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

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  1. 1. A History of Medical Cannabis Research (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. 0 200 400 600 800 1000 1200 1400 1600 1800 2000 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 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Medline-Indexed Publications, "cannabis OR cannabinoid(s)“,1960-2012 • Total: 24,023 -- 2.3 publications/day for last 20 years • 2013 projected: 280 in first 38 days2689.
  4. 4. HUMAN FACE • MS patient: http://www.youtube.com/watch?v=B8_5Ebs jk8I • Parkinson's patient: http://www.youtube.com/watch?v=AvtD1ziz Lng
  5. 5. marijuana hash(ish)
  6. 6. Mahlburg et al 2001 Genome sequenced, 2011
  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 a report, that has I think, been quoted here before, by a hospital pharmacist in Tunis, Dr. Bouquet. Dr. Bouquet is speaking of the medicinal use of Cannabis and has this to say: The question is: Do any preparations of Indian hemp exist possessing a therapeutic value such that nothing else can take their place for medical purposes? This is part of this pharmacist's report. The answer is "no." He submits these qualifications, however: (a) Indian hemp extract has been recommended for the preparation of corn cures, products that most often consist of a solution of salacylic acid in collodion; 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 apparently be 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 recognized by John Stuart Mill in his work on psychology, where he referred to the ability of Cannabis or Indian hemp to revive old memories, and psychoanalysis 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 Observations on the Use of Marihuana in Psychotherapy. The Marijuana 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. Photo from epocrates.com Dronabinol (Marinol™) Photo from pharmer.org FDA-Regulated Cannabinod-Based Medicines: Chemicals, Extracts, Botanicals Nabilone (Cesamet™) Cannabis Sativa L. Extracts (nabiximols, Sativex™) Cannabis Sativa L. Cigarettes Photo from nida.org Photo from wikipedia.org Photo from Russo et al. 2002 Photo from Russo et al. 2002 1985 1985 2006 Approximately 460 chemical constituents, >100 phytocannabinoids 1976
  17. 17. "During cross examination, Prof. El Sohly was asked to explain his personal commercial interests in marijuana-based products. This includes both his THC suppository and his new DEA license permitting him to grow marijuana to extract THC for sale to the pharmaceutical company, Mallinckrodt, to manufacture generic Marinol." --maps volume xvi, number 1 spring 2oo6 (Davies and Doblin, summarizing events of December 2005 hearing before federal administrative law
  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. What's in a name? that which we call a rose By any other name would smell as sweet; Shakespeare's 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 cannabinoid botanical medicine clinical research began in May 1998 when the first FDA-approved clinical study of cannabis use in a patient population in 15 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 collected3 1Hanus 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 Manag 2009; 5:153.
  23. 23. INHALED CANNABIS: SPECIFIC INDICATIONS STUDIED IN USA 33 completed and published American controlled clinical trials with INHALED cannabis studied safety, routes of administration, and use in comparison with placebos, standard drugs, and in some cases dronabinol, 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. Rocha FCM, Oliveira LMQR, Da Silveira DX. 2008. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. European Journal of Cancer Care, Epub July 3. A meta-analysis of 18 studies of cannabis or cannabinoids versus standard anti-emetics, which included 13 randomized clinical trials evaluating cannabis for treatment of nausea and vomiting in cancer patients receiving chemotherapy and 5 controlled trials evaluating specific cannabinoids for the same treatment, revealed a statistically significant difference in patient ‘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). Just FYI: Meta-analysis of Cannabinoid Medicines for Nausea and Vomiting in the Setting of Cancer Care
  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 systematic review 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 College London, 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 dosage Efficacy Adverse Effects Abrams et al. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial. PI: Donald I. Abrams, M.D., University of California, San Francisco Published in Neurology 2007 55 patients with HIV- associated neuropathic pain R, DB, PC, PL Up to three cannabis (3.95% THC) cigarettes daily for 5 days Smoked cannabis relieved chronic neuropathic daily pain (34% reduction vs.17% placebo), and 52% (vs. 24% placebo) of patients experienced a >30% reduction in pain intensity. Smoked cannabis also reduced experimentally induced hyperalgesia All patients had prior cannabis smoking experience. Anxiety, sedation, disorientation, confusion, and dizziness occurred more often in cannabis recipients, but were rated as between “none” and “mild” Ellis et al. Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial. PI: Ronald J. Ellis, M.D., Ph.D., University of California, San Diego Published in Neuropsychopharmacology 2008 34 adult patients with HIV- associated neuropathic pain R, DB, CR, PC Cannabis cigarettes of varying THC concentration (1-8%) administered 4 times daily for 5 days 46% more patients achieved at least a 30% reduction in pain relief with cannabis vs 18% in placebo All patients were taking additional analgesics. Concentration difficulties, fatigue, sedation, dry mouth, tachycardia more frequent but not dose limiting. Mostly “mild”. Two dropouts for “psychosis” and “cough”
  30. 30. Study n Design Product and dosage Efficacy Adverse Effects Wilsey et al. A Randomized, Placebo- Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain. PI: Barth Wilsey, M.D., University of California, Davis Published in the Journal of Pain, 2008 38 adult patients experienced cannabis smokers with central and peripheral neuropathic pain of different origins (e.g., physical trauma to nerve bundles, spinal cord injury, multiple sclerosis, diabetes, CRPS, type 1) R, DB, CR, PC Cannabis cigarettes zero, 3.5% or 7% THC administered in graded puffs over 2 hours Smoked cannabis reduced pain intensity at 4 hours compared with placebo; no difference was noted between the 2 doses. No effects observed on evoked pain responses. Most patients had complex regional pain syndrome. Cannabis recipients were more likely to report subjective and psychoactive drug effects including impairment and sedation; more with high dose cf. with low. No diff. in negative effects between low and placebo. There was no indication of mood changes (e.g., sadness, anxiety, fearfulness). Wallace et al. Dose- dependent effects of Smoked Cannabis on Capsaicin-Induced Pain and Hyperalgesia in Healthy Volunteers PI: Mark Wallace, M.D., University of California, San Diego Published in Anesthesiology, 2007 19 healthy volunteers with capsaicin experimental model of neuropathic pain (10 uL inj., forearm) R, DB, PC low, medium, and high dose cannabis (2%, 4%, 8% THC). 5 minutes after cannabis exposure, no effect on capsaicin-induced pain at any dose. By 45 min., significant decrease in capsaicin-induced pain with 4% dose (- 6) & a significant increase with the 8% dose (+8). There was no significant effect seen with low dose (2%). Mild to moderate side effects in 7/19 (none with 4% group); Dizziness with 3; somnolence with 1; N/V in 1 in placebo and in 8% group; HR increases of 7.9, 7.5, and 12.0 bpm, respectively. Decreased SBP by 3pts in 2% group. No Beck score changes; no sig. diff. 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 trials 2006) -Pacher et al. 2006 Pharmacological Reviews
  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 Bartholomew's 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

Editor's Notes

  • 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.
    1. 1. A History of Medical Cannabis Research (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. 0 200 400 600 800 1000 1200 1400 1600 1800 2000 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 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Medline-Indexed Publications, "cannabis OR cannabinoid(s)“,1960-2012 • Total: 24,023 -- 2.3 publications/day for last 20 years • 2013 projected: 280 in first 38 days2689.
    4. 4. HUMAN FACE • MS patient: http://www.youtube.com/watch?v=B8_5Ebs jk8I • Parkinson's patient: http://www.youtube.com/watch?v=AvtD1ziz Lng
    5. 5. marijuana hash(ish)
    6. 6. Mahlburg et al 2001 Genome sequenced, 2011
    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 a report, that has I think, been quoted here before, by a hospital pharmacist in Tunis, Dr. Bouquet. Dr. Bouquet is speaking of the medicinal use of Cannabis and has this to say: The question is: Do any preparations of Indian hemp exist possessing a therapeutic value such that nothing else can take their place for medical purposes? This is part of this pharmacist's report. The answer is "no." He submits these qualifications, however: (a) Indian hemp extract has been recommended for the preparation of corn cures, products that most often consist of a solution of salacylic acid in collodion; 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 apparently be 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 recognized by John Stuart Mill in his work on psychology, where he referred to the ability of Cannabis or Indian hemp to revive old memories, and psychoanalysis 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 Observations on the Use of Marihuana in Psychotherapy. The Marijuana 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. Photo from epocrates.com Dronabinol (Marinol™) Photo from pharmer.org FDA-Regulated Cannabinod-Based Medicines: Chemicals, Extracts, Botanicals Nabilone (Cesamet™) Cannabis Sativa L. Extracts (nabiximols, Sativex™) Cannabis Sativa L. Cigarettes Photo from nida.org Photo from wikipedia.org Photo from Russo et al. 2002 Photo from Russo et al. 2002 1985 1985 2006 Approximately 460 chemical constituents, >100 phytocannabinoids 1976
    17. 17. "During cross examination, Prof. El Sohly was asked to explain his personal commercial interests in marijuana-based products. This includes both his THC suppository and his new DEA license permitting him to grow marijuana to extract THC for sale to the pharmaceutical company, Mallinckrodt, to manufacture generic Marinol." --maps volume xvi, number 1 spring 2oo6 (Davies and Doblin, summarizing events of December 2005 hearing before federal administrative law
    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. What's in a name? that which we call a rose By any other name would smell as sweet; Shakespeare's 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 cannabinoid botanical medicine clinical research began in May 1998 when the first FDA-approved clinical study of cannabis use in a patient population in 15 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 collected3 1Hanus 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 Manag 2009; 5:153.
    23. 23. INHALED CANNABIS: SPECIFIC INDICATIONS STUDIED IN USA 33 completed and published American controlled clinical trials with INHALED cannabis studied safety, routes of administration, and use in comparison with placebos, standard drugs, and in some cases dronabinol, 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. Rocha FCM, Oliveira LMQR, Da Silveira DX. 2008. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. European Journal of Cancer Care, Epub July 3. A meta-analysis of 18 studies of cannabis or cannabinoids versus standard anti-emetics, which included 13 randomized clinical trials evaluating cannabis for treatment of nausea and vomiting in cancer patients receiving chemotherapy and 5 controlled trials evaluating specific cannabinoids for the same treatment, revealed a statistically significant difference in patient ‘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). Just FYI: Meta-analysis of Cannabinoid Medicines for Nausea and Vomiting in the Setting of Cancer Care
    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 systematic review 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 College London, 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 dosage Efficacy Adverse Effects Abrams et al. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial. PI: Donald I. Abrams, M.D., University of California, San Francisco Published in Neurology 2007 55 patients with HIV- associated neuropathic pain R, DB, PC, PL Up to three cannabis (3.95% THC) cigarettes daily for 5 days Smoked cannabis relieved chronic neuropathic daily pain (34% reduction vs.17% placebo), and 52% (vs. 24% placebo) of patients experienced a >30% reduction in pain intensity. Smoked cannabis also reduced experimentally induced hyperalgesia All patients had prior cannabis smoking experience. Anxiety, sedation, disorientation, confusion, and dizziness occurred more often in cannabis recipients, but were rated as between “none” and “mild” Ellis et al. Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial. PI: Ronald J. Ellis, M.D., Ph.D., University of California, San Diego Published in Neuropsychopharmacology 2008 34 adult patients with HIV- associated neuropathic pain R, DB, CR, PC Cannabis cigarettes of varying THC concentration (1-8%) administered 4 times daily for 5 days 46% more patients achieved at least a 30% reduction in pain relief with cannabis vs 18% in placebo All patients were taking additional analgesics. Concentration difficulties, fatigue, sedation, dry mouth, tachycardia more frequent but not dose limiting. Mostly “mild”. Two dropouts for “psychosis” and “cough”
    30. 30. Study n Design Product and dosage Efficacy Adverse Effects Wilsey et al. A Randomized, Placebo- Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain. PI: Barth Wilsey, M.D., University of California, Davis Published in the Journal of Pain, 2008 38 adult patients experienced cannabis smokers with central and peripheral neuropathic pain of different origins (e.g., physical trauma to nerve bundles, spinal cord injury, multiple sclerosis, diabetes, CRPS, type 1) R, DB, CR, PC Cannabis cigarettes zero, 3.5% or 7% THC administered in graded puffs over 2 hours Smoked cannabis reduced pain intensity at 4 hours compared with placebo; no difference was noted between the 2 doses. No effects observed on evoked pain responses. Most patients had complex regional pain syndrome. Cannabis recipients were more likely to report subjective and psychoactive drug effects including impairment and sedation; more with high dose cf. with low. No diff. in negative effects between low and placebo. There was no indication of mood changes (e.g., sadness, anxiety, fearfulness). Wallace et al. Dose- dependent effects of Smoked Cannabis on Capsaicin-Induced Pain and Hyperalgesia in Healthy Volunteers PI: Mark Wallace, M.D., University of California, San Diego Published in Anesthesiology, 2007 19 healthy volunteers with capsaicin experimental model of neuropathic pain (10 uL inj., forearm) R, DB, PC low, medium, and high dose cannabis (2%, 4%, 8% THC). 5 minutes after cannabis exposure, no effect on capsaicin-induced pain at any dose. By 45 min., significant decrease in capsaicin-induced pain with 4% dose (- 6) & a significant increase with the 8% dose (+8). There was no significant effect seen with low dose (2%). Mild to moderate side effects in 7/19 (none with 4% group); Dizziness with 3; somnolence with 1; N/V in 1 in placebo and in 8% group; HR increases of 7.9, 7.5, and 12.0 bpm, respectively. Decreased SBP by 3pts in 2% group. No Beck score changes; no sig. diff. 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 trials 2006) -Pacher et al. 2006 Pharmacological Reviews
    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 Bartholomew's 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

    Editor's Notes

  • 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.
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