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MEDICAL USE OF CANNABIS– with a focus on Neuromuscular Disorders Gregory T. Carter, MD, MS Medical Director Muscular Dystrophy Association Regional Neuromuscular.

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Presentation on theme: "MEDICAL USE OF CANNABIS– with a focus on Neuromuscular Disorders Gregory T. Carter, MD, MS Medical Director Muscular Dystrophy Association Regional Neuromuscular."— Presentation transcript:

1 MEDICAL USE OF CANNABIS– with a focus on Neuromuscular Disorders Gregory T. Carter, MD, MS Medical Director Muscular Dystrophy Association Regional Neuromuscular Center Olympia, WA

2 Overview of Lecture the colorful history of cannabis in America: Politics, Paranoia, and Harry Anslinger Pharmacology Clinical Applications Research – from bench to bedside

3 Cannabis cannabis is one of the oldest known psychoactive plants First reported use as medicine > 5000 years ago Introduced into Western medicine in 1840s by Dr. W.B. OShaughnessy One of earliest non-food plants cultivated –fiber for rope, seeds for oil and birdseed –mixture of leaves, stems, tops –1960s: 1-3% THC; 1990s: up to 8-10%

4 The chemical makeup of cannabis The active ingredients in cannabis are cannabinoids, a group of terpenophenolic compounds The cannabinoids are concentrated in a viscous resin that is produced in glandular structures known as trichomes, these are the tiny, sticky hair like formations you see at the end of buds.

5 Some of the more prominent cannabinoids include: Delta-9-tetrahydrocannabinol (THC) Cannabidiol (CBD) Cannabinol (CBN) Tetrahydrocannabivarin (THCV) Cannabichromene (CBC) Cannabicyclol (CBL) Yet still another est other cannabinoids!

6 Cannabis – medical uses Has been used medicinally, spiritually, and recreationally for thousands of years Promoted for putative analgesic, sedative, antiinflammatory, antispasmodic and anticonvulsant properties Glaucoma (decreases intraocular pressure) Antiemetic (reduce nausea and vomiting) Enhance appetite (e.g., AIDS patients)

7 History of Cannabis Chinese cultures were growing marijuana more than 3000 years ago. there are 3,000-year-old Egyptian mummies that containing cannabis traces The first written account of cannabis cultivation (ostensibly used as medical marijuana) is found in Chinese records dating from 28 B.C.

8 Examples of Flowers from Different Clones Bubble Gum Big Bud Dutch Northern Lights

9 That came from Cannabis seeds

10 Preparing the flowers to use Wet flowers on a scale (L) Dried flowers ready to use (R)

11 Hashish –dried resin from top of female plant –THC usually 2-5%, but up to 15% Hash Oil –organic extraction from hashish –THC usually ~ 10-20% up to 70%

12 Photo from Dronabinol (Marinol) Photo from FDA-Regulated Cannabinod-Based Medicines: Chemicals, Extracts, Botanicals Nabilone (Cesamet ) Cannabis Sativa L. Extracts (Sativex) Cannabis Sativa L. Cigarettes Photo from Photo from Photo from Russo et al Approximately 460 chemical constituents, >100 phytocannabinoids 1976

13 SF General Hospital Inpatient Clinical Trials WardSmoked Cannabis in HIV Neuropathy, Pilot Study

14 A different kind of pharmacy


16 Meanwhile, back at the warehouse


18 Here in the United States, circa 1900… many cannabis based medications were produced by Eli-Lilly, Parke Davis, and Sharp Dohme (now Merck Sharp Dohme). Tinctures Pills Liniments

19 Cannabis Tincture, circa 1910, Parke Davis

20 Cannabis for neuropathic pain…in 1906

21 Cannabis for Neuralgia 1925

22 And then along came Harry…

23 Harry Anslinger Had NO formal medical training Our first drug czar Despite being anti-drug, he authorized a pharmacist near the White House to supply morphine for addicted Senator Joseph McCarthy during the communist crusades. Openly prosecuted doctors for over-prescribing, sending some to prison Single-handedly created Reefer Madness Anslinger was privately funded by William Randolph Hearst who wanted to eliminate hemp as an industrial competitor This also allowed Anslinger, an avowed racists, to rid the southwest of Hispanics

24 Thanks to one man… cannabis was criminalized in the United States by 1942 against the advice of the AMA And just for entertainment value, we had…


26 The laws started to change… Every government-appointed commission investigating marijuana's medical potential has issued favorable findings. This include 1) The Nixon appointed Shafer Commission in ) the U.S. Institute of Medicine in ) the Australian National Task Force on Cannabis in ) the U.S. National Institutes of Health Workshop on Medical Marijuana in 1997 Institute of Medicine affirmed: "Scientific data indicate the potential therapeutic value of cannabinoid drugs... for pain relief, control of nausea and vomiting, and appetite stimulation.... Except for the harms associated with smoking, the adverse effects of marijuana use are within the range tolerated for other medications. Predictably, federal authorities ignored the IOM's recommendations

27 More history the Drug Enforcement Agency (DEA) did finally held public hearings on the issue before an administrative law judge. Two years later, Judge Francis Young ruled that "Marijuana has been accepted as capable of relieving distress of great numbers of very ill people, and doing so with safety under medical supervision. It would be unreasonable, arbitrary and capricious for DEA to continue to stand between those sufferers and the benefits of this substance in light of the evidence in this record." Young recommended, "The Administrator transfer marijuana from Schedule I to Schedule II, to make it available as a legal medicine." DEA Administrator John Lawn rejected Young's determination, effectively continuing the federal ban on the medical use of marijuana by patients.

28 Fifteen states and counting Since 1996, voters in fifteen states -- Alaska, Arizona, California, Colorado, Hawaii, Maine, Michigan, Montana, Nevada, New Jersey, New Mexico, Oregon, Rhode Island, Vermont and Washington -- and the District of Columbia have adopted initiatives exempting patients who use marijuana under a physician's supervision from state criminal penalties.Alaska ArizonaCaliforniaColoradoHawaiiMaine MichiganMontanaNevadaNew JerseyNew MexicoOregonRhode IslandVermont WashingtonDistrict of Columbia Yet states may not authorize medical marijuana clinical trials without federal approval. All medical marijuana research must meet NIDA approval and receive funding from the National Institutes of Health (NIH).

29 CLINICAL PHARMACOLOGY OF CANNABIS 95-99% plasma protein bound hydroxylation, oxidation, and conjugation for rapidly clearance from plasma First-pass metabolism with oral admin. (11-OH-THC) Elimination over several days (adipose) Breast milk distribution Pregnancy Category C Excretion: days to weeks 20-35% found in urine 65-80% found in feces 5% as unchanged drug (when given PO) Works via RECEPTOR BASED MECHANISMS

30 Cannabinoid Receptors

31 Key ECS Elements AEA also an endovanalloid at TRPV1 (with 5-20-fold lower affinity cf with CB1); also PPARy

32 The CB 1 Receptor Activation negatively coupled to adenylate cyclase, suppresses neuronal Ca 2+ conductance, inhibits inward rectifying K + conductance suppression of neuronal excitability

33 Difference Between Classical and Retrograde Neurotransmission

34 Physiological Effects of Endocannabinoids

35 Common Misconceptions No evidence-based studies demonstrating that chronic cannabis use can cause or exacerbate schizophrenia Smoking cannabis is not associated with an increased risk of developing COPD or lung Ca –In fact, protective effects of cannabis smoking seen in two large retrospective, population- based case-control studies

36 Clinically Useful Drug Interactions When THC co-administered with CBD, as can occur with the usage of some strains of herbal cannabinoid medicines and certain cannabinoid-based extractions –anxiogenic, dysphoric, and possibly short-term memory interrupting effects of THC are mitigated Evidence suggests cannabinoid drugs can enhance the analgesic activity of co- administered opioids –Opioid dose reductions

37 Neuropathic Pain 3-8% prevalence in industrialized countries Due to direct damage to or abnormal functioning of the nervous system 2/2 infections, diabetes, trauma, stroke, etc. Often refractory to existing treatments Currently available treatments: gabapentin and other anticonvulsants, NMDA receptor antagonists – limited by their SE NP medicine market forecast: expected to double to $5.2 bil by 2018

38 Cannabinoid Suppression of Neuropathic Pain – Basic Science Cannabinoids have been shown to suppress neuropathic nociception in at least 9 different animal models of surgically-induced traumatic nerve or nervous system injury 1 –Chronic constriction injury: infraorbital nerve, saphenous nerve –Partial nerve ligation: sciatic, saphenous –Spinal nerve ligation: L5 –Spared nerve injury –Spinal cord injury –Tibial nerve injury –Streptozotocin-induced diabetic neuropathy 1 Rahn EJ and Hohmann AG. Cananbinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside. Neurotherapeutics :4,

39 Cannabinoid Suppression of Neuropathic Pain – Basic Science In CCI of infraorbital nerve model, CB1 receptor upregulation was observed in both the ipsalateral and contralateral superficial layer of the trigeminal caudal nucleus (I>C) CB2 receptor immunoreactivity is increased in the ipsilateral dorsal horn after L5 spinal nerve transection Saphenous partial nerve ligation increased u-opioid, CB1, and CB2 receptor protein levels in ipsalateral/contralateral hind paw skin, DRG, and ipsalatera/contralateral L-cord (1-7 days post-surgery) Tibial nerve injury upregulation of CB1 receptor mRNA in the contralateral thalamus, 1 day post-surgery SCI modelmechanical allodynia was reduced with chronic administration of WIN (mixed CB agonist) with no decrease in effectiveness, unlike morphine 1 Rahn EJ and Hohmann AG. Cananbinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside. Neurotherapeutics :4,

40 Cannabinoid Suppression of Pain Analgesia: different mechanism than opiates, some synergy though. Spasticity: likely GABA mediated Appetite enhancement: hippocampal? Anti-emetic: cerebellar? Elevated levels of the CB1 receptor - like the opioids are found in areas of the brain that modulate nocioceptive processing CB1 and CB2 agonists have peripheral analgesic actions CBs may also exert anti-inflammatory effects Analgesic effects not blocked by opioid antagonists

41 Results: Neurology RCT Abrams et al Neurology 2007

42 EBM One Clinical trials Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL. Cannabis in painful HIV- associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68(7): Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, Bentley H, Atkinson JH. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009;34(3): Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65(6):812-9.

43 Cochrane reviews Phillips TJ, Cherry CL, Cox S, Marshall SJ, Rice AS. Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta- analysis of randomised controlled trials. PLoS One 2010; 28;5(12):e Martín-Sánchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med 2009; 10(8): Campbell FA, Tramèr MR, Carroll D, Reynolds DJ, Moore RA, McQuay HJ. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 2001; 323(7303):13-6.

44 Cochrane reviews Smith PF. The safety of cannabinoids for the treatment of multiple sclerosis. Expert Opin Drug Saf May;4(3): Mills RJ, Yap L, Young CA. Treatment for ataxia in multiple sclerosis. Cochrane Database Syst Rev 2007; Jan 24;(1):CD Machado Rocha FC, Stéfano SC, De Cássia 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 2008;17(5):

45 Other Neuropathic Indications spasticity and pain associated with multiple sclerosis, amyotrophic lateral sclerosis, or spinal cord injury; physical or verbal tics caused by Tourette's syndrome. Refractory seizure disorder Nerve pain, nausea and loss of appetite resulting from chemotherapy, radiotherapy or HIV combination therapy

46 So how does this all work in clinic? Methods of Use Pros and Cons of inhalation versus ingestion How to educate patients in usage and dosage

47 Vaporization of cannabis – safe alternative to smoking examples

48 How do vaporizers work? When cannabinoids are heated to between 285 °F (140 °C) and 392 °F (200 °C) they literally boil and vaporize. Studies show that vaporization is most effective at around 338 °F (170 °C) a vaporization temperature over 392 °F (200 °C) will burn the cannabis, creating unwanted smoke.

49 –Serum levels after inhalation Blood levels 17.2 THC Administration

50 Absorption –slow absorption with oral Blood levels 17.2 THC Administration Rated high 17.4

51 rapid initial drop due to redistribution to fats slower metabolism in liver metabolites may persist for a week 9-THC (11-OH- 9-THC) is more potent than 9-THC Primary metabolic product of 9-THC (11-OH- 9-THC) is more potent than 9-THC Delay between peak plasma levels and peak effect

52 With so many choices…how do I pick the RIGHT medicine?? Sativa? Indica? Genetic clones? Hashish? Oils?

53 And how do I use it? Vaporize? Ingestion? Transdermal?

54 Start by understanding the differential effects of major cannabinoids Cannabis strains with high levels of both THC and CBD will create a strong energetic high. This is typical of Cannabis Sativa (or Sativex!!) low levels of THC and high levels of CBD will be more of a body, sleepy feeling. This is typical of Cannabis Indica Tetrahydrocannabivarin (THCV) is found primarily in strains from African and Asian cannabis. THCV intensifies THC effects Cannabis with a potent smell (aka skunk) indicates a high level of THCV. Some cannabinoids, including Cannabichromene (CBC) and Cannabicyclol (CBL) are not psychoactive but may enhance the effects of THC.

55 KNOW THE SIDE EFFECTS –disinhibition, relaxation, drowsiness –feeling of well being, exhileration, euphoria –sensory - perceptual changes –recent memory impairment –balance/stability impaired –decreased muscle strength, small tremor –poor on complex motor tasks (e.g., driving)

56 Blurred vision? Psychomotor performance-dose dependent decline Performance decrement (s) 17.5

57 Effects on behavior –pseudohallucinations –synesthesias –impaired judgement, reaction time –pronounced motor impairment –increasingly disorganized thoughts, confusion, paranoia, agitation Not lethal even at very high doses

58 DOSING: Start LOW and go SLOW Adverse effects: mainly seen in new users Euphoria versus paranoia Short term memory impairment Balance, incoordination These are reversible, short lived effects (3-4 hours max) Serious adverse effects NOT seen in chronic users

59 Components of pain that may respond to cannabis Cramping (anti-spasticity) Neuropathic: allodynia, hyperpathia Mechanical: Dull, aching (anti- inflammatory)

60 Pros/Cons/Risks/Benefits Good analgesia High dosing ceiling vs minimal toxicity Risk for psychological addiction not an issue Minimal physical dependence Not many drug-drug interactions

61 Pros/Cons/Risks/Benefits Some tolerance may develop in heavy, long term users may need higher doses Patient/family will have to purchase or grow it Dronabinol is NOT as effective –

62 Dronabinol (Marinol) Dronabinol is 100% THC, the most psychoactive ingredient in cannabis. Natural cannabis is 20% THC or less The physiological effect of THC is modulated when the other cannabinoid forms are present. Dronabinol is associated with too many psychoactive effects. DEA classifies dronabinol as schedule III FDA approved dronabinol for treatment of nausea and vomiting associated with chemotherapy and anorexia associated with weight loss in patients with HIV/AIDS Dronabinol is not an appropriate substitute for natural cannabis. Dronabinol is very expensive Sativex is much better but not available in US (50% THC, 50% cannabadiol in a sublingual spray)

63 Metz, L., and S. Page Oral cannabinoids for spasticity in multiple sclerosis: will attitude continue to limit use? Lancet 362 (9395):1513. We now have as much evidence to support the use of the oral cannabinoids for spasticity in ambulatory people with multiple sclerosis as we do for many standard therapies for spasticity, including baclofen.

64 Sativex Oromucosal Extract 1:1 combination from two clonal cannabis cultivars yielding a high THC extract (Tetranabinex®) and a high CBD extract (Nabidiolex®). a botanical drug substance (BDS) of defined composition with controlled reproducibility batch to batch. THC and CBD comprise some 70% (w/w) of the total BDS, with minor cannabinoids (5 – 6%), terpenoids (6 – 7%, most GRAS), sterols (6%), triglycerides, alkanes, squalene, tocopherol, carotenoids and other minor components (also GRAS). each 100 μL pump-action spray provides 2.7mg of THC and 2.5mg of CBD, the minor components, plus ethanol: propylene glycol excipients, and 0.05% peppermint as flavouring. Intermediate onset: minutes Allows dose titration Reduces first pass metabolism Acceptable to patients

65 p=0.048* Primary Endpoint Mean change in Spasticity Score from Baseline (ITT) p=0.048* *Anova Collin C, Davies P, Mutiboko IK, Ratcliffe S. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol (3):290-6.

66 Sativex – better than marinol BUT… Sativex produced a statistically significant improvement in spasticity –Improvement gained over and above concomitant anti-spasticity medication –Improvements gained without decrease in muscle strength Sativex was well tolerated –Few withdrawals due to adverse events Extension data – sustained and continuing improvement in spasticity – Patients did not develop tolerance to Sativex over 28 weeks

67 Conclusions of National Clinical Advisory Board of the National Multiple Sclerosis Society Key recommendations for research priorities include: Better study outcome measures need to be developed. A consensus is needed on standards for trial design to test the efficacy of cannabinoids for symptomatic management. Because inhaled smoked cannabis has more favorable pharmacokinetics than administrationvia oral or other routes, research should focus on the development of an inhaled mode of administration that gives results as close to smoked cannabis as possible. Longer-term side effect data need to be obtained. There are sufficient data available to suggest that cannabinoids may have neuroprotective effects that studies in this area should be aggressively pursued.

68 Cannabis and amyotrophic lateral sclerosis Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally acting anti- inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-alpha] inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent would be required to comprehensively address the known pathophysiology of ALS. Remarkably, cannabis appears to have activity in all of those areas. Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. In the G93A-SOD1 ALS mouse, this has translated to prolonged neuronal cell survival, delayed onset, and slower progression of the disease. Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. With respect to the treatment of ALS, from both a disease modifying and symptom management viewpoint, clinical trials with cannabis are the next logical step. Based on the currently available scientific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease. Carter GT, Abood ME, Aggarwal SK, Weiss MD. Cannabis and amyotrophic lateral sclerosis: hypothetical and practical applications, and a call for clinical trials. Am J Hosp Palliat Care 2010;27(5):

69 Conclusions/Comments Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. Cannabis is also useful in management of pain, particularly neuropathic pain, spasticity, seizures, tics, siallorhea, bronchospasm,cachexia and wasting, and insomnia. Based on available scientific data,cannabis may slow progression of ALS and other neurodenerative disorders Vaporization is a safe, effective alternative to smoking Cannabis is remarkably safe, few drug interactions

70 Comments Sativex is better than Marinol but not as good as natural cannabis Cannabis plant is indiginous to North America, is relatively easy to grow, dry out, and use as medicine, following a tradition that has existed for thousands of years. This could be done for pennies Risk to society? Not much

71 What about the war on drugs? Five years after the Portugese government decriminalized the use and possession of heroin, cocaine, marijuana, LSD and other illicit street drugs, the number of deaths from street drug overdoses dropped almost 50% and the number of new HIV cases caused by using dirty needles to inject heroin, cocaine and other illegal substances plummeted from nearly 1,400 in 2000 to about 400 in 2006 Instead of going to prison, addicts go to treatment centers Under the Portuguese plan, penalties for people caught dealing and trafficking drugs are unchanged; dealers are still jailed and subjected to fines depending on the crime. No problem can be solved from the same level of consciousness that created it Albert Einstein

72 If you choose to recommend cannabis… FOLLOW THE LAW Counsel the patient and family Patient should use high quality cannabis to improve efficacy: high CBD, CBN, lower THC – do not need to be high to get pain relief Use a delivery route that maximizes benefits and minimizes side effects

73 How to prescribe medical cannabis

74 Primum Non Nocere:

75 Thanks… Q&A Contact info:

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