A History of Medical Cannabis Research and Endocannabinoid System - Dr. Sunil Aggarwal

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  • Diagram 2. (Above). Representation of mature secretory gland. Disc cells, attached to leaf or bract by stipe cells and basal cells (below stipe), release fibrillar wall matrix into secretory cavity where it contributes to thickening of subcuticular wall (wall) during enlargement of secretory cavity. Plastids (P) in disc cells produce secretions which accumulate outside plasma membrane, pass through cell wall as hyaline areas to form secretory vesicles (L) in secretory cavity. Vesicles in contact with subcuticular wall release contents to contribute to growth of cuticle during enlargement of secretory cavity. THC occurs in walls, fibrillar matrix and other contents surrounding the vesicles, but not in the vesicles; little THC is present in the disc cells. Nucleus = black; vacuole = V; vesicles = L; plastids = P; endoplasmic reticulum = ER.
  • A History of Medical Cannabis Research and Endocannabinoid System - Dr. Sunil Aggarwal

    1. 1. A History of Medical CannabisResearch (and Development) Sunil Kumar Aggarwal, M.D., Ph.D.
    2. 2. Obligatory Declarations• Neither I, nor any member of my family, have a financial relationship with any commercial interest• This talk will discuss FDA-unapproved uses of drugs
    3. 3. 1000 1400 1600 1800 2000 1200 200 400 600 800 0 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986• 2013 projected: 280 in first 38 days2689. 1987 1988 1989 1990 1991• Total: 24,023 -- 2.3 publications/day for last 20 years 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 Medline-Indexed Publications, "cannabis OR cannabinoid(s)“,1960-2012 2005 2006 2007 2008 2009 2010 2011 2012
    4. 4. HUMAN FACE• MS patient: http://www.youtube.com/watch?v=B8_5Ebs jk8I• Parkinsons patient: http://www.youtube.com/watch?v=AvtD1ziz Lng
    5. 5. marijuana hash(ish)
    6. 6. Genomesequenced, 2011 Mahlburg et al 2001
    7. 7. Brief History of Modern Medicinal Use of Cannabis• Introduced in Europe ~1840 by a young Irish doctor, William O’Shaughnessy, who served in India for East India Trading Company, where use was widespread• In the following decades, a short period of popularity in Europe and the United States• >28 (>200?) different medicinal preparations were available with cannabis as active ingredient…recommended for indications as various as menstrual cramps, asthma, cough, insomnia, support of birth labor, migraine (superior remedy for this per Sir William Osler, MD), throat infection and withdrawal from opium use(source Hazekamp diss, Antique Cannabis Museum)
    8. 8. Introduction of Drug Producing Cannabis in the US• the million Mexican laborers• port city of New Orleans• via East Indian immigrants to California• major pharmaceutical production houses in early 20th century• via mail order catalogues, ‘tea’ pads, and World Fairs and International Expositions
    9. 9. 1937 Marihuana Tax Act• Congressional Record rife with lurid tales of homicidal mania, racial slurs, and fears of miscegenation  enhances threat level of marijuana use in civil society• William Woodward, MD, JD, Legislative Counsel, American Medical Association; Chair, Council on Scientific Affairs – "future investigation may show...substantial medical uses for Cannabis“• AMA stood virtually alone in their opposition to the bill – cannabis not inherently dangerous – had already been part of the United States Pharmacopoeia for nearly a century – had irreplaceable, already-accepted and future-promising medical utilities that would go unrealized• NYAM 1944 (La Guardia Cmte Report) – a final push for empiricism
    10. 10. Dr. Woodward:...That there are medical uses for Cannabis is admitted in areport, that has I think, been quoted here before, by a hospital pharmacist inTunis, Dr. Bouquet. Dr. Bouquet is speaking of the medicinal use of Cannabis andhas this to say:The question is: Do any preparations of Indian hemp exist possessing a therapeuticvalue such that nothing else can take their place for medical purposes?This is part of this pharmacists report.The answer is "no."He submits these qualifications, however: (a) Indian hemp extract has been recommended for the preparation ofcorn cures, products that most often consist of a solution of salacylic acid incollodion; the action of the Cannabis extract is nil.I believe the average physician will readily admit that.…He still admits that there are exceptions in which Cannabis cannot apparentlybe successfully substituted for.
    11. 11. (c) The work of F. Pascal (Thesis, Toulouse 1934--Contribution to the Study of Cannabis indica.) seems to show that Indian hemp has remarkable properties in revealing the subconscious; hence it can be used for psychological, psychoanalytical, and psychotherapeutic research, though only to a very limited extent.These are the present uses recognized-----Mr. Lewis: Are there any substitutes for the latter psychological use?Dr. Woodward: I know of none. That use, by the way, was recognizedby John Stuart Mill in his work on psychology, where he referred tothe ability of Cannabis or Indian hemp to revive old memories, andpsychoanalysis depends on revivification of hidden memories.
    12. 12. What’s in a name? Marijuana• "(A)ll parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds, or resin; but shall not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination."
    13. 13. Hermon HC. (1969). Preliminary Observationson the Use of Marihuana in Psychotherapy. TheMarijuana Review, 1, 14-17.
    14. 14. • only psychiatrist in the United States licensed by the Federal Bureau of Narcotics and Dangerous Drugs to research, prescribe, and import marijuana • Senior Psychiatrist at Grafton State Hospital in Massachusetts • “a duly appointed researcher under Class V of the Marihuana Tax Act” Dr. Harry Chramoy Hermon“My main interest in Cannabis is as a psychoadjuvant...[in] mainly the psychoanalytically-oriented psychotherapy... “
    15. 15. • "I found marihuana to be an excellent agent facilitating the psychedelic and transcendental experience as a facilitator of the psychotherapeutic process: not a panacea but a helpful tool under proper circumstances."• "Under the influence of marihuana one is able to dream while fully conscious, i.e., without distortions and symbol formation by our conscious censor...When one stops to think about it one sees the tremendous potentialities and fantastic future of this discovery."• "Marihuana in psychiatry could be used as an emollient, facilitating the psychotherapeutic process by lowering the conscious censorship and allowing the unconscious conflicts to reappear in their "status nascendi" form...serve[s] as a powerful detergent, washing away the accumulated sediments of the conscious defense mechanisms and enabling us to see ourselves in the real virgin form.“• "Marihuana therapy might be contraindicated for individuals with a grossly hysterical personality structure and for borderline schizophrenics with underlying paranoid or self-destructive tendencies.”
    16. 16. FDA-Regulated Cannabinod-Based Medicines: Chemicals, Extracts, Botanicals Photo from pharmer.orgPhoto from epocrates.com Photo from Russo et al. 2002 Photo from nida.org Dronabinol Nabilone Cannabis Sativa L. Cannabis Sativa L. (Marinol™) (Cesamet™) Extracts Cigarettes (nabiximols, Sativex™ ) Photo from Russo et al. 2002 Approximately 460 chemical constituents, >100 Photo from wikipedia.org phytocannabinoids 1985 1985 2006 1976
    17. 17. "During cross examination, Prof. El Sohly wasasked to explain his personal commercialinterests in marijuana-based products. Thisincludes both his THC suppository and hisnew DEA license permitting him to growmarijuana to extract THC for sale to thepharmaceutical company, Mallinckrodt, tomanufacture generic Marinol." --mapsvolume xvi, number 1 spring 2oo6 (Daviesand Doblin, summarizing events ofDecember 2005 hearing before federaladministrative law judge)
    18. 18. What’s in a name? Marijuana• "(A)ll parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds, or resin; but shall not include the mature stalks of such plant, fiber produced from such stalks, oil or cake made from the seeds of such plant, any other compound, manufacture salt, derivative, mixture, or preparation of such mature stalks (except the resin extracted therefrom), fiber, oil, or cake, or the sterilized seed of such plant which is incapable of germination."
    19. 19. Whats in a name? that which we call a rose By any other name would smell as sweet;Shakespeares Romeo and Juliet, 1600
    20. 20. State Clinical Trials in the 1980s• Musty et al: “Effects of smoked cannabis and oral 9- tetrahydrocannabinol on nausea and emesis after cancer chemotherapy: A review of state clinical trials”• 7 health department-sponsored clinical trials• 748 patients who received smoked cannabis• 345 patients who received oral THC for the treatment of nausea and vomiting following cancer chemotherapy• Tennessee (1983),Michigan (1982), Georgia (1983), New Mexico (1983 and 1984), California (1989), and New York (1990).• patients who received smoked cannabis experienced 70- 100% relief from nausea and vomiting• oral THC users experienced 76-88 percent relief
    21. 21. The contemporary era of American cannabinoidbotanical medicine clinical research began inMay 1998 when the first FDA-approved clinicalstudy of cannabis use in a patient population in15 years enrolled its first subject.
    22. 22. Cannabinoid Medical Research by the Numbers • Scientific Literature: 15000+ articles on chemistry and pharmacology of Cannabis and cannabinoids; 2000+ articles on endocannabinoids1 • 1975–2009: at least 110 controlled clinical studies of cannabis or other cannabinoids published; over 6100 patients with a wide range of conditions assessed2 • United States Inhaled Cannabis Clinical Trials as of early 2009: 33 published, approximately 1/3 of gold-standard design. Cf. with placebos, standard drugs, or oral THC3 • 1 federally funded long term tri-decadal “study”—no official longitudinal data collected31Hanus LO: Pharmacological and therapeutic secrets of plant and brain (endo)cannabinoids. Med Res Rev. 2009; 29: 213-271.2Hazekamp A, Grotenhermen F. Review on clinical studies with cannabis and cannabinoids 2005-2009. Cannabinoids. 2010;5(special issue):1-21.3Aggarwal SK et al. Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions. J Opioid Manag2009; 5:153.
    23. 23. INHALED CANNABIS: SPECIFIC INDICATIONS STUDIED IN USA33 completed and published American controlled clinical trials withINHALED cannabis studied safety, routes of administration, and use incomparison with placebos, standard drugs, and in some casesdronabinol, in:• appetite stimulation in healthy volunteers,• the treatment of HIV neuropathy and other types of chronic and neuropathic pain, both pathological and experimentally induced,• spasticity in multiple sclerosis,• weight loss in wasting syndromes,• intraocular pressure in glaucoma,• Dyspnea in asthma, both pathological and experimentally• induced, and• emesis, both secondary to cancer chemotherapy and experimentally induced.• NEARLY ALL SHOWED BENEFIT FAVORING INHALED CANNABIS
    24. 24. Just FYI: Meta-analysis of Cannabinoid Medicines for Nausea and Vomiting in the Setting of Cancer Care systematic review and meta-analysis. European Journal of Cancer Care, Epub July 3. sativa on chemotherapy-induced nausea and vomiting among cancer patients: Rocha FCM, Oliveira LMQR, Da Silveira DX. 2008. Therapeutic use of CannabisA meta-analysis of 18 studies of cannabis or cannabinoids versus standard anti-emetics, which included 13 randomizedclinical trials evaluating cannabis for treatment of nausea and vomiting in cancer patients receiving chemotherapy and 5controlled trials evaluating specific cannabinoids for the same treatment, revealed a statistically significant difference inpatient ‘preference for one of the study drugs’ in favor of Cannabis or its components versus a standard antiemetic drug(n = 1138; RR = 0.33; CI = 0.24–0.44; P < 0.00001; NNT = 1.8).
    25. 25. Cannabinoids for Treatment of Chronic Non-Cancer Pain; a Systematic Review of Randomized Trials. Br J Clin Pharmacol. 2011 Mar 23. doi: 10.1111/j.1365-2125.2011.03970.x. [Epub ahead of print] Lynch ME, Campbell F. Department Anesthesia, Psychiatry, Dalhousie University Department of Anaesthesia and Pain Medicine, Hospital for Sick Children, University of Toronto• included neuropathic pain, fibromyalgia, RA, and mixed chronic pain• 18 RCTs , 2003-2010, 766 participants in total. 4 trials assessed inhaled cannabis• "Overall the quality of trials was excellent,"• "Fifteen of the eighteen trials that met inclusion criteria demonstrated a significant analgesic effect of cannabinoid as compared to placebo, several reported significant improvements in sleep. There were no serious adverse effects.“• inhaled cannabis trials "found a positive effect with no serious adverse side effects."• "Of special importance is the fact that two of the trials examining smoked cannabis demonstrated a significant analgesic effect in HIV neuropathy, a type of pain that has been notoriously resistant to other treatments normally used for neuropathic pain. In the trial examining cannabis based medicines in rheumatoid arthritis a significant reduction in disease activity was also noted, this is consistent with pre-clinical work demonstrating that cannabinoids are anti-inflammatory.“
    26. 26. Conclusion:• "[C]annabinoids are a modestly effective and safe treatment option for chronic non-cancer (predominantly neuropathic) pain. Given the prevalence of chronic pain, its impact on function and the paucity of effective therapeutic interventions, additional treatment options are urgently needed. More large-scale trials of longer duration reporting on pain and level of function are required."
    27. 27. Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematicreview and meta-analysis of randomised controlled trials.PLoS One. 2010 Dec 28;5(12):e14433.Phillips TJ, Cherry CL, Cox S, Marshall SJ, Rice AS.Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial CollegeLondon, Chelsea and Westminster Hospital Campus, London, United Kingdom• Significant pain from HIV-associated sensory neuropathy affects ∼40% of HIV infected individuals treated w/ ART .. urgent need to develop effective pain management strategies for this condition.• Prospective, double-blinded RCTs investigating the pharmacological treatment of painful HIV-SN with sufficient quality assessed using a modified Jadad scoring method.• RESULTS: Of 44 studies identified, 19 were RCTs. Of these, 14 fulfilled the inclusion criteria. Interventions demonstrating greater efficacy than placebo were smoked cannabis NNT 3.38 95%CI(1.38 to 4.10), topical capsaicin 8%, and recombinant human nerve growth factor (rhNGF). No superiority over placebo was reported in RCTs that examined amitriptyline (100mg/day), gabapentin (2.4 g/day), pregabalin (1200 mg/day), prosaptide (16 mg/day), peptide-T (6 mg/day), acetyl-L-carnitine (1g/day), mexilitine (600 mg/day), lamotrigine (600 mg/day) and topical capsaicin (0.075% q.d.s.).• CONCLUSIONS: Evidence of efficacy exists only for capsaicin 8%, smoked cannabis and rhNGF. However, rhNGF is clinically unavailable and smoked cannabis cannot be recommended as routine therapy. Evaluation of novel management strategies for painful HIV-SN is urgently needed.
    28. 28. $8.7-million -- California Center for Medicinal Cannabis Research• 7 separate, government-authorized, gold- standard design clinical trials of the safety and efficacy of smoked and vaporized inhaled cannabis for specific indications conducted at University of California medical centers over a 10 year period from 2002-2012 involving over 300 human subjects• in an article entitled “Medical Marijuana: Clearing Away the Smoke”, reported all trials independently showed benefit.
    29. 29. Study n Design Product and Efficacy Adverse Effects dosageAbrams et al. 55 patients R, DB, PC, PL Up to three cannabis Smoked cannabis All patients had priorCannabis in painful with HIV- (3.95% THC) relieved chronic cannabis smokingHIV-associated sensory associated cigarettes daily for 5 neuropathic daily experience. Anxiety,neuropathy: A randomized neuropathic days pain (34% reduction sedation,placebo-controlled trial. pain vs.17% placebo), and disorientation, 52% (vs. 24% confusion, andPI: Donald I. Abrams, placebo) of patients dizziness occurredM.D., University of experienced a >30% more often inCalifornia, San Francisco reduction in pain cannabis recipients,Published in Neurology intensity. Smoked but were rated as2007 cannabis also between “none” and reduced “mild” experimentally induced hyperalgesiaEllis et al. 34 adult R, DB, CR, PC Cannabis cigarettes 46% more patients All patients wereSmoked Medicinal patients with of varying THC achieved at least a taking additionalCannabis for Neuropathic HIV- concentration (1-8%) 30% reduction in analgesics.Pain in HIV: A associated administered 4 times pain relief with ConcentrationRandomized, Crossover neuropathic daily for 5 days cannabis vs 18% in difficulties, fatigue,Clinical Trial. pain placebo sedation, dry mouth, tachycardia morePI: Ronald J. Ellis, M.D., frequent but not dosePh.D., University of limiting. MostlyCalifornia, San Diego “mild”. TwoPublished in dropouts forNeuropsychopharmacology “psychosis” and2008 “cough”
    30. 30. Study n Design Product and Efficacy Adverse Effects dosageWilsey et al. 38 adult patients R, DB, CR, PC Cannabis cigarettes Smoked cannabis Cannabis recipientsA Randomized, experienced cannabis zero, 3.5% or 7% reduced pain were more likely toPlacebo- smokers with central THC administered in intensity at 4 hours report subjective andControlled, and peripheral graded puffs over 2 compared with psychoactive drugCrossover Trial of neuropathic pain of hours placebo; no effects includingCannabis Cigarettes different origins difference was noted impairment andin Neuropathic Pain. (e.g., physical between the 2 doses. sedation; more with trauma to nerve No effects observed high dose cf. with bundles, spinal cord on evoked pain low. No diff. inPI: Barth Wilsey, injury, multiple responses. Most negative effectsM.D., University of sclerosis, diabetes, patients had complex between low andCalifornia, Davis CRPS, type 1) regional pain placebo. There wasPublished in the syndrome. no indication ofJournal of Pain, mood changes (e.g.,2008 sadness, anxiety, fearfulness).Wallace et al. Dose- 19 healthy R, DB, PC low, medium, and 5 minutes after Mild to moderatedependent effects of volunteers with high dose cannabis cannabis exposure, side effects in 7/19Smoked Cannabis on capsaicin (2%, 4%, 8% THC). no effect on (none with 4%Capsaicin-Induced experimental model capsaicin-induced group); DizzinessPain and of neuropathic pain pain at any dose. By with 3; somnolenceHyperalgesia in (10 uL inj., forearm) 45 min., significant with 1; N/V in 1 inHealthy Volunteers decrease in placebo and in 8% capsaicin-induced group; HR increasesPI: Mark Wallace, pain with 4% dose (- of 7.9, 7.5, and 12.0M.D., University of 6) & a significant bpm, respectively.California, San increase with the 8% Decreased SBP byDiego dose (+8). There was 3pts in 2% group. no significant effect No Beck scorePublished in changes; no sig. diff.Anesthesiology, 2007 seen with low dose (2%). seen on neuropsych testing.
    31. 31. SF General Hospital Inpatient Clinical Trials Ward—Smoked Cannabis in HIV Neuropathy, Pilot Study
    32. 32. Results: Neurology RCT Abrams et al Neurology 2007
    33. 33. Spasticity as measured by mean combined scores on the modified Ashworth scale, before and after treatment, on each day of each phase of the trial. Corey-Bloom J et al. CMAJ 2012;184:1143-1150©2012 by Canadian Medical Association
    34. 34. Corey-Bloom et al. 2012 cont’d• Decrease on the visual analogue scale of pain by 5.28 points• Scores for the timed walk did not differ significantly between treatment and placebo (p = 0.2)• smoked cannabis was associated with acute cognitive effects among the participants of our study, as shown by their performances on the PASAT. The clinical significance of this result is uncertain; despite the transient decrease in scores, patients were still within normal ranges for their ages and levels of education. It is worth noting that conventional treatments such as baclofen and tizanidine hydrochloride may also affect cognition,• Withdrawals from treatment were due to adverse events (two patients felt uncomfortably “high”, two had dizziness and one had fatigue), the schedule being too demanding (one patient) and pain unrelated to the study (one patient). Of the patients who withdrew, three had no previous exposure to cannabis, two had only some exposure (> 1 yr since last use) and two had been exposed during the previous year. None of our participants had episodes of hypertension, hypotension, tachycardia or bradycardia requiring medical intervention.
    35. 35. Large MS clinical Trial = + results• A large multicenter study involving 33 clinical centers and 660 MS patients in the United Kingdom and United States and supported by the UK Medical Council aimed to explore the effects of cannabis extract (Cannador) or synthetic THC (Marinol) versus placebo on spasticity, pain, tremor, bladder function, and cognitive function [Cannabinoids in Multiple Sclerosis (CAMS) study; Zajicek et al., 2003, 2004]. There was no change in Ashworth score, tremor, irritability, depression, or tiredness after 15 weeks of treatment with Marinol or Cannador. However, there were significant improvements in patient-reported spasticity, pain, and sleep quality. Unexpectedly, there was also a reduction in hospital admissions for relapse in the two active treatment groups. Adverse side effects were generally minor and similar to those with placebo. Remarkably, in the 12-month follow-up of the original CAMS study of 657 patients, muscle spasticity measured by the Ashworth scale was significantly improved in the THC- treated group. The Rivermead Mobility Index was also improved, indicative of reduced disability.• In conclusion, controlled clinical trials with cannabinoids have demonstrated their efficacy in eliciting symptomatic improvements in MS patients. These results suggest that there is place for the use of cannabis in the treatment of MS, which should be confirmed in further larger-scale clinical trials. (Scroll MS trialsal. 2006 Pharmacological Reviews -Pacher et 2006)
    36. 36. Phase III study with marijuana done• J Neurol. 2012 Nov 21. [Epub ahead of print]• A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis.• Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, Ratcliffe S.• Pain and Anaesthesia Research Centre, St Bartholomews Hospital, London, UK.• “Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP.”• 339 pts
    37. 37. Access, Delivery, and Distress• Access: Medical marijuana amnesty, information, treatment monitoring• Delivery of maturated germplasm: environmental plant genetic resources• Coping with distress and structural violence
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