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

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

Cannabis and PTSD: A Clinical Trial Update

The Marijuana for Symptoms of PTSD in US Veterans clinical trial being conducted by the Multidisciplinary Association for Psychedelic Studies (MAPS, a Santa Cruz-based 501 (c)(3) a private non-profit research organization)  is believed to be the first randomly controlled clinical trial to evaluate medical marijuana as a treatment for post-traumatic stress disorder (PTSD) in US military (1).  Officially, the study title is “Placebo Controlled, Triple Blind, Randomized Crossover Study of the Safety and Efficacy of Four Different Potencies of Smoked Marijuana in 76 Veterans with Chronic, Treatment-Resistant Posttraumatic Stress Disorder (PTSD)”.  The study protocol with inclusion and exclusion criteria can be found here .

The principal investigator of this federally-approved study is Sue Sisley, MD with help from Marcel Bonn-Miller, MD (coordinating PI formerly of the University of Pennsylvania) and co-investigator Paula Riggs, MD (University of Colorado) and the project is funded by a $2, 156, 000 grant from the State of Colorado. Although the project was approved in 2014, it has been plagued by a variety of political and legal issues.

First, the National Institute on Drug Abuse (NIDA) which is the only legal source of marijuana for federally sanctioned research in the US has been unable to provide the Cannabis required for the study. Incidentally, the only legal grower of Cannabis in the US is the University of Mississippi. The university was awarded that license in 1968. However, recent reports suggest that the Cannabis provided by the university is contaminated with lead, yeast and mold which could raise concerns about efficacy and safety if used in the trial (2). Also, the university has not established testing guidelines for the Cannabis that is produces.

Second, the study was initiated in Phoenix, Arizona because the city’s VA hospital has a very high density of treatment resistant PTSD patients (those who continue to experience symptoms despite undergoing VA-sanctioned treatment and/or therapy) and Dr. Sisley was on the faculty at the University of Arizona. Unfortunately, Dr. Sisley was fired from the university for political reasons. This delayed the start of the study and has subsequently slowed its progress.

Finally, Phoenix VA hospital administrators have been slow and unwilling to provide Dr. Sisley with the data that she and her team need to identify patients to complete enrollment for the study. At present, 22 patients have been enrolled and treated. Investigators must screen 6,000-8,000 veterans to identify the remaining 54 patients to complete the study (3).

The MAPS trial has the support of most veteran groups including the American Legion, Iraq and Afghanistan Veterans of America, Veterans of Foreign Wars and Disabled American Veterans.  However, the Trump administration has clearly its distaste for all things Cannabis and, despite anecdotal evidence that Cannabis can help treat PTSD and traumatic brain injury (4), the current political climate has made it difficult to conduct this very important clinical trial.  According to Dr. Sisley, “All we get from them [VA hospital administrators] is polite responses about marijuana being federally illegal.” (3)

To put PTSD in perspective, America loses an estimated 15,000 veterans each year to drug overdoses and suicide. It is a shame that the federal government will not allow a scientifically-designed clinical trial to be conducted to help determine whether or not Cannabis is a safe and effective treatment for PTSD.  Thankfully, PTSD can be treated with Cannabis in many states that have already legalized medical marijuana.

References

  1. http://www.maps.org/research/mmj/marijuana-us
  2. http://www.pbs.org/newshour/updates/scientists-say-governments-pot-farm-moldy-samples-no-guidelines/
  3. http://www.thecannabist.co/2017/08/29/veterans-administration-ptsd-marijuana-study-enrollment
  4. https://www.nytimes.com/2017/09/01/opinion/marijuana-legalization-veterans.html?ref=todayspaper

 

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 Extraction: Myths and Truths

There was an interesting article recently published by Markus Roggen PhD an organic chemist and cannabis expert, who reviewed the “dos” and “don’ts” when conducting Cannabis extractions.  DIY cannabis extractions are currently very popular because of the recent dabbing craze. Nevertheless, perhaps the most important point of the article concerns the need for quality control in the cannabis extraction industry to ensure that consumers “get what they are paying for” and that the products they use are safe.

We are in the early days of industrial scale cannabis extractions and like other industries, e.g. food and beverage, pharmaceuticals and biotechnology etc,  where production must be regulated and quality control measures enforced, similar quality standards that guide extractions and production must be created for the cannabis industry.  While this may not be viewed favorably by some current leaders of the cannabis industry, it will be necessary to establish the credibility of the industry and ensure the quality and safety of cannabis and its products as the industry continues to evolve and mature.