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 Its Effect on High Blood Pressure

According to recent estimates, about 75 million American adults have has high blood pressure (1), a condition commonly referred to as hypertension. If untreated, it can lead to cardiovascular disease, which is characterized by an increased risk of stroke, heart attack, and even heart failure. Hypertension was the cause of over 400,000 deaths in 2014 (1).

A number of factors, including poor diet, stress, physical inactivity, alcohol, and tobacco use increase the risk of developing hypertension (1). Hypertension can be managed by taking medications, reducing sodium in the diet, getting daily physical activity, and quitting smoking (2).

Previous reports suggest that consumption of cannabis and certain cannabinoids e.g, cannabidiol (CBD) may help to lower high blood pressure and represent a new treatment option for hypertension (3-5).   Further, results from a 15 year longitudinal study called the Coronary Risk Development in Young Adults (CARDIA) which followed 3,617 black and white young adults suggested that cannabis consumption was not independently associated with increased cardiovascular risk (6). However, study authors cautioned that it was associated with unhealthy behaviors including high caloric diet, tobacco smoking and other illegal drug use.

In a more recent retrospective analysis of 1213 young adults (20 years and older)—57% used cannabis—Yankey et al. (7) showed that cannabis use may increase the risk of death from hypertension. Study results suggested that cannabis users had more than three times the risk of death from hypertension-related causes. Moreover, increased duration of cannabis use was also associated with a greater risk of death from hypertension. However, it is important to note that the researchers acknowledged the difficulty of measuring frequency and quantities of marijuana used by study participants and the likelihood that illegal use was underreported (7). Put simply, there are confounding variables that call into question the conclusions of the study.

In summary, the positive or negative effects of cannabis consumption on cardiovascular health and disease still remain to be conclusively determined. New well designed and better controlled clinical studies will be necessary to verify or refute the effects of cannabis and cannabinoids on cardiovascular function and their ability to manage hypertension.

References

  1. https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_bloodpressure.htm  Accessed August 23, 2017
  2. http://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/high-blood-pressure/art-20046974  Accessed August 23, 2017
  3. Pacher P, Batkal S, Kunos G. Cardiovascular pharmacology of cannabinoids. Handb Exp Pharmacol 2005; 168:599-625
  4. Randall MD, Harris D, Kendall DA, Ralevic V. Cardiovascular effects of cannabinoids. Pharmacol Ther. 2002;95:191–202.
  5. Hiley CR, Ford WR. Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling. Biol Rev Camb Philos Soc. 2004;79:187–205
  6. Rodondi N, Pletcher MJ, Liu K, Hulley SB, Sidney S  Marijuana use, diet, body mass index and cardiovascular risk factors (from the CARDIA study). Am J Cardiol 2006; 98:478-484
  7. Yankey B, Rothenberg R, Strasser S, Ramsey-White K, Okosun IS Effect of marijuana use on cardiovascular and cerebrovascular mortality: A new study using the National Health and Nutrition Survey linked mortality file. Eur J Preventive Cardiol 2017; DOI: 10.1177/2047487317723212 [Epub ahead of print]

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

Cannabidiol (CBD) and Opioid Addiction

Opioids provide effective analgesic relief against acute and chronic pain.  Rates of opioid prescription have skyrocketed over the past two decades and opioid addiction is extremely high among users reaching almost 50% (1, 2).  As opioid prescription and addiction rates rise, overdose deaths in the US have nearly tripled in the past 15 years (3).

Cannabidiol (CBD) is a non-psychoactive cannabinoid that has been reported to dampen the “reward properties” of drugs like cocaine, amphetamine and opioids in animal models (4, 5). Put simply, CBD might be able to block the urge of users to continue to use these highly addictive drugs.

In a recent study conducted at the University of Mississippi, Markos et al (6) injected separate groups of mice with either saline (control) or morphine in combination with different doses of CBD. The treated mice were then subjected to drug/no drug conditioning experiments.  The results from these experiments showed that morphine-conditioned mice displayed a robust preference for morphine. This robust morphine preference was significantly attenuated in mice that also received morphine plus CBD (10 mg/kg). Further, CBD (10 mg/kg) alone did not exhibit any rewarding or aversive properties in saline-conditioned mice. This finding is the consistent with the work of others who also found that CBD lacks psychotomimetic, aversive or reward properties (7-10).

Taken together, these results suggest CBD can block opioid reward behavior, i.e. deter the subsequent use of opioids, and may be useful as a treatment in opioid addiction treatment settings.  However, while these results may be encouraging, controlled, human clinical studies with CBD must be performed to determine whether or not the cannabinoid may be useful as a pharmacologic intervention to help treat opioid addiction.

References

  1. Dart RC, Surratt HL, Cicero TJ, Parrino MW, Severtson SG, Bucher-Bartelson B, Green JL. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med 2015; 372: 241–248
  2. Højsted J, Sjøgren P. Addiction to opioids in chronic pain patients: a literature review. Eur J Pain 2007; 11: 490–518
  3. 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 2016; 65: 1445–1452
  4. Parker L, Burton P, Sorge R, Yakiwchuk C, Mechoulam R. Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmachology 2004; 175: 360–366
  5. Katsidoni V, Anagnostou I, Panagis G. Cannabidiol inhibits the reward facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. Addict Biol 2013; 18: 286–296
  6. Markos JR, Harris HM, Gul W, ElSohly MA, Sufka KJ.  Effects of cannabidiol on morphine conditioned place preference in mice. Planta Med 2017 12/13 DOI: 10.1055/s-0043-117838
  7. Parker L, Burton P, Sorge R, Yakiwchuk C, Mechoulam R. Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmachology 2004; 175: 360–366
  8. Katsidoni V, Anagnostou I, Panagis G. Cannabidiol inhibits the reward facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. Addict Biol 2013; 18: 286–296
  9. Mechoulam R, Parker L, Gallily R. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol 2002; 42: 11S‑19S
  10. Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus L. Cannabidiol – recent advances. Chem Biodivers 2007; 4: 1678–1692

Cannabis Testing Services: A New Alternative Career Opportunity For Life Scientists

Increased use of medical cannabis, coupled with a growing trend to legalize cannabis for recreational use, has created a niche for companies that offer analytical cannabis testing services.  Not surprisingly, the cannabis testing market is dominated by North American companies with an annual market size of roughly $822 million in 2016 (1).  The size of this market is expected to reach approximately $1.4 billion by 2021 (1).

Typical services offered by cannabis testing companies include:

  • Potency testing
  • Terpene profiling
  • Pesticide screening
  • Residual solvent screening
  • Heavy metal testing
  • Genetic testing
  • Microbial analysis

Most of these analyses involve the use of standard laboratory instruments (and related software packages including 1) liquid chromatography (LC), 2) gas chromatography (GC), 3) mass spectrometry, 4) atomic spectroscopy and 5) automated DNA sequencing/genomic analyses.

While the analytical services offered by these companies may sound esoteric to  lay cannabis audiences, they are very familiar to life scientists with backgrounds in biochemistry, organic chemistry, molecular biology, pharmacology, botany, plant pathology and a host of other life science disciplines.  That said, the rapid growth of the cannabis testing industry has created job opportunities  for life scientists who are trained and skilled in the above mentioned analytical methods.

Industry leaders in cannabis analytical services  who may be looking to hire new employees can be divided into two distinct categories; companies that develop hardware and software to conduct the analyses and companies that actually provide analytical services to clients.  Companies involved in hardware and software development  include:

  1. Agilent Technologies Inc (hardware/software)
  2. Shimadzu Corporation (hardware/software)
  3. PerkinElmer, Inc (hardware/software)
  4. Millipore Sigma (hardware/software)
  5. AB Sciex LLC (hardware/software),
  6. Waters Corporation (hardware/software)
  7. Restek Corporation (hardware/software)

Leading companies that offer analytical services to clients include:

  1. Accelerated Technologies Laboratories Inc (hardware/software)
  2. LabLynx Inc. (hardware/software)
  3. Steep Hill Labs, Inc (analysis)
  4. CannaSafe Analytics (analysis)
  5. Pharm Labs LLC (analysis)
  6. Digipath Labs, Inc (analysis)

Because  the number of traditional life sciences job continue to decline and remain highly competitive, now may be a good time for entry level life life scientists to consider a career shift to the cannabis testing services market. However, do not wait or linger.  This market, like the traditional life sciences job market may be quickly  over subscribed!

References

  1. Cannabis testing market expect to reach $1.4 billion by 2021. http://www.marketsandmarkets.com/PressReleases/cannabis-testing.asp Accessed August 7, 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.

What is CBN And Why It May Be Important

Cannabinol or CBN is a weak psychoactive cannabinoid found only in trace amounts in Cannabis (1).  It is mostly a degradation product (metabolite) of Δ-9-tetrahydrocannabinol (THC) [2].

Studies suggest that CBN acts as a weak agonist of CB1 receptors and has a higher affinity for CB2 receptors albeit lower than the affinity of THC for CB2 receptors (3, 4)..

Because CBN is a partially-selective agonist of CB2 receptors it has been suggested to have a plethora of therapeutic benefits including 1) pain relief, 2) sedative effects, 3) anti-inflammatory and antibacterial activity, 4) anticonvulsive properties, 5) bone growth promotion and 6) appetite stimulation (5-9). However, it is important to note that much more research must performed with CBN to validate or refute its potential therapeutic and clinical effects.

References

  1. Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE. (1975) Effects of delta9-tetrahydrocannabinol and cannabinol in man. Pharmacology 1975; 13:502-512.
  2. McCallum ND, Yagen B, Levy S, Mechoulam R. Cannabinol: a rapidly formed metabolite of delta-1- and delta-6-tetrahydrocannabinol. Experientia 1975; 31:520-521.
  3. Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK. Novel cannabinol probes for CB1 and CB2 cannabinoid receptors. Journal of Medicinal Chemistry  2000; 43:3778-3785.
  4. Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC. Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sciences 1998; 63:1-6.
  5. Zymont PM, Andersson DA, Hogestatt ED  Δ-9-tetrahydrocannabinol and cannbiol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism  J Neurosci 2002; 22:4720-4727.
  6. Appendino G, Gibbons S, Giana A, Pagani A et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study.  J Nat Prd 2008; 71:1427-1430.
  7. Ludovic Croxford J Yamamura T. Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J.Neuroimmunol. 2005: 166:3-18.
  8. Farrimond JA, Whalley BJ, Williams CM Cannabinol and cannabidiol exert opposing effects on rat feeding patterns.  Psychopharmacology (Berl) 2012; 223:117-129.
  9. Cannabis 101: What is CBN and what are the benefits of this cannabinoid? https://www.leafly.com/news/cannabis-101/what-is-cbn-and-what-are-the-benefits-of-this-cannabinoid  2015. Accessed August 3, 2017

Development of a Molecular Test That Identifies Strains of Cannabis sativa

As the legal cannabis industry continues to mature, it has become increasingly apparent that the need for rapid and simple tests for forensic investigations and industrial quality control has become crucial.  To that end, a group of Japanese investigators developed a polymerase chain reaction (PCR) method called loop-mediated isothermal amplification (LAMP) that can differentiate Cannabis sativa from hemp (1, 2).

The assay is based on gene amplification of highly conserved DNA sequences of the tetrahydrocannabinolic acid (THCA) synthase gene that plays a major role in the Cannabis THC biosynthetic pathway.  Researchers used this test on 21 known Cannabis sativa varieties and were able to detect THCA sequence in each of them within 90 minutes (1).  In additional experiments, the researchers were able to distinguish between multiple strains of Cannabis sativa (which all possessed THCA DNA sequences) and multiple varieties of hemp (which do not possess detectable THCA sequences (2).  Based on these results, the researchers suggested that LAMP represents a rapid, sensitive, highly specific and convenient (in the field) method for detecting Cannabis sativa and differentiating it from non-psychoactive Cannabis varieties.

While this research represents a step in the right direction for forensic analysis and industrial Cannabis quality control, LAMP in its current form does not allow differentiation between different varieties of Cannabis sativa. Additional molecular analyses of different Cannabis genomes and a more in depth evolutionary analysis of genetic divergence in THCA genes from different cannabis varieties will be required to make this test useful in forensic analysis of different cannabis brands and industrial quality control programs.

  References 

  1. Kitamura M, Aragane M, Nakamura K, Watanabe K, Sasaki Y  Development of Loop-mediated isothermal amplification (LAMP) assay for rapid detection of Cannabis sativa Biol Pharm Bull. 2016; 39:1144-1149.
  2. Kitamura M, Aragane M, Nakamura K, Watanabe K, Sasaki Y  Rapid identification of drug-type strain in Cannabis sativa using loop-mediated isothermal amplification assay. J Nat.Med 2017;71:86-95.