Cannabis Officially Enters the Craft Beer Craze

It should come as no surprise that cannabis has finally found its way into the the craft beer craze that has dominated world alcoholic beverage markets for the past decade or so.  Last week, LGC Capital, Cresco Pharma and Baltic Beer Company announced a joint venture company called CLV Frontier Brands with the goal of developing a full beverage portfolio using proprietary cannabis terpene blends and hemp ingredients.

According to reports, CLV plans on crafting four premium beers (that contain different terpene blends and other “innovative ingredients”) with a global release of the first batch of beer in Spring 2018.  While Humboldt Brewery and a partnership between Lagunitas Brewing and Absolute/Xtracts  already brew Hemp Ale with toasted hemp seeds and an IPA with terpenes respectively,  CLV joint venture represents the first aggressive effort to bring cannabis and hemp-based  craft beers  to the global stage.  CLV plans on building a pilot brewing facility in Tallinn, Estonia and has identified potential distribution partners in Europe, East Asia, Central and Latin America, Africa and Canada/Australia and New Zealand.

Noticeably absent from the distribution list of potential partners is the US.  Although terpenes, non-psychoactive cannabinoids that give different cannabis strains distinctive odors and flavors are generally recognized as safe (GRAS) by the US Food and Drug Administration (FDA) and classified as food additives, cannabis is a schedule 1 drug and anything derived from it is illegal at the federal level in the US.  Consequently, because  the beers will be brewed overseas and require shipping to the US they will not be legally available in the US (even in states where cannabis has been legalized) because interstate shipping is regulated by the federal government.  That said, I suspect that some of CLV’s products may make it into the heads of cannabis craft beer enthusiasts!

Currently Approved Cannabis-based Pharmaceuticals and Some in the Pipeline

Because of historical negative perceptions and ongoing legal concerns, only a few cannabis-based pharmaceuticals are currently licensed for clinical use. In the United States and Europe the synthetic Δ-9-THC drugs nabilone (Cesmet®) and dronabinol (Marinol®) and dronabinol (Marinol®) are approved for treatment and prevention of chemotherapy-induced nausea and vomiting (CINV; 1).  Another synthetic Δ-9-THC product, Syndros (dronabinol oral solution) received approval in 2016 for the treatment of anorexia associated with weight loss in patients with AIDS and for cancer patients with CINV who failed to adequately respond to conventional antiemetic treatments.

GW Pharmaceuticals’ Sativex®, an extract containing THC and CBD, is approved in 27 countries Europe and elsewhere for the treatment of spasticity associated with multiple sclerosis and, in Canada, is also approved as an adjunctive treatment for cancer pain (1) The CB1 cannabis receptor agonist rimonabant (Acomplia®) was approved for use in Europe to treat obesity but was discontinued because of serious adverse effects (2)

While the approved cannabis-based pharmaceutical list is quite short, there are several compounds and extracts that are currently being evaluated in human clinical trials for regulatory approval. Sativex®, which received FDA fast track designation, has completed Phase 3 clinical testing and an application for approval has been filed at FDA. Another GW Pharmaceuticals product called Epidiolex® received FDA orphan drug status and is currently in mid to late stage clinical testing as a treatment for orphan pediatric epilepsy including Dravet Syndrome and Lennox Gastaut syndrome

Other companies, including Arena Pharmaceuticals, are attempting to develop cannabis-based drugs and mimetics that treat pain by binding to certain types of cannabis receptors found throughout the body (3). Removing cannabis’ psychotropic effects and preserving its pain-relieving benefits is the major objective for this new class of pharmaceuticals.  Although these drugs are still in early stages of development, using them rather than addictive opioids to manage chronic pain would be an important step in combating the US opioid epidemic.

Although the future of cannabis-based pharmaceuticals in the US  is brighter than it has been over the past 50 years, there are still some major hurdles and obstacles that must be overcome. To gain some insight into some of these, please read 2015 testimony to Congress given by Douglas C. Throckmorton, M.D. Deputy Director for Regulatory Programs Center for Drug Evaluation and Research Food and Drug Administration.

Moreover, the approval process for cannabis-based pharmaceuticals has an additional layer of complexity as compared with conventional pharmaceuticals.  Because cannabis and its products are classified as Schedule 1 drugs according to the US Drug Enforcement Agency (DEA), a product that garners FDA approval must also be reviewed by DEA for scheduling recommendations. To that end, FDA usually provides DEA with a scientific and medical evaluation to help with scheduling.  Scheduling classification is important because it affects the controls necessary for prescribing, supplying, or storing the product.  At present cannabis’ Schedule 1 status means that it and any products derived from it have no medicinal value or benefit and consequently are illegal in the US.  Nevertheless, it is extremely likely that any newly approved cannabis-based pharmaceuticals  will be rescheduled as Schedule II or Schedule III drugs as was  FDA’s previous experience with nabilone, dronabinol and Syndros.  That said, permanently removing  cannabis and its products form the Schedule 1 list would  undoubtedly help to speed development and subsequent regulatory approval of potentially life-altering cannabis-based pharmaceuticals.

References

  1. Ladin, DA, Soliman E, Griffin L and Van Dross, R. Preclinical and clinical assessment of cannabinoids as anti-cancer agents. Front Pharmacol. Oct. 2016; 7: 361 DOI: 10.3389/fphar.2016.00361
  2. Fijal, K, Filip M. Clinical/therapeutic approaches for cannabinoid ligands in central and peripheral nervous system diseases: mini review. Clin Neuropharmacol 2016; 39:94-101.
  3. Mintz CS, Fabrizio AJ, Nison E. Cannabis-Derived Pharmaceuticals. J. Comm. Biotechnol. 2015; 21:16-30.

 

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

 

Cannabis Extracts, Cannabinoids and Cancer Treatment

There is a growing body of evidence that cannabinoids may have anti-tumor and cancer–fighting effects (1, 2).

Numerous studies have demonstrated inhibition of tumor growth in vitro and in animal models of disease for a variety of cancers including glioblastoma, breast, prostate, thyroid, colon, skin, pancreatic, leukemia and lymphoma (3).

The exact mechanism by which cannabinoids exert their anti-tumor effects is thought to occur via suppression of proliferative cell signaling pathways, inhibition of angiogenesis (blood vessel formation) and cell migration, stimulation of apoptosis (programmed cell death) and induction of autophagy (intracellular degradation) [3, 4].  Interestingly, cannabinoid receptors CB1 and CB2 have been found in higher concentrations on tumor cells than on surrounding normal tissue for a variety of cancers (5, 6).  Also, several studies suggest that cannabinoids may selectively inhibit tumor cell growth and proliferation while sparing normal tissue (3, 7).

Although cannabinoids exhibit possible anti-tumor effects, only a single Phase 1  clinical trial that assessed the safety and efficacy of THC in 9 patients with treatment refractory glioblastoma multiforme has been published (8).

However, at present, there are only two Phase 2 clinical trials underway or completed to assess the effect of cannabis extracts on solid tumor growth (NCT02255292) and glioblastoma (NCT01812603).  Clearly, more clinical studies are necessary to determine whether or not Cannabis extracts or different cannabinoids (singly or in combination) can be used as safe and effective cancer treatments for solid tumors.

References

  1. Bowles DW, O’Bryant CL, Camidge DR, Jimeno A. (2012) The intersection between cannabis and cancer in the United States. Critical Reviews in Oncology/Hematology 83(1):1-10.
  2. Lynch ME, Campbell F. (2011) Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British Journal of Clinical Pharmacology 72(5):735-744.
  3. Pisanti S, Malfitano AM, Grimaldi C, et al. (2009) Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents. Best Practice & Research. Clinical Endocrinology & Metabolism 23(1):117-131.
  4. Salazar M, Carracedo A, Salanueva IJ, et al. (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. The Journal of Clinical Investigation 119(5):1359-1372.
  5. Caffarel MM, Andradas C, Mira E, et al. (2010) Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Molecular Cancer 9:196.
  6. Qamri Z, Preet A, Nasser MW, et al. (2009) Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Molecular Cancer Therapeutics 8(11):3117-3129.
  7. Flygare J, Sander B. (2008) The endocannabinoid system in cancer-potential therapeutic target? Seminars in cancer biology 18(3):176-189.
  8. Guzman M, Duarte MJ, Blazquez C, et al. (2006) A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. British Journal of Cancer 95(2):197-203.

What is Dabbing and Why Is It So Popular?

Dabbing is a relatively  new method of delivery that involved placing a small amount of Cannabis extracts or oils—a dab—onto a heated surface (usually titanium or quartz and known as a “nail”) and vaporizing it on contact. Like vaporization, cannabinoids pass directly from the lungs to the bloodstream and produce immediate effects.  It is important to note, that dabbing can accommodate only Cannabis extracts or oils not actual Cannabis flower or plant material.

Dabbing requires a delivery device  colloquially  known as a “dab or oil rig” (Fig. 1)

Fig 1.  A dab rig.  Source: You Tube Video

In a recent paper entitled “Tracking Dabbing Using Search Query Surveillance: A Case Study in the US” Zhang et al. (1) found, that based on the volume of Google searches from  2004-2015, dabbing is rapidly growing in popularity among US Cannabis users (Fig. 2).

Fig. 2.  National trends for dabbing-related Google searches in the US, 2004-2015. (from Zhang et al)

The researchers also found a coincidental increase in the number of searches associated with e-cigarettes or electronic nicotine delivery systems (ENDS; Fig. 2)

The average dabbing searches were significantly higher in states in which medical and recreational Cannabis were legalized as compared with states with only medical Cannabis legalization ( P=.02)  [Fig. 3].

Fig. 3.   Map of raw searches for dabbing in the US, 2004-2015. (from Zhang et al)

While it is not clear why dabbing has become increasingly popular, it is likely that this delivery methods offers Cannabis users with doses that are higher in delta-9-tetrahydrocannabinol (THC) and other cannabinoids.  Interestingly, the authors suggest that dabbing surpassed Cannabis edibles and smoking in the middle of 2013 as the preferred alternative form of Cannabis consumption.

Despite its growing popularity, dabbing is not without risk.  This will be the subject of another post!

REFERENCES

  1. Zhang Z, Zheng X, Zeng, DD, Leischow S. Tracking dabbing using search query surveillance: a case study in the United States.  J. Med Internet Res. 2016; 18:e252.