Presentation on theme: "MEDICAL USE OF CANNABIS– with a focus on Neuromuscular Disorders"— Presentation transcript:
1MEDICAL USE OF CANNABIS– with a focus on Neuromuscular Disorders Gregory T. Carter, MD, MS Medical DirectorMuscular Dystrophy Association Regional Neuromuscular Center Olympia, WA
2Overview of Lecturethe colorful history of cannabis in America: Politics, Paranoia, and Harry AnslingerPharmacologyClinical ApplicationsResearch – from bench to bedside
3Cannabis cannabis is one of the oldest known psychoactive plants First reported use as medicine > 5000 years agoIntroduced into Western medicine in 1840’s byDr. W.B. O’ShaughnessyOne of earliest non-food plants cultivatedfiber for rope, seeds for oil and birdseedmixture of leaves, stems, tops1960’s: 1-3% THC; 1990’s: up to 8-10%
4The 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.
5Some 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!
6Cannabis – medical uses Has been used medicinally, spiritually, and recreationally for thousands of yearsPromoted for putative analgesic, sedative, antiinflammatory,antispasmodic and anticonvulsant propertiesGlaucoma (decreases intraocular pressure)Antiemetic (reduce nausea and vomiting)Enhance appetite (e.g., AIDS patients)
7History of CannabisChinese cultures were growing marijuana more than 3000 years ago.there are 3,000-year-old Egyptian mummies that containing cannabis tracesThe first written account of cannabis cultivation (ostensibly used as medical marijuana) is found in Chinese records dating from 28 B.C.
8Examples of Flowers from Different Clones “Bubble Gum”“Big Bud”“Dutch Northern Lights”
10Preparing the flowers to use Wet flowers on a scale (L)Dried flowers ready to use (R)
11Hashish Hash Oil dried resin from top of female plant THC usually 2-5%, but up to 15%Hash Oilorganic extraction from hashishTHC usually ~ 10-20% up to 70%
12FDA-Regulated Cannabinod-Based Medicines: Chemicals, Extracts, BotanicalsPhoto from pharmer.orgPhoto from epocrates.comPhoto from Russo et al. 2002Photo from nida.orgDronabinol (Marinol™)Nabilone (Cesamet™)Cannabis Sativa L. Extracts (Sativex™)Cannabis Sativa L. CigarettesPhoto from Russo et al. 2002Approximately 460 chemical constituents, >100 phytocannabinoids1976Photo from wikipedia.org19851985200612
13SF General Hospital Inpatient Clinical Trials Ward—Smoked Cannabis in HIV Neuropathy, Pilot Study 13
23Harry 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 competitorThis also allowed Anslinger, an avowed racists, to rid the southwest of Hispanics
24Thanks to one man…cannabis was criminalized in the United States by 1942against the advice of the AMAAnd just for entertainment value, we had…
26The laws started to change… Every government-appointed commission investigating marijuana's medical potential has issued favorable findings.This include1) The Nixon appointed Shafer Commission in 19722) the U.S. Institute of Medicine in 19823) the Australian National Task Force on Cannabis in 19944) the U.S. National Institutes of Health Workshop on Medical Marijuana in 1997Institute 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
27More historythe 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.
28Fifteen 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).
29CLINICAL PHARMACOLOGY OF CANNABIS 95-99% plasma protein boundhydroxylation, oxidation, and conjugation for rapidly clearance from plasmaFirst-pass metabolism with oral admin. (11-OH-THC)Elimination over several days (adipose)Breast milk distributionPregnancy Category CExcretion: days to weeks 20-35% found in urine65-80% found in feces5% as unchanged drug (when given PO)Works via RECEPTOR BASED MECHANISMS
30Cannabinoid Receptors Cannabinoid receptors are G-protein–coupled receptors consisting of seven transmembrane-spanning domainsCB1 receptors are located in several areas of the brain and in a variety of tissues such as adipose tissue, liver, muscle, the GI tract, pancreas, and sensory neuronsCB2 receptors are located in immune cells and do not appear to play a role in energy balance or food intakeDevane WA et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:Munro S et al. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61-65.Ameri A. The effects of cannabinoids on the brain. Prog Neurobiol. 1999;58:Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:Cota D, Woods SC. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:30
31AEA also an endovanalloid at TRPV1 (with 5-20-fold lower affinity cf with CB1); also PPARy Key ECS ElementsKey ECS ElementsThe ECS consists of two G-protein–coupled receptors, CB1 and CB2, and the endogenously produced ligands that activate these receptorsCannabinoid receptors are found throughout the body and are normally bound by a family of endogenous lipids, the endocannabinoidsThe first cannabinoid receptor (CB1) was cloned in Both CB receptor types belong to the G-protein coupled–receptor superfamilyCB1 receptors are widely distributed in the central nervous system (CNS) including hippocampus, cerebellum, and basal gangliaMainly localized presynapticallyModulate the release of -aminobutyric acid, dopamine, noradrenaline, and glutamateAlso expressed in peripheral tissues including adipose tissue, lung, presynaptic sympathetic nerve terminals, vascular endothelial and smooth muscle cells, and hematopoetic cellsCB2 receptors, first cloned in 1993, are mainly expressed in the immune cellsAEA and 2-AG are the 2 best-studied endocannabinoids; they are lipid-derived agonists that bind to and activate CB1 and CB2 receptorsFelder CC, Glass M. Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol 1998;38:De Petrocellis L, Cascio MG, Di Marzo V. The endocannabinoid system: a general view and latest additions. Br J Pharmacol. 2004;141:Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74:Roche R, Hoareau L, Bes-Houtmann S, et al. Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutaneous adipocytes. Histochem Cell Biol. 2006;126:31
32The CB1 ReceptorActivation negatively coupled to adenylate cyclase, suppresses neuronal Ca2+ conductance, inhibits inward rectifying K+ conductance suppression of neuronal excitabilityThe CB1 ReceptorThe CB1 receptor is a member of the rhodopsin subfamily of G-protein–coupled receptors. It consists of 7 transmembrane helicesG-protein–coupled receptors are the largest family of cell-surface receptors; they consist of a single polypeptide chain that threads back and forth across the lipid bilayer seven timesThe issue of whether cannabinoid actions were mediated by receptors was resolved when functional inhibition of adenylyl cyclase was observed following the addition of Δ9-tetrahydrocannabinol to neuroblastoma cells. Treatment with pertussis toxin blocked this effect, indicating that cannabinoid action involved a Gi/o proteinDemuth DG, Molleman A. Cannabinoid signalling. Life Sci. 2006;78:Shim JY, Welsh WJ, Howlett AC. Homology model of the CB1 cannabinoid receptor: sites critical for nonclassical cannabinoid agonist interaction. Biopolymers. 2003;71:Howlett AC, Fleming RM. Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol. 1984;26:32
33Difference Between Classical and Retrograde Neurotransmission Classical Neurotransmitter (ie, acetylcholine)In a classical neurotransmitter system, for example, acetylcholine, an action potential invades presynaptically, thereby causing depolarization, which triggers the opening of calcium voltage-gated channelsCalcium ions flood in (they are at higher concentration in the extracellular solution) and interact with the synaptic vesicles, allowing for the release of stored neurotransmitter (exocytosis). Acetylcholine spills out into the synaptic cleft (exocytosis) and diffuses across the synaptic cleftThe neurotransmitter (acetylcholine) interacts with receptors at the postsynaptic membrane; these receptors tend to be ligand-gated channels, so they open when neurotransmitter bindsIons flow through the ligand-gated channels, causing a change in the postsynaptic membrane potential. This is the critical step that initiates the cascade of downstream physiologic effectsThe neurotransmitter is then degraded by the enzyme acetylcholinesterase Retrograde Neurotransmitter (ie, endocannabinoid)ECS paradigm: in contrast to the classical paradigm, endocannabinoids are not stored in vesicles. An action potential that triggers the opening of calcium channels activates the synthesis of endocannabinoids from membrane-bound lipid precursors. This takes place postsynapticallyEndocannabinoids are released and diffuse freely into the synaptic cleft. The transport mechanism is currently unknownEndocannabinoids then bind to and activate CB1 receptors located presynaptically. This reverse path is referred to as retrograde signaling. After binding to the CB1 receptors the G proteins are stimulated to relay the signals to regulate a number of cellular processesThe importance of this signaling paradigm is that the ECS is normally quiet until endocannabinoids are synthesized on demand, they are taken up back into cells rapidly, and degraded immediately. Thus, they act locally at the site of synthesisDi Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005;8:Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004;3:Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature. 2001;410:Vaughan CW, Christie MJ. Retrograde signalling by endocannabinoids. Handb Exp Pharmacol. 2005:33
34Physiological Effects of Endocannabinoids The ubiquitous expression of various components of the ECS, as well as its presence in lower-level organisms, indicates a vital role for this system in normal physiology. In general, the ECS—and the CB1 receptor in particular—is believed to regulate energy balance and behaviors such as food intake, fear, and anxiety, and to modulate lipid and glucose metabolismSince at least 300 AD, cannabis has been known to stimulate hunger and increase appetite, especially for sweet and palatable food. The ECS is postulated to connect the physical and emotional responses to stress with appetite and energy regulation. As such, it is hypothesized to function as a general stress-recovery system, which remains silent under normal physiologic conditions. Preclinical data using direct and indirect CB1 receptor agonists as well as CB1 receptor antagonists support an anxiolytic role for the ECSIt is postulated that the ECS becomes transiently activated in response to stressful stimuli to protect steady-state homeostatic activity of neuropeptides, hormones, and neurotransmitters. This hypothesis is supported by data showing that the ECS affects a wide variety of physiologic processes, including nociception (pain sense), motor control, memory and learning, appetite, food intake, and energy balance. After stressful stimuli, ECS activation promotes food ingestion, relaxation, pain reduction, and extinction of aversive memories. In this scenario, the ECS-induced drive to eat may be viewed as the need to replenish energy stores to recover from one of the physiologic consequences of stressOther functions of the ECS in normal physiology may be related to immune function, neuroprotection, fertility, and bone massCota D, Woods S. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12: ; De Petrocellis L, Cascio MG, Di Marzo V. The endocannabinoid system: a general view and latest additions. Br J Pharmacol. 2004;141: ; Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27:73-100; Ameri A. The effects of cannabinoids on the brain. Prog Neurobiol. 1999;58: ; Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112: ; Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005;8: ; Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89: ; Correa F, Mestre L, Molina-Holgado E, et al. The role of cannabinoid system on immune modulation: therapeutic implications on CNS inflammation. Mini Rev Med Chem. 2005;5: ; van der Stelt M, Trevisani M, Vellani V, et al. Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels. Embo J. 2005;24: ; Wang H, Dey SK, Maccarrone M. Jekyll and hyde: two faces of cannabinoid signaling in male and female fertility. Endocr Rev. 2006;27: ; Idris AI, van 't Hof RJ, Greig IR, et al. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med. 2005;11: ; de Oliveira Alvares L, Genro BP, Vaz Breda R, Pedroso MF, Da Costa JC, Quillfeldt JA. AM251, a selective antagonist of the CB1 receptor, inhibits the induction of long-term potentiation and induces retrograde amnesia in rats. Brain Res. 2006;1075:60-67; Arenos JD, Musty RE, Bucci DJ. Blockade of cannabinoid CB1 receptors alters contextual learning and memory. Eur J Pharmacol. 2006;539: ; Mikics E, Dombi T, Barsvari B, et al. The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice. Behav Pharmacol. 2006;17: ; Guindon J, De Lean A, Beaulieu P. Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain. Pain. 2006;121:85-93.34
35Common Misconceptions No evidence-based studies demonstrating that chronic cannabis use can cause or exacerbate schizophreniaSmoking cannabis is not associated with an increased risk of developing COPD or lung CaIn fact, protective effects of cannabis smoking seen in two large retrospective, population-based case-control studies
36Clinically 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 extractionsanxiogenic, dysphoric, and possibly short-term memory interrupting effects of THC are mitigatedEvidence suggests cannabinoid drugs can enhance the analgesic activity of co-administered opioidsOpioid dose reductions
37Neuropathic Pain 3-8% prevalence in industrialized countries Due to direct damage to or abnormal functioning of the nervous system2/2 infections, diabetes, trauma, stroke, etc.Often refractory to existing treatmentsCurrently available treatments: gabapentin and other anticonvulsants, NMDA receptor antagonists – limited by their SENP medicine market forecast: expected to double to $5.2 bil by 201837
38Cannabinoid 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 injury1Chronic constriction injury: infraorbital nerve, saphenous nervePartial nerve ligation: sciatic, saphenousSpinal nerve ligation: L5Spared nerve injurySpinal cord injuryTibial nerve injuryStreptozotocin-induced diabetic neuropathy1Rahn EJ and Hohmann AG. Cananbinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside. Neurotherapeutics :4,38
39Cannabinoid 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 transectionSaphenous 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-surgerySCI model—mechanical allodynia was reduced with chronic administration of WIN (mixed CB agonist) with no decrease in effectiveness, unlike morphine1Rahn EJ and Hohmann AG. Cananbinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside. Neurotherapeutics :4,39
40Cannabinoid Suppression of Pain Analgesia: different mechanism than opiates, some synergy though.Spasticity: likely GABA mediatedAppetite enhancement: hippocampal?Anti-emetic: cerebellar?Elevated levels of the CB1 receptor - like theopioids are found in areas of the brain thatmodulate nocioceptive processingCB1 and CB2 agonists have peripheral analgesic actionsCBs may also exert anti-inflammatory effectsAnalgesic effects not blocked by opioid antagonists
41Results: Neurology RCT Abrams et al Neurology 200741
42EBM 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.
43Cochrane reviewsPhillips 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):e14433.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.
44Cochrane reviewsSmith 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):CDMachado 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):
45Other 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 disorderNerve pain, nausea and loss of appetite resulting from chemotherapy, radiotherapy or HIV combination therapy
46So how does this all work in clinic? Methods of UsePros and Cons of inhalation versus ingestionHow to educate patients in usage and dosage
47Vaporization of cannabis – safe alternative to smoking examples
48How 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.
49Serum levels after inhalation THC AdministrationBlood levels17.2
51rapid initial drop due to redistribution to fats slower metabolism in livermetabolites may persist for a weekPrimary metabolic product of 9-THC (11-OH-9-THC) is more potent than 9-THCDelay between peak plasma levels and peak effect
52With so many choices…how do I pick the RIGHT medicine?? Sativa?Indica?Genetic clones?Hashish?Oils?
53And how do I use it?Vaporize?Ingestion?Transdermal?
54Start 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 IndicaTetrahydrocannabivarin (THCV) is found primarily in strains from African and Asian cannabis.THCV intensifies THC effectsCannabis 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.
55KNOW THE SIDE EFFECTS disinhibition, relaxation, drowsiness feeling of well being, exhileration, euphoriasensory - perceptual changesrecent memory impairmentbalance/stability impaireddecreased muscle strength, small tremorpoor on complex motor tasks (e.g., driving)
57Effects on behavior Not lethal even at very high doses pseudohallucinationssynesthesiasimpaired judgement, reaction timepronounced motor impairmentincreasingly disorganized thoughts, confusion, paranoia, agitationNot lethal even at very high doses
58DOSING: Start LOW and go SLOW Adverse effects: mainly seen in new usersEuphoria versus paranoiaShort term memory impairmentBalance, incoordinationThese are reversible, short lived effects (3-4 hours max)Serious adverse effects NOT seen in chronic users
59Components of pain that may respond to cannabis Cramping (anti-spasticity)Neuropathic: allodynia, hyperpathiaMechanical: Dull, aching (anti-inflammatory)
60Pros/Cons/Risks/Benefits Good analgesiaHigh dosing ceiling vs minimal toxicityRisk for psychological addiction not an issueMinimal physical dependenceNot many drug-drug interactions
61Pros/Cons/Risks/Benefits Some tolerance may develop in heavy, long term users may need higher dosesPatient/family will have to purchase or grow itDronabinol is NOT as effective –
62Dronabinol (Marinol)Dronabinol is 100% THC, the most psychoactive ingredient in cannabis. Natural cannabis is 20% THC or lessThe 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 IIIFDA approved dronabinol for treatment of nausea and vomiting associated with chemotherapy and anorexia associated with weight loss in patients with HIV/AIDSDronabinol is not an appropriate substitute for natural cannabis.Dronabinol is very expensiveSativex is much better but not available in US (50% THC, 50% cannabadiol in a sublingual spray)
63Metz, 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.”
64Sativex 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: minutesAllows dose titrationReduces first pass metabolismAcceptable to patients
65Primary Endpoint Mean change in Spasticity Score from Baseline (ITT) 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.*Anova
66Sativex – better than marinol BUT… Sativex produced a statistically significant improvement in spasticityImprovement gained over and above concomitant anti-spasticity medicationImprovements gained without decrease in muscle strengthSativex was well toleratedFew withdrawals due to adverse eventsExtension datasustained and continuing improvement in spasticityPatients did not develop tolerance to Sativex over 28 weeks
67Conclusions 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.
68Cannabis 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):
69Conclusions/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 disordersVaporization is a safe, effective alternative to smokingCannabis is remarkably safe, few drug interactions
70CommentsSativex is better than Marinol but not as good as natural cannabisCannabis 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 penniesRisk to society? Not much
71What 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 2006Instead of going to prison, addicts go to treatment centersUnder 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
72If you choose to recommend cannabis… FOLLOW THE LAWCounsel the patient and familyPatient should use high quality cannabis to improve efficacy: high CBD, CBN, lower THC – do not need to be high to get pain reliefUse a delivery route that maximizes benefits and minimizes side effects