Novel Delivery Methods for Medical Cannabis Users

There is no doubt that vaping is better than smoking cannabis but even vaping can lead to respiratory problems. Moreover many medical cannabis users do not want the negative stigma commonly associated with “smoking weed.” Finally, in certain states, including New York, where medical cannabis is legal, dispensaries are not allowed to sell leaf or plant-like material to patients.  This is causing medical cannabis companies to figure out creative ways in which to deliver cannabinoid-based products and remain compliant with individual state mandates and cannabis regulations.

Interestingly, many of these so-called innovative delivery methods for cannabis are routine delivery technologies that have already been tested, refined and approved by the US Food and Drug Administration (FDA). or example,  Colorado-based Next Frontier Biosciences, founded by former biotechnology executives and research scientists,  recently created a micro dosing-based, nasal mist delivery system intended for the pain management market segment. Likewise, similar companies with biotechnology and healthcare backgrounds are also developing time-release transdermal patches, sublingual sprays and suppository-based systems.  These developments suggest that the medical cannabis industry is beginning to mature and is likely to become mainstream in the not-too-distant future.

Several Major Universities To Offer Cannabis Courses and Even Grow Some on the Side!

In a previous blog post I wrote that several community colleges and lesser know universities were offering summer and/or continuing education classes about cannabis.  While these course offerings were impressive, most were community-based and specifically designed to support local cannabis growers and the emerging cannabis business in these locales.

More recently, however, several major universities including Ohio State University, the University of Washington, the University of Vermont and the University of California-Davis announced that they will offer courses designed to provide students and healthcare professionals with an understanding of the physiology, medical and legal implications of cannabis use.

And, quite surprisingly, Louisiana State University has entered into a private agreement with a Las Vegas-based biopharmaceutical pharmaceutical company GB Sciences to cultivate and supply cannabis for disease indications that the company plans to treat including chronic pain, arthritis, cardiovascular problems, asthma and inflammatory bowel disease. While LSU entered into this agreement, it is not clear whether or not it relationship with GB Sciences may affect its sources of federal funding because cannabis is still illegal at the federal level.

Nevertheless, it is becoming abundantly clear that academia sees an opportunity to get into the cannabis business one way or the other. Below is a sampling of the cannabis courses and seminars that are currently being offered.

The University of Vermont offers a medical marijuana and cannabis certification course for clinicians who want the latest information regarding medical cannabis and possible healthcare applications of the plant.

The Moritz College of Law at Ohio State University offers a seminar style course on the legalization of cannabis that will examine the social and historical backdrop of intoxicant prohibition, and assess the legal reforms and political debates now having an impact on the control and regulation of marijuana distribution and use.

The University of Washington offers a course for healthcare professionals on the use of medical cannabis to treat chronic pain.

The University of California-Davis will offer a course to biology majors that will cover the biology of cannabis and cannabinoids as well as their physiological effects in multiple systems, underlying mechanisms and therapeutic values. It also will survey the history of cannabis use, cover the endocannabinoid system and discuss potential medical targets for cannabis and their relative effectiveness.

Finally, there is a big push at University of California at Los Angeles to create a research center to study the medicinal effects of cannabis on a variety of disease indications.

References

  1. http://cannabisscienceblog.com/2017/06/15/69/ accessed September 25, 017
  2. https://www.businessreport.com/article/lsu-finalizes-medical-marijuana-agreement-gb-sciences/ accessed September 25, 2017
  3. http://learn.uvm.edu/com/program/cannabis-science-and-medicine/ accessed September 25, 2017
  4. http://moritzlaw.osu.edu/academics/course-explorer/category/criminal-law/ accessed September 25, 207
  5. http://adai.uw.edu/mcacp/ accessed September 25, 2017
  6. http://www.ucdmc.ucdavis.edu/physiology/ accessed September 25, 2017
  7. http://dailybruin.com/2017/05/23/editorial-ucla-must-build-marijuana-research-center-study-effects-of-legalization/ accessed September 25, 2017

Cannabis Pharmacokinetics, Metabolism and Detection

THC (Δ-9-tetrahydrocannabinol) is the main psychoactive cannabinoid found in cannabis and the primary molecule used for detection among cannabis users. Therefore, it is important to understand THC’s pharmacokinetics (distribution in the body), its metabolism (how it is broken down by the body) and the basis of the laboratory tests used for its detection.

The primary routes of administration of cannabis include smoking/vaporization and ingestion. Not surprisingly, the route of administration affects the absorption characteristics of THC. When cannabis is smoked or vaporized, there is a rapid onset of action (within minutes) with absorption of roughly 10%-35% of available THC in the product (1). THC is mainly absorbed through the bloodstream (2).

Peak THC plasma concentrations (blood levels) occur within 8 minutes after smoking or vaporization (1). In contrast, onset of action following ingestion occurs within 1-3 hours with 5%-20% absorption of THC (1). Peak plasma levels are observed after 2-6 hours after ingestion (1).

THC is primarily metabolized via the liver cytochrome P450 (CYP) system into a psychoactive compound, 11-hydroxy-THC (11-OH-THC) (2). 11-OH-THC is further metabolized into several inactive forms with 11-nor-9-carboxy-▵ 9-tetrahydrocannabinol (THC-COOH) as the dominant inactive metabolite (2). Because THC is highly lipophilic (fat-loving) it is mainly distributed in adipose (fat) tissue, liver, lung and spleen (1, 2).

THC’s elimination half-life —50% elimination of the initial absorbed dose of THC—can range from 2-57 hours following inhalation. The half-life of 11-OH-THC (the active metabolite of THC) is 12-36 hours (1, 2). Twenty (20) percent of THC is excreted in the urine whereas up to 65% is eliminated in feces (2). Within 5 days, nearly 90% of THC is eliminated from the body (2).

Urine immunoassays are typically used to detect THC-COOH in persons being tested for cannabis consumption. After a single use, THC can be detected in the urine for up to 7 days. With chronic cannabis consumption, THC can be detected in urine for 10-30 days. A sensitive test called enzyme-multiplied immunoassay technique (EMIT) can detect urine levels as low as 20-100 ng/ml.

Results from these screening tests indicate prior cannabis exposure but they cannot determine the amount used or degree of clinical effects after use. At present, detection of 50 ng/mL is considered positive for employees undergoing drug testing.  False-positive results can occur with ibuprofen, naproxen, dronabinol, efavirenz, and hemp seed oil. False-positive test results are unlikely from second-hand smoke inhalation, unless this exposure occurs in an unventilated space (1).

Blood tests can also be used to detect THC; however, detected levels cannot be associated with clinical effects. Hair sampling tests that use gas chromatography and mass spectrometry assays are available for cannabis screening. These screening methods can be used to test for multiple cannabinoids, including THC, THC-OH, THC-COOH, CBN and CBD (3). Cannabinoids enter the hair through capillaries and sweat and can be detected up to 3 months after exposure (3, 4). However, detection depends on heaviness of use and potency of marijuana consumed (4). 

References

  1. Russo L, Caneva D Cannabinoid poisoning. http://emedicine.medscape.com/article/833828-overview#a5  Accessed Aug. 9, 2017
  2. Sharma P, Murthy P, Srinivas Bharath MM Chemistry metabolism and toxicology of cannabis: clinical implications Iran J. Psychiatry 2012; 7:149-156
  3. Huestis MA, Mitchell JM Cone EJ Detection times of marijuana metabolites in urine by immunoassay and GC-MS J Anal Toxicol 1995; 19:443-449.
  4. Taylor M, Henderson R, Lingford-Hughes A, Macleod J, Sullivan J, Hickman M Comparison of cannabinoids in hair with self-reported cannabis consumption in heavy, light and non-cannabis users. Drug Alcohol Rev. 2017; 36-220-226.

Anticancer Properties of Cannabis and Cannabinoids

The anticancer effects of cannabis and individual cannabinoids are thought to be mediated via interaction of these compounds with their cognate receptors; cannabinoid receptor 1 (CB1) and CB2). CB1 receptors are widely distributed in the central nervous system (CNS) and brain whereas CB2 receptors are mainly found in the immune system with much lower and more restricted distribution in CNS (1,2)

Early in vitro studies using tumor cell lines and tumor xenograft mouse models suggest that cannabinoids can inhibit solid tumors and hematologic malignancies including  gliomas (brain tumors), adenocarcinomas of the lung, breast, colon, pancreas and melanoma and also myeloma and lymphoma (3-5).

Although not completely elucidated, the mechanism of action of cannabinoids as anticancer agents has been attributed to induction of programmed cell death or apoptosis (via interaction with CB1 receptors), inhibition of angiogenesis or blood vessel growth (reduction in the expression of endothelial growth factor and its receptors) and a decrease in the activity of matrix metalloproteinase 2 which can lead to decreased tumor cell invasiveness and metastasis (6-8).  In addition, cannabinoids possess potent anti-inflammatory and antioxidant properties that can also help to combat cancer (9). Finally, cannabinoids administered in combinations with conventional chemotherapy agents or radiation treatment have been observed to enhance antitumor activity (10-12).

While these preliminary findings are encouraging, much more basic research must be performed to identify the actual anticancer/anti-tumor action of cannabinoids and the individual cancer indications that would benefit most from their use. Once these things are established, large scale controlled human clinical trials will be necessary for regulatory approval of these agents as cancer treatments.

References

  1. Howlett AC. The cannabinoid receptors. Prostaglandins Other Lipid Mediat 2002; 68-69: 619–31
  2. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N,Makriyannis A, Piomelli D, Davison JS,Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 2005; 310: 329–32
  3. Velasco G, Galve-Roperh I, Sanchez C, Blazquez C, Guzman M. Hypothesis: cannabinoid therapy for the treatment of gliomas? Neuropharmacology 2004; 47:315–23.
  4. Velasco G, Sánchez C, Guzmán M. Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 2012; 12:436–44.
  5. McAllister SD, Soroceanu L, Desprez PY. The antitumour activity of plant-derived non-psychoactive cannabinoids. J Neuroimmune Pharmacol 2015; 10:255–67.
  6. Massi P, Solinas M, Cinquina V, Parolaro D. Cannabidiol as potential anti cancer drug. Br J Clin Pharmacol 2013; 75:303–12.
  7. Chakravarti B, Ravi J, Ganju RK. Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget 2014; 5:5852–72.
  8. Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol Ther 2015; 97:575–86.
  9. Abrams, DJ. Integrating cannabis into clinical cancer care. Curr Oncol. 2016; 23:S8-S14.
  10. Donadelli M, Dando I, Zaniboni T, et al. Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ros-mediated mechanism. Cell Death Dis 2011;2:e152.
  11. Torres S, Lorente M, Rodriguez-Fornes F, et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 2011;10:90–103.
  12. Scott KA, Daigleish AG, Liu WM. The combination of cannabidiol and Δ9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol Cancer Ther 2014;13:2955–67.

Treating Patients: Integrating Cannabis into Clinical Cancer Care

There is a growing body of evidence that cannabis and certain cannabinoids may offer potential therapeutic benefits to cancer patients (1). Mainly, cannabis may be beneficial in the management of a wide range of cancer-related symptoms including neuropathic pain (2-4) chemotherapy induced nausea and vomiting (CINV; 5-9), anorexia (10), insomnia (11) and depression (12,13).

Unfortunately, most oncologists trained during the era of cannabis prohibition (1930s to present) have no knowledge of how to use cannabis and its products in routine medicine practice or clinical care.  More problematic is the lack of research and clinical data on which oncologist can base treatment decisions or make care recommendations. That said, what must be done before oncologists and cancer care professionals can feel comfortable using cannabis in cancer care and treatment?

First, rigorous basic research must be performed to clearly demonstrate that cannabis and cannabinoids indeed possess anticancer/antitumor properties. This will require a clear understanding of the mechanism of action of these compounds and the identification of the receptors/transcriptional factors etc that mediate their anticancer effects.

Second, once preclinical data are confirmed, rigorous double-blind, placebo controlled human clinical trials (with sufficient numbers of participants) must be performed to confirm or refute the effects of cannabis/cannabinoids on recognized and clearly defined  oncology indications  e.g., solid tumors, blood malignancies, etc.

Third, if cannabis and cannabinoids are to used for adjunctive cancer care and disease management purposes, than other large scale, well-designed clinical trials must be performed to demonstrate the safety and efficacy of these treatments.  Anecdotal evidence and results from small clinical studies are not sufficient for regulatory approval nor widespread acceptance of the use of cannabis and cannabinoids for cancer/chemotherapy symptom management.

Finally, for all of this to happen, cannabis and its products must be rescheduled from a Schedule 1 drug (illegal with no recognized therapeutic value) to either a Schedule 2 or Schedule 3 classification.  This would effectively decriminalize cannabis at the national level and allow federal funds and resources to be leveraged for basic research and clinical testing of cannabis and its products.

If all of these things should come to pass, then oncologists may be able to add cannabis and cannabinoids to treat and care for patients living with cancer.

References

  1. Abrams, DJ. Integrating cannabis into clinical cancer care. Curr Oncol. 2016; 23:S8-S14
  2. Deshpande A, Mailis-Gagnon A, Zoheiry N, Lakha SF. Efficacy and adverse effects of medical marijuana for chronic noncancer pain: systematic review or randomized controlled trials. Can Fam Physician 2015; 61:e372–81
  3. Andreae MH, Carter GM, Shaparin N, et al. Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data. J Pain 2015; 16:1221–32.
  4. Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain 2015; 16:616–27.
  5. Chang AE, Shiling DJ, Stillman RC, et al. Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomized evaluation. Ann Intern Med 1979; 91:819–24
  6. Duran M, Perez E, Abanades S, et al. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol 2010; 70:656–63
  7. 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 2001; 323:16–21.
  8. Machado Rocha FC, Stefano SC, De Cassia Haiek R, Rosa Oliveira LM, Da Silveira DX. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care (Engl) 2008; 17:431–43.
  9. Smith LA, Azariah F, Lavender VT, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev 2015; 11:CD009464.
  10. Strasser F, Luftner D, Possinger K, et al. on behalf of the Ca nnabis-In-Cachex ia-Study-Group. Compa rison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia–cachexia syndrome: a multicenter, phase iii, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol 2006; 24:3394–400.
  11. Russo, EB, Guy GW Robson PJ. Cannabis pain and sleep: lessons learned from therapeutic clinical trials of Sativex®, a cannabis-based medicine. Chemistry and Biochemistry 2007; 4:1729-1743
  12. de Mello Schier AR, de Oliveira Ribeiro NP, Countinho DS, et al. Antidepressant-like and anxiolytic-like effects of cannabidiol: a chemical compounds of Cannabis sativa. CNS Neruol Disord Drug Targets 2014; 13:953-960
  13. Bricker JB, Russo J, Stein MB, Sherbourne C, Craske M, Schraufnagel TJ, Roy-Byrne P Does occasional cannabis sue impact anxiety and depression treatment outcome?  Results from a randomized effectiveness trial. Depress Anxiety 2007; 24:392-398

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

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

A Cannabis Factoid

According to a 2016 article in Wired Magazine, in 1993, the average THC content in commercially available cannabis was roughly 3 percent by weight. By 2008, through traditional breeding programs, the THC content (potency) had nearly  tripled.  In 2017, analyses suggested that the world wide THC content of some strains of cannabis may be 12-16 percent or as high as 37 percent by weight (1-5). Recent genetic analysis suggest that this increase may be a  result of gene amplification with high THC-producing plants having multiple copies of THC biosynthetic genes.

Many cannabis  industry experts contend that the exponential increases in THC levels  can be directly attributed to the so-called “war on drugs” that forced illegal growers to abandon outdoor cultivation in favor of indoor growing operations. Unlike outdoor growing operations, indoor cultivation permits more controlled growing environments, less need for pesticides  and a reduced likelihood of theft of mature plants.  However, as the concentration of THC increased, so did prevailing market prices of cannabis. These price increases helped growers to absorb the higher cost  of indoor climate control and artificial lighting without cutting into profit margins. Ironically, however, the legal use of cannabis for medical and recreational use in many US States, has allowed growers to move their illicit indoor growing operations into legal, full scale greenhouse cultivation.  This, in turn, is currently causing the the price of cannabis to plunge in many states.

While THC concentration are at all time highs (pun intended), less attention has been paid to genetic manipulation of cannabis plants for medicinal use that contain high levels of cannabinoids other than THC. This area represents the next era of genetic manipulation of the Cannabis genome.

Stay tuned…..

References

  1. Radwan MM, Elsohly MA, Slade D, Radwan MM et al. Cannabinoid ester constituents from high-potency Cannabis sativa Phytochemistry 2008 69:2627-26-33
  2. Niesink RJ, Rigter S, Koeter NW, Brunt TM, Potency trends of delta=(9)-tetrahydrocannabinol, cannabidiol and cannbinol in cannabis in the Netherlands 2005-2015. Addiction 2015; Aug1 [Epub ahead of print]
  3. Swift W, Wong A, Li KM, Arnold JC, McGregor I Analysis of cannabis seizures in NSW Australia: cannabis potency and cannabinoid profile. PLoS one 2013; 8: e70052
  4. Zamengo L, Frison G, Bettin C, Sciarrone R, Variability of cannabis potency  in the Venice area (Italy): a survey over the period 2010-2012. Drug Test Anal 2014:6:46-51
  5. Bruci Z, Papoutsis I, Athanaselis S, Nikolaou P, et al. First systematic evaluation of the potency of Cannabis sativa plants grown in Albania Forensic Sci In 2012; 222:40-46.

 

 

 

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