5/8/03 Presented to the Medical Board of California

8/1/03

Presented to the Medical Board of California Topic: Packet of Vital Information on Medical Cannabis

I encourage doctors to familiarize ourselves with the abundant literature easily available on this safe and effective medicine.

Contents:

• July, 2003 Medical Cannabis Resource List (3 pages)
• Risks Associated with cannabis use/Missoula Chronic Use Study (Russo et al, 2002) (1 pg)
• Review of Therapeutic Effects (Grotenhermen and Russo, 2002) (5 pages)

July, 2003
Medical Cannabis Resource list

JOURNAL
Journal of Cannabis Therapeutics; quarterly;$60/year; www.haworthprsss.com
BOOKS

• Russo and Grotenhermen; Cannabis and Cannabinoids, Pharmacology, Toxicology, and Therapeutic Potential; Haworth Press, 2002; http://www.haworthpress.com
• Institute of Medicine, National Academy of Sciences: Marijuana and Medicine, Assessing the Science Base; National Academy Press, 1999 Full text available online at:   www.nap.edu
• Marijuana Myths, Marijuana Facts; Zimmer and Morgan; The Lindesmith Center, 1997 Phone 800-444-2524, $12.95
• Grinspoon and Bakalar: Marihuana, the Forbidden Medicine; Yale University Press, 1997
• Mathre:  Cannabis in Medical Practice: A Legal, Historical and Pharmacological Overview of the Therapeutic Use of Marijuana;  1997
• Mikurya: Marijuana: Medical Papers 1839-1972;  Medi-Comp Press, 1973

WEB RESOURCES:

• Dr. Lester Grinspoon:   www.rxmarijuana.com
• GW Pharmaceuticals, PLC:   www.gwpharm.com
• Cannabis Research Library:  www.druglibrary.org/crl/
• Alliance for Cannabis Therapeutics:  www.marijuana-as-medicine.org
• Schaeffer Library of Drug Policy: www.druglibrary.org/schaffer
• 1937 Marijuana Tax Act (text): www.druglibrary.org/schaffer/hemp/taxact/mjtaxact.htm
• Dr. Tod Mikuriya: www.mikuriya.com
• Physicians for Human Rights: www.phrusa.org
• Patients Out of Time: www.medicalcannabis.com
• Americans for Safe Access: www.safeaccessnow.org
• International Association for Cannabis as Medicine: www.cannabis-med.org
• NORML website on Medical Use: www.norml.org/index.cfm?Group_ID=3376#evidence 

FURTHER RESOURCES:

• Review of Human Studies on Medical Use of Marijuana by Dale H. Gieringer, Ph.D. www.norml.org/index.cfm?Group_ID=4393 for complete report:www.norml.org/pdf_files/ReviewofHumanStudies.pdf
• Medical marijuana reports: www.norml.org/index.cfm?Group_ID=3472
• Medical Studies Regarding Cannabis www.hempevolution.org/study/study.htm
• AAMC's webpage (American Alliance for Medical Cannabis) on Common Medical Uses for Cannabis (Marijuana): www.letfreedomgrow.com/index_se_cmu.htm
• Drug Policy Alliance's webpage on medical marijuana: www.drugpolicy.org/marijuana/medical/
• From the U.S government's own National Academy of Science: The Institute of Medicine 1999 report (complete text available on-line): Marijuana and Medicine: Assessing the Science Base Chapter 4: THE MEDICAL VALUE OF MARIJUANA AND RELATED SUBSTANCES books.nap.edu/books/0309071550/html/137.html
• Also from the Institute of Medicine (complete text available on-line): Marijuana As Medicine?: The Science Beyond the Controversy (2000)www.nap.edu/books/0309065313/html/
• Multidisciplinary Association for Psychedelic Studies webpage on medical use: www.maps.org/mmj/
• UK House of Lords report 11/4/98
Science and Technology - Ninth Report www.publications.parliament.uk/pa/ld199798/ldselect/ldsctech/151/15101.htm

Risks associated with marijuana use:

Missoula Chronic Clinical Cannabis Use Study (2002) Russo, Mathre, Byrne, Velin, Bach, Sanchez-Ramos, Kirlin ("Chronic Cannabis Use in the Compassionate Investigational New Drug Program:
An Examination of Benefits and Adverse Effects of Legal Clinical Cannabis")
(studied 4 of the 7 remaining patients in the program, who have used a known dosage of standardized, heat-sterilized quality-controlled supply of low-grade medical marijuana for 11 to 27 years.)
1st pt in 1976;  closed to new patients in 1992.
Conclusions and recommendations:

1. Cannabis smoking, even of a crude, low-grade product, provides effective symptomatic relief of pain, muscle spasms, and intraocular elevations in selected patients failing other modes of treatment.
2. These clinical cannabis patients are able to reduce or eliminate other prescription medicines and their accompanying side effects.
3. Clinical cannabis provides an improved quality of life in these patients.
4. The side effect profile of NIDA Cannabis in chronic usage suggests some mild pulmonary risk.
5. No malignant deterioration has been observed.
6. No consistent or attributable neuropsychological or neurological deterioration has been observed.
7. No endocrine, hematological or immunological sequelae have been observed.
8. Improvements in a clinical cannabis program would include a ready and consistent supply of sterilized, potent, organically grown unfertilized female flowering top material, thoroughly cleaned of extraneous inert fibrous matter.
9. It is the authors' opinion that the Compassionate IND program should be reopened and extended to other patients in need of clinical cannabis.
10. Failing that, local, state and federal laws might be amended to provide regulated and monitored clinical cannabis to suitable candidates.

Review of Therapeutic Effects

verbatim from:
Russo and Grotenhermen; Cannabis and Cannabinoids, Pharmacology, Toxicology, and Therapeutic Potential; Haworth Press, 2002; www.haworthprsss.com  ($39.95 plus shipping and handling), page 124-132
HIERARCHY OF THERAPEUTIC EFFECTS
To do justice to the scientific evidence with regard to different indications, a hierarchy of therapeutic effects can be devised.
In this overview no distinction will be made between isolated THC (dronabinol) and natural cannabis products.  Indications for THC will be regarded as indications for cannabis and vice versa.
1. Established effect:  Nausea and vomiting, anorexia, and weight loss.
2. Relatively well-confirmed effect: spasticity, painful conditions, especially neurogenic pain, movement disorders, asthma, glaucoma.
3. Less confirmed effect: allergies, inflammation, infection, epilepsy, depression, bipolar disorders, anxiety disorder, dependency and withdrawal.
4. Basic research stage: autoimmune disease, cancer, neuroprotection, fever, disorders of blood pressure.
This hierarchy may not necessarily reflect the actual clinical benefit derived by patients employing cannabinoid treatments,  Additional research will likely result in new correlations.  For example, benefit of cannabis in mood disorders would have to be classified as a less confirmed effect only a short time ago.  Recent controlled clinical investigations of THC in Tourette's Syndrome give hope that cannabis and cannabinoids may be eventually be regarded as established indications in this disorder within a few years.  Results of a clinical study at the Medical School of Hannover, Germany, examining the use of cannabis products spread quickly in self-help organizations in the German language area in Europe, and the benefit of cannabis in this disease is now well known by many patients.  Anecdotes as to the efficacy of cannabis/THC in indications that have not been confirmed in controlled studies must be judged with caution.

INDICATIONS

Spasticity
In small clinical trials of delta-9-tetrahydrocannabinol, nabilone, and cannabis, a beneficial effect on spasticity caused by multiple sclerosis or spinal cord injury has been observed.  Among other positively influenced symptoms were pain, paraesthesia, tremor, and and ataxia.  In folk medicine there are reports of improved bowel and bladder control.  Some anecdotal evidence of a benefit of marijuana in spasticity due to central lesions also exists.
Movement Disorders
There are some positive anecdotal reports of therapeutic response to cannabis in Tourette's syndrome, dystonia, and tardive dyskinesia.  The use in Tourette's syndrome is currently being investigated in clinical studies.  Many patients achieve a modest improvement, however some show a considerable response or even complete symptom control.
Cannabidiol in dosages between 100 and 600 mg per day produced improvements of 20 to 50 percent in five patients with dystonia.  In MS patients, benefits on ataxia and reduction of tremor have been observed following the administration of THC.  Despite occasional positive reports, no objective success has been found in parkinsonism or Huntington's disease.  However, cannabis products may prove useful in levodopa-induced dyskinesia in Parkinson's disease without worsening the primary symptoms.
Pain
Few clinical studies of cannabinoids in painful conditions exist.
In 2 trials, oral THC proved to be effective against cancer pain in doses of 15 an 20 mg respectively.  However some patients experienced intolerable side effects.  In a single case double-blind study a patient with familial Mediterranean fever clearly reduced his need for opiates while receiving THC (50 mg per day divided in five doses) in comparison to placebo.
According to reports from pain therapists, the simultaneous administration of opiates and cannabis appears to be promising, particularly since cannabis does not cause respiratory depression.  Cannabis has been successfully used in modern folk medicine in a multitude of painful conditions, among them migraine and other forms of headaches, musculoskeletal disorder, arthritis, neuralgias, neuropathy, dysmenorrhea, ulcerative colitis, Crohn's disease, etc.
Anorexia and Cachexia
An appetite-enhancing effect of THC is observed with daily divided doses totalling 5 mg.  When required, the daily dose may be increased to 20 mg.  In a long-term study of 94 AIDS patients, the appetite-stimulating effect of THC continued for months, confirming the appetite enhancement noted in a shorter six-week study.  THC doubled appetite on a visual analogue scale in comparison to placebo.  Patients tended to retain a stable body weight over the course of seven months.
A positive influence on body weight was also reported in 15 patients with Alzheimer's disease who were previously refusing food.  Surprisingly, THC also decreased the observed severity  of disturbed behavior. 
In patients diagnosed with primary anorexia nervosa there was no measurable cannabinoid effect, presumable because the underlying pathological mechanism is not loss of appetite.
In the nineteenth century, cannabis was employed in indigestion and stomachache associated with appetite loss."
Nausea and Vomiting
Treatment of side effects associated with antineoplastic therapy is the indication for cannabinoids which has been most documented, with about 40 studies (THC, nabilone, other THC analogues, marijuana).  Most trials were conducted in the 1980s.  THC has to be dosed relatively highly (5 mg/m2 body surface, every 4 to 6 h, four times a day), so that resultant dose effects may occur comparatively frequently.  THC was inferior to high-dose metoclopramide in one study.  There are no comparisons of THC to the modern 5-HT3 (serotonin) antagonists (e.g., ondansetron, granisetron).
Whereas dronabinol has a diminished acceptance in the treatment of side effects of chemotherapy, in folk medicine cannabinoids remain popular and are often used in other causes of nausea including AIDS and hepatitis.
Glaucoma
In 1971, during a systematic investigation of its effects in healthy marijuana users, it was observed that cannabis reduces intraocular pressure.  In the following 12 years a number of studies in healthy individuals and glaucoma patients with marijuana and several natural and synthetic cannabinoids were conducted.  Marijuana decreased intraocular pressure by an average of 25 to 30 percent, occasionally  up to 50 percent, the effect lasting 4 to 6 h.  Some nonpsychotropic cannabinoids (CBD, CBG,CBN), and to a lesser extent, some noncannabinoid constituents of the hemp plant also decrease intraocular pressure.  A polysaccharide-containing water-soluble marijuana-derived material (MDM), and a nonpsychotropic alcoholic extract of marijuana, named Canasol, are used in the Caribbean area for glaucoma treatment.
Epilepsy
The use of cannabis in epilepsy is among this historically oldest indications.  Animal experiments provide evidence of the antiepileptic effects of some cannabinoids.  The anticonvulsant activity of the drugs phenytoin and diazepam have been potentiated by THC.  According to a few case reports from the past three decades, some epileptic patients continue to utilize cannabis to control an otherwise unmanageable seizure disorder.  Cannabis use may occasionally precipitate convulsions.  In contrast to THC, there is no development of tolerance to the antiepileptic effects of CBD.
Asthma
Experiments examining the antiasthmatic effect of THC or cannabis date mainly from the 1970s, and all are acute studies.  The effects of a marijuana cigarette (2 percent THC) or oral THC (15 mg), respectively ,approximately correspond to those obtained with therapeutic doses of common bronchodilator drugs (salbutamaol, isoprenaline).  Following inhalation, the effect lasts about two hours.  Since inhalation of cannabis products may irritate the mucous membranes, oral administration or another alternative delivery system would be preferable.  Very few patients developed bronchitic constriction after inhalation of THC.
Pruritus and Allergies
Pruritus is caused by a complex process, involving different neurotransmitters, the hormonal system, blood vessels of the skin, psyche, and other systems.  Some aspects this process seem to be influenced by THC and might explain positive effects reported by a number of patients.  The immunomodulatory action of THC suggests an antiallergic effect.
Dependency and Withdrawal
According to historical and modern case reports cannabis is a good remedy to combat withdrawal in dependency on benzodiazepines, opiates, and alcohol.  For this reason, some have referred to it as a gateway drug back.  In this context, both the reduction of physical withdrawal symptoms and stress connected with discontinuance of drug abuse may play a role in its observed benefits.
Psychiatric Symptoms
An improvement of mood in reactive depression has been observed in several clinical studies with THC.   Additional case reports claiming benefit of cannabinoids in other psychiatric symptoms and diseases, such as sleep disorders, anxiety disorders, bipolar disorders, and dysthymia, also exist.  Evidence suggests that positive symptoms of psychoses (delusions, hallucinations, etc.) may have origins in an increased dopaminergic activity whereas the negative symptoms (apathy, anhedonism, emotional retreat, etc.) result from enhanced cholinergic activity.  The use of cannabis may eventually decrease negative symptoms and increase positive symptoms.  Various authors have expressed different viewpoints concerning psychiatric syndromes and cannabis.  Although some emphasize the problems caused by cannabis--in the sense of a comorbid dependency problem, others promote the therapeutic possibilities in the sense of the self-medication theory.  Quite possibly cannabis products may be either beneficial or harmful, depending on the particular case.  The attending physician and the patient should be open to a critical examination of the topic, and a frankness to both possibilities.
Autoimmune Diseases and Inflammation
In a number of painful syndromes secondary to inflammatory processes (e.g., ulcerative colitis, arthritis), cannabis products may act not only as analgesics but also demonstrate anti-inflammatory potential.  For example, some patients employing cannabis report a decrease in their need for steroidal and nonsteroidal drugs.  Moreover, some reports suggest positive effects of cannabis self-medication in allergic conditions.  It is as yet unclear whether cannabis products may have a relevant effect on causative processes of autoimmune diseases.
In a study on rats, oral cannabis was effective against an infection with Trypanosoma brucei brucei.  Lancz and colleagues noted that incubation with THC decreased herpes simplex virus infectivity in vitro in both a time and dose dependent manner up to 80 percent, so that ointments containing THC may be of benefit in the treatment of infections with herpes simplex.
Miscellaneous, Mixed Syndromes
A number of positive patient reports on medical conditions cannot be easily assigned to the previous categories, such as tinnitus, chronic fatigue syndrome, restless legs syndrome,  and others.  A common indication for cannabis in the nineteenth century was pain reduction during birth and support of labor, an effect occasionally used also in modern folk medicine.
Cannabis products often show very good effects in diseases with multiple symptoms.  These include painful conditions that have an inflammatory origin (e.g., arthritis), or those that are accompanied by increased muscle tone (e.g., menstrual cramps, spinal cord injury), or in diseases with nausea and anorexia accompanied by pain, anxiety, and depression, respectively (e.g.,AIDS, cancer, hepatitis C).
Frank Henry Lucido, M.D.
Curriculum Vitae