivery of cannabis-derived pharmaceutical depending upon the therapeutic indication of interest.

Fourth, efforts must be initiated to get Cannabis-derived pharmaceuticals on the drug formularies of state government insurers and third party insurance companies. At present, medical marijuana costs are usually not reimbursable by conventional health insurance companies (4) and out-of-pocket expenditures can be costly especially for those individuals who suffer from long term, chronic clinical indications like cancer, multiple sclerosis and epilepsy. However, if Cannabis-derived pharmaceuticals are approved by the US Food and Drug Administration (and are rescheduled) it is likely that these drugs will be covered by government and third party healthcare payers (5).

Finally, safeguards must be put into place to ensure protection against misuse, fraud and abuse of Cannabis-derived pharmaceuticals by healthcare providers and patients. The development of novel metered dose devices to deliver these products will help to limit misuse and abuse.

References

  1.  https://daggacouple.co.za/wp-content/uploads/2014/07/Economies_Scale_Production_Cannabis_Oct-22-20131.pdf Accessed July 18, 2017
  2. https://www.fda.gov/food/guidanceregulation/cgmp/  Accessed July 18, 2017
  3. https://www.medicaljane.com/category/cannabis-classroom/consuming-cannabis/   Accessed July 18, 2017
  4. http://www.cheatsheet.com/money-career/why-your-health-insurance-wont-cover-medical-marijuana.html/?a=viewall  Accessed July 18, 2017
  5. http://www.medicalmarijuanainc.com/medical-marijuana-covered-health-insurance/ Accessed July 18, 2017

 

Commercializing Cannabis-Derived Pharmaceuticals: Legal and Regulatory Challenges

The current regulatory and legal landscape for cannabis and cannabis-derived products is extremely difficult and fraught with numerous challenges. For example, in the US, cannabis and products derived from it (including hemp) are federally classified as Schedule I drugs according to the US Controlled Substances Act (1). This means that cannabis and its products have been deemed to have “no currently accepted medical use in treatment in the US” (heroin and LSD are also schedule I drugs), are harmful and consequently, are illegal (2).

Not surprisingly, its Schedule 1 classification has seriously hindered cannabis research in the US and made it extremely challenging for drug companies developing cannabis-derived pharmaceutical products (3). However, over the past decade or so, 29 states including the District of Columbia have enacted legislation that permits some form of cannabis consumption for medical purposes (4). Yet, despite this, cannabis and products derived from it remain illegal at the federal level and during interstate transport (even between states where medical marijuana has been legalized) is illegal and criminally punishable (2).

The confusion regarding cannabis use at the state and federal levels has given rise to two distinct types of companies that are attempting to commercialize cannabis (and products derived from it) for medicinal purposes. The first of these are commonly referred to as medical marijuana or medical cannabis companies. Typically, products from these companies are botanical extracts or actual plant materials derived from specific cannabis strains with anecdotally-reported medicinal properties that can be topically applied, ingested, smoked or vaporized. Patients require a “prescription” (card) from a state-licensed physician to obtain medical marijuana and it can only be used in states that permit consumption of cannabis for medical purposes. It is important to note, that while a prescription is required for medical cannabis use, these products do not require human clinical testing for safety, tolerability and efficacy (like other prescription drugs) prior to their sale in states where medical marijuana is legal.

In contrast with medical marijuana companies, biopharmaceutical companies including GW Pharma, Zynerba, Insys, Kannalife, Aphios and others (Table 1) are committed to developing cannabis-derived pharmaceuticals using conventional US Food and Drug Administration regulatory approval pathways. UK-based GW Pharma is the clear leader in cannabis-derived pharmaceutical space—its flagship product Sativex®, a plant extract, has been approved as a treatment for cancer-related pain and MS spasticity in 27 countries outside the US (5).

While the business case for developing pharmaceutical cannabis-derived pharmaceuticals is a sound one, the time and cost necessary for regulatory approval will be much greater than that for commercializing medical marijuana. At present, the United State Food and Drug Administration (FDA) has signaled a willingness to review new drug applications for cannabis-based pharmaceuticals (6). However, the agency has yet to issue definitive guidance for regulatory approval of these products and to date has not approved any application for cannabis-based products (6). Nevertheless, garnering FDA regulatory approval for cannabis–derived pharmaceuticals may offer several competitive advantages over numerous medical marijuana products that currently dominate the US market.

First, the average cost per patient of Sativex® to treat MS spasticity in countries where it has been approved has been estimated to be roughly $16,000 (6). Several studies indicate  (7, 8) that the high price of Sativex® will make it unlikely to be considered cost effective by regulators in countries with government-mandated national formularies like the UK, Ireland and Australia. However, this should not be an impediment in the US market because the federal government does not set drug prices and third-party payers dictate formulary placement and set drug reimbursement rates.

Second, unlike medical marijuana (which as previously state is a Schedule 1 drug), FDA approved cannabis-based pharmaceuticals like dronabinol and nabilone have been classified or reclassified as Schedule 2 (opioids) or Schedule 3 (codeine) drugs (5, 9). Federal regulators are likely to apply the same scheduling criteria to the next generation of FDA-approved cannabis-derived pharmaceuticals like Sativex® and others. Rescheduling will effectively allow these products to compete with medical marijuana because unlike medical marijuana—which is legal in only 29 states and cannot be transported across state borders—approved cannabis-derived pharmaceuticals can be legally prescribed, sold and used in all 50 states and US territories.

Finally, and perhaps most importantly, physicians may be inclined to prescribe FDA-approved cannabis drugs as compared with medical marijuana because they have been evaluated in human clinical trials and officially deemed to be safe and effective treatments for specific therapeutic indications.. In marked contrast, medical marijuana can be prescribed and sold in states where it is legal without going through any formal drug review process. While this is unlikely to interfere with possible therapeutic benefits offered by medical cannabis questions concerning product safety, effectiveness and reproducibility about these products are likely to continue to  arise until industry best practices are implemented and standardized.

References

  1. https://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm  Accessed July 17, 2017
  2. https://www.dea.gov/druginfo/ds.shtml  Accessed July 17, 2017
  3. https://www.brookings.edu/wp-content/uploads/2016/06/Ending-the-US-governments-war-on-medical-marijuana-research.pdf  Accessed July 17, 2017
  4. http://medicalmarijuana.procon.org/view.resource.php?resourceID=000881 Accessed July 17, 2017
  5. https://www.gwpharm.com/products-pipeline/sativex  Accessed July 17, 2017
  6. https://www.fda.gov/newsevents/publichealthfocus/ucm421163.htm  Accessed July 17, 2017
  7. Pharmacoeconomic NCF. Cost-effectiveness of Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®) as add-on treatment, for symptom improvement in patients with moderate to severe spasticity due to MS who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy. 2014. http://www.ncpe.ie/wp-content/uploads/2013/01/Summary-v1.pdf.
  8. Lu L, Pearce H, Roome C, Shearer J, Lang IA, Stein K. Cost effectiveness of oromucosal cannabis-based medicine (Sativex(R)) for spasticity in multiple sclerosis. PharmacoEconomics. Dec 1 2012;30(12):1157-1171.
  9. https://www.deadiversion.usdoj.gov/fed_regs/rules/1998/fr1105.htm  Accessed July 17, 2017

CBG: The Lesser Known Cannabinoid

Cannabigerol (CBG) a non-psychoactive cannabinoid, gets a lot less attention than its mediahound cousins, THC and CBD.  However, like those molecules, CBG has been found to exhibit a variety of medicinal properties that may be beneficial to patients with various illnesses.

First, in a mouse model of colitis ( a type of inflammatory bowel disease), intracolonic administration of CBG substantially reduced cellular markers of inflammation (1).  Second, CBG was found to exhibit neuroprotective properties in two experimental models of Huntington’s disease (2). Third CBG inhibited the growth of chemically-induced colorectal cancer and xenograft tumors in a mouse model through a known receptor-mediated colorectal tumor pathway (3). Fourth, CBG was found to be an effective appetite stimulant in pre-satiated rats (4 ). Finally CBC exhibits antibacterial properties against drug resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA) [5] and inhibits smooth muscle contractions in a mouse model of bladder dysfunction (6).

Of course, a lot more research must be done before any or all of the above mentioned effects of CBG are validated or proven.  However, the appetite stimulating properties of the molecule are anecdotally linked to the so-called “munchies” that occur after smoking Cannabis.  Clinical studies involving volunteers willing to smoke CBG-less Cannabis may be a good way to verify or refute this idea!

References

  1. Borelli F, Fasolino I, Roman B, Capasso R, Maiello F et al. Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochem Pharmacol 2013; 85:1306-1316.
  2. Valdeolivas S, Navarrete C, Cantarero I, Bellido ML, Munoz E, Sagredo O Neuroprotective properties of cannabigerol in Huntington’s disease: studies in R6/2 mice and 3-nitropropionate-lesioned mice  Neurotherapeutics 2015; 12:185-199
  3. Borreli F, Pagano E, Romano B, Panzera S, Maiello F, Coppola D et al. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, A Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis 2014;35:2787-2797
  4. Brierley D, Samuels J, Duncan M, Whalley BJ, Williams CM Cannabigerol is a novel, well-tolerated appetite stimulant in pre-satiated rats. Psychopharmacology(Berl) 2016; 233:3603-3613.
  5. Appendino A, Gibbons S, Giana A, Pagani A Grassi G,Stavri M,Smith E Rahman M. Antibacterial cannabinoids from Cannabis sativa: A structure-activity study J. Nat. Prod. 2008: 71:1427-1430
  6. Pagano E, Montanaro V, Di Girolamo A, Pistone A, Altieri V, Ziawiony JK, Izzo AA, Capasso R. Effect of non-psychotropic plant-derived cannabinoids on bladder contractility: focus on cannabigerol. Nat Prod Commun 2015 10:1009-1012

Treating Cancer-Related Symptoms with Cannabis

In the 1970s, purified and synthetic cannabinoids were being evaluated as palliative treatments for cancer related symptoms (1). One of the earliest recognized clinical indications for cannabinoids was cancer induced nausea and vomiting (CINV) [2].

A 1988 prospective open label trial found that inhaled cannabis effectively controlled CINV in 78% of 56 cancer patients who had inadequate control of nausea and vomiting with conventional anti-emetics (3). Also, a later report that evaluated 30 trials and over 1300 participants determined that synthetic THC molecules such as nabilone and dronabinol were more effective than conventional anti-emetics in controlling acute CINV (2). This led to the early approval of dronabinol and nabilone as treatments for CINV but their use as a treatment for CINV has not been widespread (2,3)

A quick search of the clinical trials site www.clinical trials.gov revealed that there are no US clinical trials currently underway to further evaluate the use of Cannabis as a treatment for CINV.  Moreover, there are no natural Cannabis products e.g. extracts, sprays etc, on the market today that have received US Food and Drug Administration (FDA) approval as a treatment for CINV.

Inhaled Cannabis, and extracts containing THC and CBD have been clinically found to be more effective in treating cancer-related neuropathic pain than placebo (3, 4) but their effectiveness compared with conventional pain medications is uncertain (2). Yet, despite this, GW Pharma’s Sativex® (an extract that contains 1:1 ratio of Δ-9-tetrahydrocannabinol (THC) and cannabidiol [CBD]) is an approved treatment for cancer-related pain in 27 countries outside of the US (5).

There are currently 4 US clinical trials in (various phases) that are underway to determine the effects on Sativex® on advanced cancer pain and chemotherapy-induced neuropathic pain (Table 1). Regulatory experts expect Sativex® to garner FDA approval for both indications.

References

  1. Guzman M, Duarte MJ, Blazquez C, et al. A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. British Journal of Cancer 2006; 95:197-203.
  2. Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2002; 323:16-21.
  3. Bowles DW, O’Bryant CL, Camidge DR, Jimeno A. The intersection between cannabis and cancer in the United States. Critical Reviews in Oncology/Hematology 2012; 83:1-10
  4. Notcutt W, Price M, Miller R, et al.  Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia 2004; 59:440-452.
  5. https://www.gwpharm.com/products-pipeline/sativex  Accessed July 12, 2017