1. A History of Medical Cannabis
Research (and Development)
Sunil Kumar Aggarwal, M.D., Ph.D.

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

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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. 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. marijuana hash(ish)

6. Mahlburg et
al 2001
Genome
sequenced,
2011

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)

9. 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

10. 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

11. 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.

12. (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.

15. 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."

16. Hermon HC. (1969). Preliminary Observations
on the Use of Marihuana in Psychotherapy. The
Marijuana Review, 1, 14-17.

17. • 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... “

18. • "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.”

19. 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

21. "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

22. 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."

23. 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

24. 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

25. 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.

26. 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.

27. 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

28. 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

29. 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.“

30. 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."

31. 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.

32. $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.

33. 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”

34. 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.

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

36. Results: Neurology RCT
Abrams et al Neurology 2007

37. 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

38. 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.

39. 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

40. 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

42. 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