Alan Shackelford, M.D. · after cannabis use in 30 patients (26 males) with CD. 21 of 30 patients...

Alan Shackelford, M.D.

Amarimed of Colorado

Amarimed.com

Graduate, University of Heidelberg School of Medicine

Post-graduate training, Harvard Medical SchoolInternal medicine, Nutritional medicine, Behavioral medicine,

Research Fellow, Harvard Medical School

• Brief introduction to cannabis botany

• Brief history of cannabis use as a medical treatment

• Medical uses of cannabis supported by research

• Example of a medical use of cannabis

Why This Matters

• Three cannabis varieties:

• Cannabis sativa, C. indica, C. ruderalis

• Sativa: Tall, tree-like; Indica: Short, bushy; Ruderalis: short, “weedy”, autoflowering

• 400+ different compounds in the cannabis plant

• Three cannabis varieties:

• Cannabis sativa, C. indica, C. ruderalis

• Sativa: Tall, tree-like; Indica: Short, bushy; Ruderalis: short, “weedy”, autoflowering

• 400+ different compounds in the cannabis plant

• +/- 68 are unique to cannabis (cannabinoids)

• Three cannabis varieties:

• Cannabis sativa, C. indica, C. ruderalis

• Sativa: Tall, tree-like; Indica: Short, bushy; Ruderalis: short, “weedy”, autoflowering

• 400+ different compounds in the cannabis plant

• +/- 68 are unique to cannabis (cannabinoids)

• THC is primary psychoactive compound

• Three cannabis varieties:

• Cannabis sativa, C. indica, C. ruderalis

• Sativa: Tall, tree-like; Indica: Short, bushy; Ruderalis: short, “weedy”, autoflowering

• 400+ different compounds in the cannabis plant

• +/- 68 are unique to cannabis (cannabinoids)

• THC is primary psychoactive compound

• Others: antioxidant, anti-inflammatory, neuroprotectant, neuroregulatory

• Three cannabis varieties:

• Cannabis sativa, C. indica, C. ruderalis

• Sativa: Tall, tree-like; Indica: Short, bushy; Ruderalis: short, “weedy”, autoflowering

• 400+ different compounds in the cannabis plant

• +/- 68 are unique to cannabis (cannabinoids)

• THC is primary psychoactive compound

• Others: antioxidant, anti-inflammatory, neuroprotectant, neuroregulatory

• Cannabidiol (CBD) ? most important of them

Emperor Wu Di

141-87 B.C.E.

• Textiles

• Paper

• Medications:

Rheumatic pain

Constipation

Malaria

Female reproductive

disorders

Exodus 30:23

• דרור-מר, בשמים ראש, לך-ואתה קח כג חמש

• ; בשם מחציתו חמשים ומאתים-וקנמן, מאות-וקנה

• חמשים ומאתים, בשם

Atharva Veda 1400 - 2000 B.C.E.

Freedom from distress

Dyspepsia

Nervous disorders

Severe pain

Insomnia

Dysentery

Gonorrhoea

Loss of appetite

Dr. William Brooke O’Shaughnessy 1808 - 1889

ON THE PREPARATIONS OF THE

INDIAN HEMP, OR GUNJAH (CANNABIS INDICA);

THEIR EFFECTS ON THE ANIMAL SYSTEM IN HEALTH,AND THEIR UTILITY IN THE TREATMENT OF TETANUS AND OTHER CONVULSIVE DISEASES

Transactions of the Medical and Physical Society of Bengal, 1838-1840, pp. 421-461.

Prescription Uses for Cannabis Sajous's Analytic Cyclopedia of Practical Medicine (1924)

Sedative or Hypnotic:

in insomnia, senile insomnia, melancholia, mania, delirium tremens, chorea, tetanus, rabies, hay fever, bronchitis, pulmonary tuberculosis, coughs, paralysis agitans, exophtalmic goiter, spasm of the bladder, and gonorrhea.

Analgesic:

in headaches, migraine, eye-strain, menopause, brain tumors, tic douloureux, neuralgia, gastric ulcer, gastralgia (indigestion), tabes, multiple neuritis, pain not due to lesions, uterine disturbances, dysmenorrhea, chronic inflammation, menorrhagia, impending abortion, postpartum hemorrhage, acute rheumatism, eczema, senile pruritus, tingling, formication and numbness of gout, and for relief of dental pain.

Other uses:

to improve appetite and digestion, for the 'pronounced anorexia following exhausting diseases', gastric neuroses, dyspepsia, diarrhea, dysentery, cholera, nephritis, hematuria, diabetes mellitus, cardiac palpitation, vertigo, sexual atony in the female, and impotence in the male.

Harry J. AnslingerCommissioner, US Bureau of Narcotics, 1930-1962

Endocannabinoid System• arachidonoylethanolamide, 2-arachidonoylglycerol, 2-arachidonylglyceryl ether,

Virodhamine, N-acrachidonoyl-dopamine, N-Oleoethanolamine,• N-Palmitoylethanolamine

• derivatives of arachidonic acid

• CB1 receptors are densely distributed in centers in the cortex and basal ganglia involved with motor control, cognition, emotions, purposeful behavior and homeostasis

• CB2 receptors found in neurons and throughout the gastrointestinal system, where they modulate intestinal inflammatory response, and immune system

• signaling in GABA- and glutamatergic synapses and interact with other neurotransmitters

• modulators of postsynaptic transmission in the autonomic nervous system, the immune system and in microcirculation

Cannabis Research

* Alzheimer's disease

*Amyotrophic lateral sclerosis

* Cancer (breast, prostate)

* Chronic/Acute Pain

* Diabetes mellitus

* Dystonia

* Fibromyalgia

* Gastrointestinal disorders

* Gliomas

* Tourette’s syndrome

* Hepatitis C

* Human Immunodeficiency Virus (HIV)

* Hypertension

* Incontinence

* Multiple sclerosis

*Osteoporosis

* Pruritus

* Rheumatoid arthritis

* Seizures

Marijuana Myths

• Pot Kills Brain Cells

• Marijuana Causes Sterility and Lowers Testosterone

• Marijuana Causes Birth Defects

• Pot Causes High Blood Pressure

• Marijuana Damages the Immune System

• Marijuana Causes Chromosome and Cell Damage

• Marijuana Leads to Harder Drugs

• Marijuana causes schizophrenia

Pain

Inflammatory bowel disease(Crohn’s disease and ulcerative colitis)

Seizures

PainAcute

Chronic/Recurring

Sources of pain

• Acute injury• Arthritis

OsteoarthritisRheumatoid arthritisPsoriatic arthritis

• Degenerative disc and joint disease• Radiculopathic pain (sciatica)• Inflammation• Fibromyalgia• Neuropathic pain

RSD/CRPSDiabetic peripheral neuropathy

• HIV-related neuropathy• Headache• Migraine headaches• Tension headaches• Dysmenorrhea• PMS• PMDD• Muscle Spasticity• Cancer

CHRONIC/RECURENT PAIN

• 60% of Americans suffer from chronic or recurrent pain (Stanford Medical Center/ABCNews Poll (2005)

• Chronic pain affects approximately 25 percent of the U.S. population. (1)

• Almost three-fifths of adults 65 and older with pain in the United States said it had lasted for one year or more. (2)

• Nearly 1 in 5 adults in Europe, at least 75 million people, suffers from long-term pain. (3)

1,Bonica, Bonica’s Management of Pain, “History of Pain Concepts and Therapies,” 20012 Bonica, Bonica’s Management of Pain, “History of Pain Concepts and Therapies,” 20013 Pain in Europe Study, 2003

Treatment of Pain

Treatment of Pain

• Many different treatments

Treatment of Pain

• Many different treatments:

• Medications

– NSAIDS

– Opiates

Treatment of Pain

• Many different treatments:

• Medications

– NSAIDS

– Opiates

• Alternative Modalities:

– Accupunture

– Meditation

Treatment of Pain

• Medications

– NSAIDS

– Opiates

Ulcers and GastrointestinaI bleeding linked to NSAID use

• More than 100,000 Americans hospitalized each year

• 15,000 to 20,000 Americans die each year

The American College of Gastroenterology, 2007

Deaths resulting from prescription drug use in United States

Death rates more than doubled between 1999 and 2007

Unintentional opioid-related overdose deaths increased from about 3000 to 12 000 between 1999 and 2007.

2010: 6,631 Women, 10,020 Men = 16,652National Center for Injury Prevention and Control. Centers for Disease Control and Prevention, 2010 & 2013

2010:

38,329 DeathsDeaths from prescription drugs are now the leading cause of unintentional death in the United States, ahead of motor vehicle crashes.

Centers for Disease Control and Prevention, September 2011

Unintentional Drug Overdose Deaths, United States

Number of Deaths due to a Marijuana Overdose

0

UNITED STATES DEPARTMENT OF JUSTICE

Drug Enforcement Administration

_______________________________________

)

In The Matter Of )

) Docket No. 86-22

MARIJUANA RESCHEDULING PETITION )

_______________________________________)

OPINION AND RECOMMENDED RULING, FINDINGS OF

FACT, CONCLUSIONS OF LAW AND DECISION OF

Administrative LAW JUDGE.

FRANCIS L. YOUNG, Administrative Law Judge

DATED: SEP 6 1988

Marijuana, in its natural form, is one of the safest therapeutically active

substances known to man. By any measure of rational analysis marijuana can

be safely used within a supervised routine of medical care.

Smoked cannabis for chronic neuropathic pain: a randomized controlled trial

Ware MA et al, Canadian Medical Association Journal, October 5, 2010 vol. 182 no. 14

Chronic neuropathic pain affects 1%–2% of the

adult population and is often refractory to standard pharmacologic treatment.

23 participants, mean age 45.4 years, 12 women

A single inhalation of 25 mg of 9.4% tetrahydrocannabinol herbal cannabis three times daily for five days reduced the intensity of pain, improved sleep and was well tolerated.

Cannabinoid–Opioid Interaction in Chronic Pain

Abrams DI et al, Clinical Pharmacology & Therapeutics 90, 844-851, December 2011.

24 participants were enrolled, 13 of whom were on morphine treatment and 11 on oxycodone

Pain ratings on day 1 (before exposure to vaporized cannabis) and on day 5 (after exposure to vaporized cannabis)

Participants in both groups reported statistically significant reductions in pain ratings on day 5 as compared with day 1

Pain was significantly decreased (average 27%, 95% confidence interval ) after the addition of vaporized cannabis

We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects.

Inflammatory bowel disease(Crohn’s disease and ulcerative colitis)

Crohn’s disease and ulcerative colitis(Inflammatory Bowel Diseases/IBD)

Crohn’s disease and ulcerative colitis(Inflammatory Bowel Diseases/IBD)

* Autoimmune disorder

* Chronic or recurring inflammation of the gastrointestinal tract

* 1.4 million persons in the United States, similar numbers in Latin America

* 700,000 physician visits

* 100,000 hospitalizations

* Disability in 119,000 patients

Crohn’s disease and ulcerative colitis(Inflammatory Bowel Diseases/IBD)

* 75% of patients with Crohn’s disease and 25% of those with ulcerative colitis will require surgery

* Health care costs of more than $1.7 billion a year (USA)

• Commonly require a lifetime of care.

• No medical cure (CDC)

Centers for Disease Control and Prevention (CDC) 2013

Treatment of Crohn’s disease with cannabis: an observational study

Naftali T et al. Israeli Medical Association Journal. 2011 Aug;13(8):455-8.

In this retrospective observational study we examined disease activity, use of medication, need for surgery, and hospitalization before and after cannabis use in 30 patients (26 males) with CD.

21 of 30 patients (70%) improved significantly after treatment with cannabis.

The need for other medication was significantly reduced.

Fifteen of the patients had 19 surgeries during an average period of 9 years before cannabis use, but only 2 required surgery during an average period of 3 years of cannabis use.

Impact of Cannabis Treatment on the Quality of Life, Weight and Clinical Disease Activity in Inflammatory Bowel Disease Patients: A

Pilot Prospective Study Lahat A et al. Digestion. 2012;85(1):1-8.

[W]e have found that treatment with inhaled cannabis improves quality of life in patients with long-standing CD [Crohn's disease] and UC [ulcerative colitis]. Treatment was also shown to cause a statistically significant rise in patients’ weight after 3 months of treatment, and improvement in clinical disease activity…

Patients reported a statistically significant physical pain reduction during treatment…

“None of our patients complained of any side effect that disturbed their working ability. In fact…there was a statistically significant improvement in patients’ ability to work after treatment."

Cannabis Induces a Clinical Response in Patients With Crohn's Disease: A Prospective Placebo-Controlled Study.

Naftali T et al. Clinical Gastroenterology and Hepatology, May 4, 2013

• 21 patients with Crohn's Disease Activity Index (CDAI) > 200

• No response to therapy with steroids, immunomodulators, or anti-tumor necrosis factor-α agents.

• Cannabis, twice daily

• Cigarettes containing 11.5 mg of (THC) or placebo (cannabis flowers without THC)

• Disease activity and laboratory tests were assessed during 8 weeks of treatment and 2 weeks thereafter.

Cannabis Induces a Clinical Response in Patients With Crohn's Disease: A Prospective Placebo-Controlled Study.

Naftali T et al. Clinical Gastroenterology and Hepatology, May 4, 2013

• Complete remission in 5 of 11 subjects in the cannabis group (45%) and 1 of 10 in the placebo group.

• A clinical response (decrease in CDAI score of >100) was observed in 10 of 11 subjects in the cannabis group and 4 of 10 in the placebo group

• Three patients in the cannabis group were weaned from steroid dependency.

• Subjects receiving cannabis reported improved appetite and sleep, with no significant side effects.

Seizures

• 1-2% of the population

• 3 million North Americans, 4-7 million in Latin America

• 300,000 new cases/year in USA

• Generalized seizures: absence seizures, atypical absence seizures, myoclonic seizures, atonic and tonic seizures, clonic seizures, and tonic-clonic seizures

• Partial seizures: simple and complex partial seizures and secondary generalized seizures

• Direct and indirect costs of epilepsy in the US: $12.5 billion (1995) (2014: $20 billion) (1)

• 30 – 40%: Treatment-resistant seizure disorders. Adults: $4 billion (1995) (2014: $7 billion) (1)

• Murray M et al. Cost of refractory epilepsy in adults in the USA. Epilepsy Research, 23(2): 139-148, 1996

• first recorded use of cannabis to treat a seizure disorder: 1464 in Baghdad

• Cunha JM et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21: 175-185, 1980.

• Added cannabidiol (CBD) to the pharmaceutical regimen of 8 patients whose seizures were poorly controlled

• improvement in 7 of the 8, with significant improvement in 4 patients compared with placebo

Dravet syndrome (DS), or severe myoclonic epilepsy in infancy (SMEI)

• Rare syndrome with an incidence of between 1:20,000 and 1:40,000

• Mutation of the SCN1A gene located within a cluster of three sodium channel genes including SCN2A and SCN3A on chromosome 2q24

• Leads to abnormalities in sodium channel function

• Generalized tonic-clonic seizures in the first 6 to 12 months of life

• Progression to myoclonic jerks, unilateral tonic-clonicseizures and later to absence seizures and complex-partial seizures

Dravet syndrome (DS), or severe myoclonic epilepsy in infancy (SMEI)

• Status epilepticus is common, may last for extended periods of time

• Seizures are generally treatment resistant

• May be potentiated by anti-epileptic medications such as phenytoin, phenobarbital, carbamazepine and lamotrigine

• Invariably developmental delayed

• Elevated mortality estimated to be 10% by age 6 and 20% by age 20

Colorado Seizure Patients

• 351 patients are under the age of 18

• Majority have intractable epilepsy

• Treated with High-CBD/Low-THC exctracts

• 85% significant reduction in seizures

• 95% demonstrate improvement

– Decreased frequency

– Decreased intensity

– Alteration in seizure type

Alan Shackelford, M.D.

Amarimed of Colorado

Amarimed.com

• 2009: Worker-Compensation patients requesting MMJ

– Review medical literature and research on medical uses of cannabis

• 2010: Founded Amarimed of Colorado

• 2010: Consultant to Colorado State Senator Chris Romer,

Testimony, Legislative Committees during debate on HB-1284, SB-109

• 2011: Member, Colorado Department of Revenue Medical Marijuana Advisory Work Group: Draft Rules

• 2012: Consultant to Connecticut State Legislators, testimony, joint State and House hearings: passage of PA 12-55 March, 2012.

• 2013: Consult with Ministry of Health of Israel on MMJ

• 2014: Member, Colorado Department of Public Health Medical Marijuana Scientific Advisory Council

• 2014: Initiate series of clinical trials on MMJ in Israel