THCA: The Cannabinoid That “Gets No Respect”

Δ9-Tetrahydrocannabinoic acid or THCA, like the late great Rodney Dangerfield, simply “gets no respect” when compared with higher profile cannabinoids like CBD, CBG, or CBN that are highly touted in medical cannabis circles.

THCA is the carboxylated precursor of the psychoactive cannabinoid Δ9-tetrahydrocannabinol or THC. Unlike THC, THCA is not psychoactive and can be found in high concentrations (10%-20%) in certain cannabis strains (1). Interestingly, there is a growing body of evidence that suggest that THCA may possess a variety of medically-beneficial, therapeutic properties.

First, THCA has been reported to possess potent in vitro anti-inflammatory properties similar to those exhibited by COX-2 inhibitors like Celebrex (2). Second, THCA exhibited neuroprotective effects in various tissue culture and animal models of Parkinson’s disease (3). Finally, THCA may possess antiproliferative and anti-tumor effects against prostate cancer (4)

Unfortunately, like most other cannabinoid research, additional studies must be conducted to confirm or refute possible therapeutic benefits of THCA. That said, it is a cannabinoid that deserves more respect than it is currently getting!

References

  1. Baker PB, Taylor BJ, Gough TA. The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products. J. Pharm & Pharmacol. 1981; 33:369-372.
  2. Ruhaak LR, Felth, J, Karlsson PC, Rafer JJ, et al. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa Biologic and Pharmaceutical Bull; 2011 34:774-778
  3. Moldzio R, Pacher T, Krewenka C, Kranner B, et al. Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomed 2012: 19:819-824.
  4. De Pretrocellis L, Ligresti A, Moriello AS, Iappelli M, Verde R, et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br. J. Pharmacol 2013: 168:79-102

A Role for Medical Cannabis in Combating the Opioid Epidemic

Drug overdoses and opioid-related deaths have reached epidemic proportions throughout the United States (1). Over the past 25 years or so, the number of opioid-related deaths (from prescription opioids including oxycodone, hydrocodone and methadone and heroin) quadrupled to more than 200,000 (2). In 2015 alone, opioid overdoses resulted in 33,901deaths (1, 2) and in 2016 nearly half of all opioid-related deaths involved prescription opioids (CDC). Today, opioid-related deaths in the US surpass combined deaths caused by both car accidents and guns annually (2, 3).

Cause of the Epidemic

While the exact causes of the current opioid academic are uncertain, a variety of factors including job loss, chronic unemployment, financial hardship and over-marketing/over-prescribing of opioids have been suggested. It is important to note, however that between 1981 and 2011 the number of opioid prescriptions in the US tripled from 76 million to 219 million per year (4). According to a recent survey, over 97 million people took prescription opioids in 2015 and of these, roughly 12 million used opioids without being directed by a doctor (5).  Interestingly, because of recent state legislative initiatives that restrict the opioid prescribing habits of physicians, the number prescription opioids deaths appeared to level off in 2011(6). However, since 2011 the number of heroin overdose deaths and those related to illegal “black market” synthetic opioids like fentanyl has skyrocketed (CDC) in many hard hit states like West Virginia, Pennsylvania and New Hampshire. This is because heroin and fentanyl are now much cheaper and more available than prescription opioids (6).

The current opioid epidemic is forcing many physicians to reevaluate their use of prescription opioids for pain control and to consider alternative pain management strategies. There is an emerging body of evidence that suggests that medical cannabis (smoked, vaporized or ingested) can effectively manage and control chronic non-cancer pain (6-9), reduce opioid consumption (10-15) and help to lower opioid overdose deaths (14, 15).

Medical Cannabis and Pain Management

There are numerous reports that show that smoked or vaporized medical marijuana (and cannabis extracts), used alone or in combination with opioids, can effectively treat chronic neuropathic pain, muscle pain associated with spasticity from Multiple Sclerosis and certain types of cancer pain (8,9). More important, these studies found that smoked/vaporized cannabis or its extracts induce few adverse side effects and are safe for use; even in chronic pain patients who take prescription opioids for pain management (7).

Cannabis Reduces Opioid Consumption and Lowers Overdose Deaths

Although cannabis is not approved as a treatment for pain in the US, there is new evidence from states where medical cannabis is legal that cannabis reduces opioid consumption in chronic pain patients. Several studies in the US and around the world showed that opioid use dropped by as much as 50% among chronic pain patients when they were given access to cannabis. (10, 11). Further, other studies with chronic pain patients showed that cannabis use—along with its opioid-sparring effect—enhanced patient executive cognitive performance (12). The observed improved cognitive functioning likely resulted from a 42% reduction in opioid use by these patients (12).

A study that researched the association between the existence of state medical marijuana laws and opioid overdose deaths from 1999 to 2010 found that opioid overdose deaths declined by as much as 25% in states that had medical cannabis laws in effect (14). Other research showed that reductions in opioid overdose deaths tend to improve in states where medical cannabis laws have been in effect the longest (15). For example, in California, where medical cannabis laws have been in effect since 1996, there has been a 33% drop in the number of opioid overdose deaths (14). Similar reductions were also observed in other legacy medical cannabis states such as Oregon, Colorado and the State of Washington (14,15).

Other Efforts

Several biotechnology and pharmaceutical companies are attempting to develop cannabis –derived drugs and mimetics that treat pain by binding to certain types of cannabis receptors found throughout the body (16). Removing cannabis’ psychotropic effects and preserving its pain-relieving benefits is the major objective for this new class of drugs (16). 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 curbing opioid overuse and abuse.

A Path Forward

Physicians play a critical role in prescription drug misuse and abuse prevention. To that point, continuing medical education programs that help raise awareness and educate physicians about the benefits of cannabis for pain management represents and important first step to curb over-prescription of opioids. Further, ongoing political and financial support for recent federal initiatives (17) such as enhancing access to prescription drug monitoring using health information technology, formalized collaborative efforts between insurers, health care providers, and employers to combat opioid misuse and abuse and community-based programs like the national take-back initiative—which provides a safe, secure, environmentally-responsible plan for disposing of prescription opioids and educates the public about the potential for abusing and trafficking prescription medications—will also be critical. Finally, new federal and state legislation that offers counseling and medical solutions to treat opioid abusers rather than punish them will be vital to control America’s epidemic opioid crisis.

References

  1. Rudd RA, Seth P, David F, Scholl L. Increases in Drug and opioid-involved overdose deaths — United States, 2010–2015. MMWR Morb Mortal Wkly Rep. ePub: 16 December 2016. DOI: http://dx.doi.org/10.15585/mmwr.mm6550e1  Accessed October 23, 2017
  2. CDC. Wide-ranging online data for epidemiologic research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics; 2016. Available at http://wonder.cdc.gov  Accessed October 23, 2017.
  3. Drug overdoes now kill more Americans than guns. CBS News 2016 https://www.cbsnews.com/news/drug-overdose-deaths-heroin-opioid-prescription-painkillers-more-than-guns/ Accessed October 23, 2017
  4. America’s opioid epidemic is worsening. The Economist (UK) 2017    https://www.economist.com/blogs/graphicdetail/2017/03/daily-chart-3  Accessed  October 23, 2017.
  5. Hughes A, William MR, Lipari RN, Bose J. Prescription drug use and misuse in the United States: results from the 2015 national survey on drug use and health. Substance Abuse and Mental Health Services Administration (SAMHSA) 2016 https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR2-2015/NSDUH-FFR2-2015.htm  Accessed October 23, 2017.
  6. Katz J. Short answers to hard questions about the opioid crisis. The New York Times 20 https://www.nytimes.com/interactive/2017/08/03/upshot/opioid-drug-overdose-epidemic.html Accessed October 23, 2017.
  7. Jensen B, Chen J, Furnish T, Wallace M. Medical marijuana and chronic pain: a review of basic science and clinical evidence. Curr Pain Headache Rep. 2015; 19:50 doi: 10.1007/s11916-015-0524-x.
  8. Wilsey B, Marcotte, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J. Pain. 2013; 14:136-148.
  9. Andreae MH, Carter GM, Shaparin N, Suslov K, et al. Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data J. Pain 2015; 16:1221-1232.
  10. Boehnke KF, Litinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication: use in a retrospective cross-sectional survey of patients with chronic pain. J Pain. 2016; 17:739-744.
  11. Haroutounian S, Ratz Y, Ginosar Y, Furmanov K, Saifi F, Meidan R, Davidson E. The effect of medicinal cannabis on pain and quality-of-life outcomes in chronic pain: A prospective open-label study. Clin J Pain. 2016; 32:1036-1043
  12. Gruber SA, Sagar KA, Dahlgren MK, Racine MT, Smith RT, Lukas SE. Splendor in the Grass? A pilot study assessing the impact of medical marijuana on executive function. Front Pharmacol. 2016; 7: 355  eCollection 2016.
  13. Bradford AC, Bradford WD. Medical marijuana laws reduce prescription medication use in Medicare Part D. Health Aff (Millwood). 2016; 35:1230-1236.
  14. Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA. Intern Med. 2014; 174:1668-1673.
  15. Kim JH, Santaella-Tenorio J, Mauro C, Wrobel J, Cerda M, Keyes KM, Hasin D, Martins SS, Li G. State medical marijuana laws and the prevalence of opioids detected among fatally injured drivers. Am J Public Health. 2016; 106: 2032-2037.
  16. Mintz CS, Fabrizio AJ, Nison E. Cannabis-Derived Pharmaceuticals. J. Comm. Biotechnol. 2015; 21:16-30.
  17. SAMHSA’s effort to fight prescription drug misuse and abuse. https://www.samhsa.gov/prescription-drug-misuse-abuse/samhsas-effort  Accessed October 23, 2017.

Regulatory Guidelines for Product Quality Are Necessary for the Success of the Medical Cannabis Industry

While medical cannabis products do not require federal regulatory approval by the US Food and Drug Administration (FDA) in states where it is legal, the emerging medical cannabis industry ought to adopt its regulatory guidelines and practices that assure the quality of all marketed US drugs and devices. This is because, at present, no universal regulatory guidelines or requirements exist to ensure medical cannabis quality and safety. Not surprisingly, the quality attributes of medical cannabis vary wildly from state to state and even between different locations within the same city, county or state. Clearly, this is not in the best interests of medical cannabis users.

FDA established mandatory federal quality guidelines to guarantee product safety, identity, strength and purity. According to FDA, product safety means that a product is free of unexpected side effects when it is used properly by a patient. Identity guarantees that a product is exactly what its label and related informational materials say it is. Strength means that a given product consistently delivers the correct dosage and potency over its shelf life from its manufacture to its expiration. Purity indicates that a product is free from physical, biological and chemical contamination.  Put simply, these guidelines guarantee consumers that products are safe, effective and meet defined quality attributes.

The agency has developed different sets of regulatory guidelines that ensure product quality during various phases of development, manufacturing and commercialization. The existing guidelines that are relevant to the medical cannabis industry include 1) Current Good Laboratory Practices (CGMP), Current Good Clinical Practices (CGCP) and Current Good Manufacturing Practices (CGMP).

CGLPs are the guidelines that regulatory laboratory activities during preclinical development of products. This includes data collection and documentation, creation of standard operating procedures (SOPs), safety and pharmacology testing in laboratory animals, and sample preparation, handling and storage. Traditionally, CGLP helps guide development and ensure the quality of individual molecules but can be applied to extracts, tinctures and other products derived from cannabis plants.

CGCP was developed to guide the planning, conduct and analysis of human clinical trials that are required before a prescription drug can garner FDA regulatory approval. While CGCP is not relevant for most medical cannabis growers and dispensaries, it is required for companies that are currently trying to develop cannabis-derived pharmaceuticals and related products.

The set of regulatory guidelines that is most appropriate for a majority of medical cannabis growers, formulators and dispensaries is CGMP.  CGMPs were developed to assure that:

  • Raw materials used in the manufacture of pharmaceutical and biotechnology products are of known and possibly standardized quality and are free from contamination
  • A manufacturing process is proven to produce a product that consistently meets its specifications and quality attributes
  • Adequate quality control and assurance testing measures have been employed to assure that a product meets its quality specifications at the time of release to market and at the end of its shelf life

There are 10 basic CGMP principles that help t o ensure product quality, safety and efficacy. They are:

  1. Proper design and construction of facilities
  2. Validation of facilities, equipment and manufacturing processes (materials testing, cleaning, software etc)
  3. Proper maintenance of equipment, facilities and utilities
  4. Creation of SOPs (and adherence to them)
  5. Documentation of all processes, data collection, record keeping etc
  6. Employee development, on-going training and certification
  7. Contamination protection and prevention
  8. Employee health and hygiene
  9. Product manufacturing records and reports (that enable product recalls)
  10. Audits and Inspections

Following these principles will help to create a process that produces a product that is reproducibly consistent, safe and effective.

Because FDA approval is not required for medical cannabis use in states where it is legal, there is no requirement that any CGLP, CGCP or CGMP must be implemented. That said, assuring product consistency, quality, safety and effectiveness will go a long way to help establish medical cannabis brand reputation and reliability.

References

  1. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58  
  2. https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm090259.htm
  3. https://www.gpo.gov/fdsys/granule/CFR-2011-title21-vol4/CFR-2011-title21-vol4-part210

The Number of Legal Cannabis Jobs in the US Grew Over 20% Last Year

While the data are difficult to come by, a recent survey by Leafly (1) determined that the number of legal fulltime Cannabis jobs in the US grew from 122,814 job in 2016 to roughly 149,304 in 2017; a gain of 22%. Of course, not all of these jobs are directly related to Cannabis cultivation and production. These estimates include electricians, plumbers, greenhouse builders, insurance brokers, software developers, realtors and bankers.

Not surprisingly, the growth of legal US Cannabis jobs was not uniform throughout the country (8 states and the District of Columbia have legalized recreational adult Cannabis use and medical Cannabis and 23 medical Cannabis only).

Among the recreational use states, Alaska exhibited the greatest job increases (252%), followed by Maine (100%), and Nevada.  Florida (1,743 %) and Hawaii (1,692%) were the clear leaders in the medical cannabis states. It is important to note that percentages can be deceiving because they don’t represent raw job numbers. For example, if Nevada had 2 full time Cannabis jobs in 2016 and 4 in 2017 that would represent a 50% annual increase. To that point, the actual 2017 job leaders in the recreational use states are California (47,711), Colorado (26, 891), Washington State (26,556) and Oregon (10,843). Likewise, medical cannabis state job leaders in 2017 were Michigan (12,515), Arizona (6,520), Illinois (1,352) and New York (1,341).

Because of legal and political ramifications, the actual number of jobs in the US Cannabis industry is very difficult to quantify. That said, the number of full time jobs is certain to rise as the industry continues to mature in recreational use states.  Likewise, as more research and information about the therapeutic use of Cannabis become available (and mainstream physicians buy into these effects), the number of jobs in the medical cannabis will also grow. However, the 22% increase in the number of fulltime cannabis jobs over the past year suggests that the industry continues to remain strong despite an uncertain political and legal future.

References

  1. https://www.leafly.com/news/politics/cannabis-jobs-count-legal-marijuana-supports-149304-americans?mc_cid=071453b259&mc_eid=510390e56d Accessed September 13, 2017

Does a Regulatory Pathway for Cannabis-Derived Prescription Pharmaceuticals Exist in the US?

All new prescription drugs introduced to the US market must be evaluated by a “tried and true” regulatory approval process established by the Federal Food, Drug, and Cosmetic (FDC) Act of 1938 (1).  The United States Food and Drug Administration (FDA) is the federal agency that oversees new prescription drug approvals.  Of course, over the years, changes have been made to the approval process to accommodate the scientific, medical and technology advances that have been made in the biotechnology, pharmaceutical and medical devices industries.

While the approval process is somewhat arcane and difficult to navigate at times, the end result is always the same. That is, approved drugs are biochemically uniform, stable, safe and effective.  Further, new drugs must posses a practical and suitable delivery system and be manufactured according to current Good Manufacturing Practices (CGMP; 2)

And, probably surprising to some, the same pathway that is used to approve new pharmaceutical and biotechnology drugs can be used to garner regulatory approval for cannabis-based  prescription drugs.  At present there are several cannabis companies, most notably, GW Pharma, that are using the pathway to get approval for their products.  However, the progress of these approvals has been greatly slowed by the fact that cannabis is federally scheduled as a Schedule 1 drug and is illegal (3). Sadly, this adds another layer of complexity to the federally-mandated regulatory approval process.

To overcome this wrinkle, 27 states including the District of Columbia (DC) have made medical marijuana legal (4).  This means that medical marijuana products sold to the public in states where it is legal do not have to go through the rigorous regulatory approval process to assure drug uniformity, quality, efficacy and safety.  Put simply, there is no regulatory oversight and the quality, safety and effectiveness of medicinal cannabis products cannot be confirmed nor guaranteed.  Ironically, this is the environment that led to the approval of the 1938 Federal Food Drug and Cosmetic Act to ensure that prescription drugs are safe and effective.

The best solution to this conundrum is to reschedule cannabis so that it is no longer illegal at the federal level. This will require medical cannabis companies to follow the new prescription drug regulatory process (that ensures product quality, efficacy and safety) before their products can be sold to US consumers.  While this may increase the time  for medical cannabis products to hit the market, it will guarantee the safety and therapeutic benefits of cannabis products for patients who suffer from diseases that cannot be controlled by conventional prescription drugs.

References 

  1. https://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm Accessed August 24, 2017
  2. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211 Accessed August 24, 2017
  3. https://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm498077.pdf  Accessed August 24, 2017
  4. https://en.wikipedia.org/wiki/Medical_cannabis_in_the_United_States  Accessed August 24, 2017

Cannabis and Post-Traumatic Stress Syndrome: It’s Complicated

There is growing anecdotal evidence that cannabis and certain phytocannabinoids may be helpful when treating persons suffering from post-traumatic stress syndrome (PTSD).  For those who may not know, PTSD is a state of mind activated by either witnessing or experiencing a shocking, frightening or horrifying episode. Many war veterans as well as sexual assault victims and others may experience PTSD at some point in their lives. At present, PTSD is a qualifying medical condition in most states where medical cannabis is legal (1).

While cannabis is fast becoming the “go to” treatment for patients with PTSD, there is currently a dearth of scientific evidence to support its effectiveness. To that point, the results from a retrospective analysis showed that only 1 in 5 studies involving cannabis and PTSD showed a small but statistically meaningful decline in PTSD symptoms for patients who used cannabis (2). Moreover, older studies suggested that cannabis use may reduce the effectiveness of conventional treatments for PTSD and may be associated with poorer clinical outcomes (1, 3).

While there is conflicting evidence about the effectiveness of cannabis as a treatment for PTSD, there is general agreement among PTSD researchers that there have not been enough controlled clinical studies to provide conclusive evidence about the benefits or harm of plant-based cannabis preparations as PTSD treatments (4). At present there are two ongoing randomized trials and 6 other studies examining outcomes of cannabis use in patients with PTSD (4). These studies are expected to be completed within 3 years.

By then, there will hopefully be a conclusive answer!

References

  1. Wilkinson ST, Stefanovics E, Rosenheck RA. Marijuana use is associated with worse outcomes in symptom severity and violent behavior in patients with posttraumatic stress disorder. J Clin Psychiatry. 2015 Sep; 76(9): 1174-80.
  2. https://www.reuters.com/article/us-health-cannabis-pain-ptsd-idUSKCN1AU2DG  Accessed August 16, 2017
  3. Manhapra A, Stefanovics E, Rosenheck R. Treatment outcomes for veterans with PTSD and substance use: Impact of specific substances and achievement of abstinence. Drug Alcohol Depend. 2015 Sep 25. pii: S0376-8716(15)01664-6. [Epub ahead of print]
  4. http://annals.org/aim/article/2648596/benefits-harms-plant-based-cannabis-posttraumatic-stress-disorder-systematic-review  Accessed August 16, 2017

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

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: 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

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