MEDICAL USE OF CANNABIS with a focus on

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

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

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

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.

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. 80 -100 other cannabinoids!

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)

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.

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

That came from • Cannabis seeds

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

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%

FDA-Regulated Cannabinod-Based Medicines: Chemicals, Extracts, Botanicals Photo from pharmer. org Photo from epocrates. com Dronabinol (Marinol™) Photo from nida. org Nabilone (Cesamet™) Cannabis Sativa L. Extracts (Sativex™) Photo from Russo et al. 2002 Cannabis Sativa L. Cigarettes Photo from Russo et al. 2002 Photo from wikipedia. org 1985 2006 Approximately 460 chemical constituents, >100 phytocannabinoids 1976

SF General Hospital Inpatient Clinical Trials Ward—Smoked Cannabis in HIV Neuropathy, Pilot Study

A different kind of pharmacy

CANNABIS AT A PHARMACY IN THE NETHERLANDS

Meanwhile, back at the warehouse

AN INDUSTRIAL GROW HOUSE – NOTE UNIFORMITY OF PLANTS

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

Cannabis Tincture, circa 1910, Parke Davis

Cannabis for neuropathic pain…in 1906

Cannabis for Neuralgia 1925

And then along came Harry…

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 Mc. Carthy 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 •

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…

• REEFER MADNESS

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 1972 • 2) the U. S. Institute of Medicine in 1982 • 3) the Australian National Task Force on Cannabis in 1994 • 4) 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

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.

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. • 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).

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

Cannabinoid Receptors

AEA also an endovanalloid at TRPV 1 (with 5 -20 -fold lower affinity cf with CB 1); also PPARy Key ECS Elements

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

Difference Between Classical and Retrograde Neurotransmission

Physiological Effects of Endocannabinoids

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, populationbased case-control studies

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 coadministered opioids – Opioid dose reductions

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

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: L 5 – 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 2009. 7: 4, 713 -737.

Cannabinoid Suppression of Neuropathic Pain – Basic Science • In CCI of infraorbital nerve model, CB 1 receptor upregulation was observed in both the ipsalateral and contralateral superficial layer of the trigeminal caudal nucleus (I>C) • CB 2 receptor immunoreactivity is increased in the ipsilateral dorsal horn after L 5 spinal nerve transection • Saphenous partial nerve ligation increased u-opioid, CB 1, and CB 2 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 CB 1 receptor m. RNA in the contralateral thalamus, 1 day post-surgery • SCI model—mechanical 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 2009. 7: 4, 713 -737.

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 CB 1 receptor - like the • opioids are found in areas of the brain that • modulate nocioceptive processing • CB 1 and CB 2 agonists have peripheral analgesic actions • CBs may also exert anti-inflammatory effects • Analgesic effects not blocked by opioid antagonists

Results: Neurology RCT Abrams et al Neurology 2007

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 HIVassociated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68(7): 515 -21. • 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): 672 -80. • 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.

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. PLo. S One 2010; 28; 5(12): e 14433. • 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): 1353 -68. • Campbell FA, Tramèr MR, Carroll D, Reynolds DJ, Moore RA, Mc. Quay HJ. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 2001; 323(7303): 13 -6.

Cochrane reviews • Smith PF. The safety of cannabinoids for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2005 May; 4(3): 443 -56. • Mills RJ, Yap L, Young CA. Treatment for ataxia in multiple sclerosis. Cochrane Database Syst Rev 2007; Jan 24; (1): CD 005029. • 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): 431 -43.

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

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

Vaporization of cannabis – safe alternative to smoking • examples

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.

– Serum levels after inhalation Blood levels THC Administration 17. 2

Absorption – slow absorption with oral THC Administration Blood levels Rated “high” 17. 4 17. 2

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

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

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

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.

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)

Blurred vision? Performance decrement (s) Psychomotor performance-dose dependent decline 17. 5

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

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

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

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

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 –

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)

Metz, L. , and S. Page. 2003. 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. ”

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. 7 mg of THC and 2. 5 mg of CBD, the minor components, plus ethanol: propylene glycol excipients, and 0. 05% peppermint as flavouring. • Intermediate onset: 15 -40 minutes • Allows dose titration • Reduces first pass metabolism • Acceptable to patients

Primary Endpoint Mean change in Spasticity Score from Baseline (ITT) p=0. 048* Collin C, Davies P, Mutiboko IK, Ratcliffe S. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol. 2007. 14(3): 290 -6. *Anova

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

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.

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 antiinflammatory 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 G 93 A-SOD 1 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): 347 -56.

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

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

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

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

How to prescribe medical cannabis

Primum Non Nocere:

Thanks… • Q&A • Contact info: gtcarter@uw. edu