A Little Dab Will Do You: Or Maybe Not?

Inhalable, noncombustible cannabis products are playing a leading role in the use of the medical and recreational cannabis products. Specifically, the practice of “dabbing” has exponentially grown in popularity in states where medical and recreational cannabis consumption has been legalized.

Dabbing involves inhaling vapors produced by placing a small amount of cannabis extract (a “dab”) on a small heated surface (the “nail”), which is connected to a water pipe ( 1 ). The most popular dabs are known as butane hash oil (BHO) dabs mainly because the concentrate is produced by passing the solvent butane over cannabis buds and leaves ( 2 ). Butane is subsequently removed from the extract under vacuum at room temperature or by heating in an oven. Differences in processing can lead to different dab consistencies that are colloquially known as shatter, budder, crumble, pull-and-snap, wax, etc (3, 4).

BHO have a tetrahydrocannabinol (THC) and cannabidiol (CBD) concentrations ranging between 50 and 90% (2). Consumers consider dabbing to be a form of vaporization, and, therefore, view it as easier on the lungs than smoking ( 5).

While delivery of harmfully-large amounts of cannabinoids (Pierre) may represent a potential danger to consumers, little is known about the toxicants that the process may produce. According to a recent paper entitled “Toxicant formation in dabbing: the terpene story (4) by a group of Portland State University researchers the high heat commonly used to heat dabs (concentrated cannabis extracts) exposes users to high levels of methacrolein (lung, throat and eye irritant), benzene (carcinogen) and other potential toxic degradation products which are known to pose human health risks (4).

The authors determined that the source of the potentially harmful degradation products may be the terpenes (compounds that give cannabis its odor and flavor) that are routinely concentrated in BHO dabs (4).  Myrcene is the most abundant terpene in cannabis, followed by limonene, linalool, pinene, caryophyllene, and humulene (4). Also, cannabis can contain trace amounts of up to 68 other terpenic compounds (6). Terpene content in BHO can range from 0.1 to 34% (4).

Another potential health risk is residual butane (a known carcinogen) that can be left behind if BHO dabs are not processed correctly (1, 2). Because of this, CO2 oil (another extraction method for dabbing) and alcohol extracts are the only allowable medical extracts to be sold under medical cannabis regulations in New York, Minnesota, Ohio and Pennsylvania (4). While commercially prepared BHO is on the rise in mature markets like California and Denver, much HBO is still made via “backyard-chemist” style operations so users beware.

Finally, while the results of this study are intriguing, I believe that much more research will be required to determine whether or not high heat terpene breakdown products pose actual health risks to dabbers.

References

  1. Stogner JM, Miller BL. The dabbing dilemma: A call for research on butane hash oil and other alternate forms of Cannabis. Subst. Abuse 2015; 36:393– 395
  2. Stogner JM, Miller BL. Assessing the dangers of “dabbing”: mere marijuana or harmful new trend? Pediatrics 2015: 136: 1– 3
  3. Pierre JM, Gandal M, Son M. Cannabis-induced psychosis associated with high potency “wax dabs” Schizophr. Res. 2016; 172:211– 212
  4. Meehan-Atrash J, Luo W, Strongin RM. Toxicant formation in dabbing: the terpene story ACS Omega, 2017; 2:6112–6117
  5. Gieringer D, St. Laurent J, Goodrich S. Cannabis vaporizer combines efficient delivery of THC with effective suppression of pyrolytic compounds J. Cannabis Ther. 2004; 4:7 – 27
  6. Ross SA, ElSohly MA. The volatile oil composition of fresh and air-dried buds of Cannabis sativa J. Nat. Prod. 1996: 59:49– 51

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

 

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

 

Optimizing Cannabis Delivery

The plethora of therapeutic benefits offered by Cannabis has largely been attributed to a class of naturally-occurring, plant-derived chemicals terpenophenolic compounds known as phytocannabinoids (1, 2). Over 60 pharmacologically-active cannabinoids have been identified to date (3).

While inhalation (smoking and vaporization) and ingestion are the most common routes of administration of Cannabis products but other routes including rectal, sublingual, transdermal, ophthalmic, intrathecal and intravenous routes have been used (4).

Smoking

Historically, smoking is the most common and easiest method for Cannabis delivery. Scientifically-speaking, smoking is inhalation of smoke produced by combustion of the Cannabis flower or concentrated forms of Cannabis. Smoking allows users to immediately feel Cannabis’ effects because inhaled smoke containing cannabinoids like THC, CBD and others (2) passes directly from the lungs into the bloodstream.  These blood-borne molecules instantaneously bind to Cannabinoid receptors, CB1 and CB2 (6, 7) and mediate the various psychoactive and therapeutic effects of Cannabis.

Vaporization

Vaporization involves heating Cannabis or concentrates//extracts to temperatures slightly lower than combustion. This technique causes cannabinoids and other molecules found in Cannabis to reach their individual boiling points (which are lower than their combustion points) and vaporize in the absence of combustion (8). By avoiding combustion, the toxic byproducts generated by smoking Cannabis are greatly reduced and the effective dose of Cannabinoids are enhanced (combustion destroys a larger percentage of cannabinoids as compared with vaporization). Like smoking, vaporized Cannabis passes directly from the lungs into the bloodstream and its effects are felt almost immediately.

 Dabbing

Dabbing is a 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 produces immediate effects. It is important to note, that dabbing can accommodate only Cannabis extracts or oils not actual Cannabis flower or plant material.

While becoming increasingly popular, dabbing can be dangerous if the right Cannabis extraction methods and appropriate equipment are not used.

Oral Delivery

Oral delivery of Cannabis and its products usually involves eating. Unlike smoking, it can take up to 2 hours or more to experience the effects of ingested Cannabis because cannabinoids are slowly absorbed into the bloodstream during digestion. Also, when ingested, Cannabis is metabolized by the liver cytochrome system and Δ-9-THC (Delta 9 Tetrahydrocannabinol) is converted to 11-hydroxy-THC, a more potent form of THC (9).

Oral delivery of Cannabis can include edibles (brownies, cookies, cakes, candy or fruit snacks), Cannabis oil/extract capsules and Cannabis-infused beverages.

Other oral delivery routes include sublingual delivery (under the tongue) or oromucosal sprays. Cannabis tinctures are frequently used for sublingual delivery and extracts are frequently delivered via the oromucosal route. Unlike ingestion, Cannabis products delivered via the sublingual or oromucosal routes are quickly delivered to the bloodstream and offer immediate effects.

Topical/Transdermal Delivery

Whereas other methods of Cannabis delivery offer systemic (body wide) effects, topical application of Cannabis salves, balms and creams generally offer more localized action (although high enough doses and repeated use of these products can sometime lead to systemic effects). These products are useful to treat arthritis, chapped skin, eczema, minor burns, muscle soreness, sunburns, swellings, joint pain, and tendonitis

Topical delivery is becoming more widespread for persons who use Cannabis for medical rather than recreational purposes. Currently, Cannabis developers are experimenting with controlled-dosage transdermal patches to treat persons with chronic illnesses (10, 11).

Cannabis Suppositories

Other Cannabis delivery method involves rectal suppositories.  Like smoking, vaporization and sublingual/oromucosal delivery, rectally-delivered Cannabis extracts/oils are rapidly absorbed into the bloodstream via the colon and provide long lasting effects. Albeit not the most appealing or dignified delivery methods, Cannabis suppositories are effective.

REFERENCES

  1. Alexander A, Smith PF, Rosengren RJ. (2009) Cannabinoids in the treatment of cancer. Cancer Letters 285(1):6-12.
  2. Aizpurua-Olaizola O, Omar J, Navarro P, Olivares M, Etxebarria N, Usobiaga A. (2014) Identification and quantification of cannabinoids in Cannabis sativa L. plants by high performance liquid chromatography-mass spectrometry. Analytical and Bioanalytical Chemistry 406(29):7549-7560.
  3. Gerra G, Zaimovic A, Gerra ML, et al. (2010) Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists. Recent patents on CNS drug discovery 5(1):46-52.
  4. .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.
  5. Aizpurua-Olaizola O, Omar J, Navarro P, Olivares M, Etxebarria N, Usobiaga A. (2014) Identification and quantification of cannabinoids in Cannabis sativa L. plants by high performance liquid chromatography-mass spectrometry. Analytical and Bioanalytical Chemistry 406(29):7549-7560.
  6. Elphick MR, Egertova M. (2001) The neurobiology and evolution of cannabinoid signaling. Philosophical transactions of the Royal Society of London. Series B, Biological Sciences 356(1407):381-408.
  7. Grotenhermen F. (2005) Cannabinoids. Current Drug Targets CNS And Neurological Disorders 4(5):507-530.
  8. Hartman RL, Brown TL, Milavetz G, Spurgin A, Gorelick DA, Gaffney G, Huestis MA. (2015 ) Controlled Cannabis Vaporizer Administration: Blood and Plasma Cannabinoids with and without Alcohol Clin Chem.;61(6):850-69
  9. Newmeyer MN, Swortwood MJ, Barnes AJ, Abulseoud OA, Scheidweiler KB, Huestis MA Free and Glucuronide Whole Blood Cannabinoids’ Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake (2016) Clin Chem. 62(12):1579-1592
  10. https://www.cannabisscience.com/index.php/news-media/cbis-latest-news/805-cannabis-science-announces-pharmaceutical-development-of-pain-patch-for-patients-with-diabetic-nerve-pain-and-fibromyalgia Accessed June 27, 2017
  11. https://cannabis.net/blog/medical/transdermal-cannabis-patches-the-future-is-here  Accessed June 27, 2017