Ethan Russo, M.D.

Chronic Cannabis Use in the Compassionate Investigational New Drug Program: An Examination of Benefits and Adverse Effects of Legal Clinical Cannabis

Ethan Russo, Mary Lynn Mathre, Al Byrne, Robert Velin, Paul J. Bach, Juan Sanchez-Ramos, Kristin Kirlin

[EXCERPTED]

ABSTRACT: The Missoula Chronic Cannabis Use Study was proposed to investigate the therapeutic benefits and adverse side effects prolonged use of "medical marijuana" in a cohort of seriously ill patients. Use of cannabis was approved through the Compassionate Investigational New Drug (IND) program of the Food and Drug Administration (FDA). Cannabis is obtained from the National Institute on Drug Abuse (NIDA), and is to examine the overall health status of 4 of the 7 surviving patients in the program. This project provides the first opportunity to scrutinize the long-term effects of cannabis on patients who have used a known dosage of standardized, heat-sterilized quality-controlled supply of low-grade marijuana for 11 to 27 years.

Results demonstrate clinical effectiveness in these patients in treating glaucoma, chronic musculoskelatal pain, spasm and nausea, and spasticity of multiple sclerosis. All 4 patients are stable with respect to their chronic conditions, and are taking many fewer standard pharmaceuticals than previously.

Mild changes in pulmonary (lung) function were observed in 2 patients, while no functionally significant attributable sequelae were noted in any other physiological system examined in the study, which included: MRI scans of the brain, pulmonary function tests, chest x-ray, neuropsychological tests, hormone and immunological assays, electroencephalography (brain wave recording), P300 testing, history, and neurological clinical examination.

These results would support the provision of clinical cannabis to a greater number of patients in need. We believe that cannabis can be a safe and effective medicine with various suggested improvements in the existing Compassionate IND program.

INTRODUCTION

The Missoula Chronic Clinical Cannabis Use Study was proposed to investigate the therapeutic benefits and adverse effects of prolonged use of "medical marijuana" in a cohort of seriously ill patients approved through the Compassionate Investigational New Drug program of the Food and Drug Administration (FDA) for legal use of cannabis obtained from the National Institute on Drug Abuse (NIDA), under the supervision of a study physician. The aim was to examine the overall health status of 8 surviving patients in the program. Four patients were able to take part, while three wished to remain anonymous, and one was too ill to participate. Unfortunately, that person, Robert Randall, succumbed to his condition during the course of the study. Thus, 7 surviving patients in the USA remain in the Compassionate IND program.

Despite the obvious opportunity to generate data on the use of cannabis and its possible sequelae in these patients, neither NIDA, other branches of the National Institute of Health, nor the FDA has published an analysis of information from this cohort. An examination of the contents of the National Library of Medicine Database (PubMed), and search engines of NIDA employing multiple combinations of key words failed to retrieve a single citation. The Missoula Chronic Cannabis Use Study thus provides a unique and important opportunity to scrutinize the long-term effects of cannabis on patients who have used a known dosage of standardized, heat -sterilized quality-controlled supply of low-grade medical marijuana for 11 to 27 years.

The results are compared to those of past chronic use studies in an effort to gain insight into the benefits and sequelae of this controversial agent in modern health care.

PREVIOUS CHRONIC CANNABIS USE STUDIES

The first systemic modern study of chronic cannabis usage was the Indian Hemp Drugs Commission Report at the end of the 19th century (Kaplan 1969; Indian Hemp Drugs Commission 1894). The British government chose not to outlaw the cultivation and commerce of the herb after ascertaining that it had negligible adverse side effects on health, even in chronic application.

Similar conclusions were obtained in the "LaGuardia Report" of 1944 (New York, NY), Mayor's committee on marihuana (Wallace, and Cunningham 1944), which was the first to employ clinical and scientific methods of analysis.

Three important systematic epidemiological studies undertaken by research teams in the 1970's exhaustively examined medical issues in chronic cannabis, but remain obscure due to limited press runs and out-of-print status. The first of these was Ganja in Jamaica: A Medical Anthropological Study of Chronic Marihuana Use (Rubin and Comitas 1975). Therapeutic claims for cannabis were mentioned, but the focus of the study was on "recreational use". Sixty men were included in a hospital study of various clinical parameters if they had maintained a minimum intake of 3 spliffs a day for a minimum of 10 years. Jamaican ganja "spliffs" (marijuana cigarettes) formed of unfertilized female flowering tops (Sinsemilla) tend to be much larger than an American joint of 500 - 1000mg. The potency of the cannabis was analyzed with measures in 30 samples ranging from 0.7 - 10.3% THC, with an average of 2.8%.

In 1977, a detailed study was undertaken in Greece, titled Hashish: Studies of Long-Term Use (Stefanis, Dornbush, and Fink 1977). Once again 60 subjects smoking for more than 10 years were selected. Hashish potency was 4 - 5% THC and was generally mixed with tobacco. Alcoholics were excluded.

In 1980, Cannabis in Costa Rica: A Study of Chronic Marihuana Use was published (Carter 1980). Forty-one subjects smoking for 10 years or more were recruited. Although 10 or more cigarettes per day were smoked, the weight of material was only 2g with an estimated THC range of 24 - 70mg per day. Thirteen samples were assayed with a range of 1.27 - 3.72%, and average of 2.2% THC. Claims of benefit for cough, asthma, headache, hangovers, anorexia, impotence, depression, and malaise were mentioned, but once more, the focus was on social use.

The current study is the first designed to examine clinical benefits and side effects of chronic clinical cannabis usage in which known amounts of quality-controlled material has been employed.

A BRIEF HISTORY OF THE COMPASSIONATE IND

Robert Randall was diagnosed with severe glaucoma at age 24 and was expected to become totally blind long before he turned 30. He soon began a fascinating medical odyssey that has been memorialized in his "personal reflection" co-authored by his wife, Alice O'Leary, titled Marijuana Rx: The Patients Fight for Medicinal Pot (Randall and O'Leary 1998), and other books (Randall 1991 A; Randall 1991b). Until the day he died at age 52 of complications of AIDS, Randall retained his vision, and remained a vocal advocate for benefits of clinical cannabis.

His own journey commenced when he independently discovered that smoking a certain amount of cannabis eliminated the annoying visual haloes produced by his glaucoma. A subsequent arrest in August 1975 for cannabis cultivation lead in turn to his dogged pursuit of the right to a legal means to supply his medicine of choice. He subsequently learned of medical support for his treatment (Helper and Frank 1971). D. Pate has published 2 or more recent reviews (Pate 1999; Pate 2001).

Through painstaking documentation and experimentation, Randall subsequently confirmed the inability of medical science to control his intraocular pressure (IOP) by any legal pharmaceutical means. In contrast, smoked cannabis in large and frequent amounts was successful, were even pure THC was not. As Dr. Helper observed in there experiments together ( Randall and O'Leary 1998, P.60 ), "...c, something other than THC or in addition to THC is helping to lower your pressures... It seems that marijuana works very well."

After a great deal of bureaucratic wrangling, Randall obtained his first government supplied cannabis in November 1976, and the legal case against him was subsequently dismissed. The material he received from his study physician was cultivated in a 5 - acre plot at the University of Mississippi, mostly from seeds of Mexican origin, and was rolled and packaged at the Research Triangle Institute in North Carolina under the supervision of the National Institute on Drug Abuse (NIDA).

Randall was encouraged to be thankful but silent about his treatment. Instead, he chose a different path (Randall and O'Leary 1998, p.134), "Having one, why go mum? There were souls to save. Better to trust my fellow citizens and shout into the darkness than rely on a devious Government dedicated to a fraudulent prohibition." He chose to make it his mission to seek approval for clinical cannabis for other patients. He developed protocols for glaucoma, multiple sclerosis, chronic pain, and AIDS that he shared with prospective medical marijuana candidates. Randall proved to be a tireless and persistent researcher, ferreting out hidden facts useful to his cause. Through the Freedom of Information Act (FOIA), he discovered in 1978 that the governments cost of cannabis cultivation and production was 90 cents per ounce (28g), with 2/3 of this cost attributable to security measures. Thus the actual cost of production approximated 1 cent per gram (US $0.01/g).

Supply and quality control issues arose frequently, and Randall and other patients experienced delays in receipt of shipments or substitution of weaker strains that required doubling of smoked intake.

The AIDS epidemic and it's subsequent involvement in the medical marijuana issue suddenly provided an unlimited supply of available patients for the Compassionate IND program, and Randall assisted them as well. Some succumbed before their supply was approved, or shortly there after. By 1991, 34 patients were enrolled in the program according to Randall (Randall an d O'Leary 1998), while other sources site the number as only 15. Facing and onslaught of new applications, the Public Health Service (PHS) in the Bush administration closed the program to new patients in March 1992. A significant number had received medical approval but were never supplied. Randall sought to ascertain who signed the ultimate termination order through the FOIA, but was never successful in his endeavor. At the time of this writing, seven patients survive in the program.

METHODS

The identities of 6 of 8 of the original Compassionate IND program subjects were known to Patients Out of Time and were contacted in relation of participating in a study of the clinical parameters sighted as concerns of chronic cannabis usage. Four subjects agreed to participate, and 3 traveled to Missoula Montana for testing at Montana Neurobehavioral Specialist, and St. Patrick Hospital on May 3- 4, 2001. One patient was tested to the extent possible in her local area due to physical limitation on travel (Patient Demographics; Table 1). Test included the following (Test Performed; Table 2); MRI scans of the brain, pulmonary function tests (Spirometry), chest X-ray (P-A and lateral), Neuropsychological test battery, hormone and immunological assays (CD4 counts), Electroencephalography (EEG), P300 testing (a computerized EEG test of memory), and neurological history and clinical examination.

Past medical records were reviewed insofar as possible and the histories were supplemented with additional information. All patients signed informed consent documents, and the St. Patrick Hospital/Community Hospital Joint Review Board (IRB) reviewed the protocol.

Problems In The Compassionate IND Program

All 4 patients described varying degrees of logistical difficulties in obtaining their medicine. All have to travel or make special arrangements with their study physician, who is the arbiter of the potency of received material. All described incidents of inadequate supply or provision of inferior quality cannabis. All have had to supplement their supplies of cannabis from illegal black market sources at times.

All have experienced inconveniences or security concerns. One, Patient C, was arrested, detained, and had some of his medicine permanately confiscated without replacement.

Patient A-C decried the lack of an official identity card that might be readily recognized by law enforcement and securities of cannabis from illegal black market sources at times.

All have experienced inconveniences or security concerns. One, Patient C, was arrested, detained, and had some of his medicine permanately confiscated without replacement.

Patient A-C decried the lack of an official identity card that might be readily recognized by law enforcement and securities personnel. Rather, All used combination of letters and other documents to convey their legal status to interested authorities, often to the accompaniment of much doubt an d suspicion. All described significant worry and anxiety about their medicine supplies, and whether official promises of continuation of the program will be honored.

A paramount issue affecting the Compassionate IND patients revolves around cannabis quality. It has been well established that recreational cannabis smokers prefer higher potency materials (Herning, Hooker ands Jones 1986; Shait and Burke 1994; Kelly et al. 1997). The same pertains to most clinical cannabis patients. Chit and Pierri (1989) published a detailed analysis of NIDA marijuana cigarettes that is worthy of review in this context. NIDA marijuana is grown outside, one crop per biennium, harvested from a 5- acre facility at the University of Mississippi. Average yield of "manicured material" is 270g per plant or 270g per sq. foot (letter from NIDA, Steven Gust to Chris Conrad August 18, 1999.). Material is shipped to the Research Triangle Institute in North Carolina where it is chopped and rolled modified tobacco cigarette machines, then stored partially dehydrated and frozen. Cigarettes average 800-900mg in weights. Material requires rehydration before usage which the IND patients usually achieve by storage over night in a refrigerated plastic bag with leaves of lettuce.

As of 1999 (letter, Steven Gust EBR, June 7 1999), NIDA had available cannabis cigarettes of 1.8%,2.*%, 3.0%, 3.4%THC and bulk cannabis of up to 5% THC content. Other cannabinoid components were not quantitated. It was further stated that the strongest material was not provided to patients in their cigarette shipments because it was too sticky and it would interfere with the rolling machines functioning (Personal communication to EBR, Steven Gust , December 1999).

Static burn rates of NIDA cannabis cigarettes were inversely related to potency (Chait and Pieri 1989), while the number of puffs that could be drawn from each cigarette 8.8. While total particulate matter increased with potency, arguably less smoked material is necessary for medicinal effect. Of more concern, carbon monoxide levels were highest in the lower potency material; that is, CO was inversely proportional to THC content. Finally, test subjects in their study of NIDA cannabis reported (pp. 66-67), "that the marihuana is inferior in sensory qualities (taste, harshness) than the marijuana they smoke outside the laboratory. Some have stated that it was the worst marijuana that they had ever sampled, or that it tasted 'chemically treated'."


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All the study patients criticized the paper employed to roll the cannabis cigarettes as harsh, and tasting poorly. NIDA cannabis cigarettes resemble Pall Mall Brand tobacco cigarettes without the logo (Figure 3).

All study patients clean their cannabis and reroll the material to varying degrees, although atleast one former IND patient, now deceased, used the NIDA cigarette unaltered.

NIDA cannabis is shipped to patients in labeled metal canisters containing three hundred cigarettes (Figure4), and material 2 or more years old upon receipt. Even under optimal storage conditions, a certain degree of oxidation of cannabinoids can be expected (Grotenhermen 2001). Most consumers prefer a supply of cured cannabis that is as fresh as possible. A close inspection of the contents of NIDA supplied cigarettes reveals them to be a crude mixture of leaf with abundant of stem and seed components (Figure 5-6). The odor is green and herbal in character. The resultant smoke is thick, acrid, and pervasive.

In contrast, a typical sinsemilla"bud" is seedless, covered with visible glandular trichomes (see journal cover), and emits a strong lemony or piney turpiniod scent. The smoke is also less disturbing from a sensory standpoint to most observers.

Wittle, Guy, and Robson (2001) describe in detail the markedly contrasting steps undertaken in a government approved clinical cannabis program in the United Kingdom. Their material is organically grown in soil with no chemical treatment under controlled indoor conditions. All male plants are eliminated, and only unfertilized female flowering tops are harvested for further processing. This material is assayed for cannabinoid and turpenoid content, with controlled ratios through genetic selection of seed strains before extraction. THC yields obtained are routinely 15- 20% (Personal Communications, GW Pharmaceuticals, 2000).

Harm reduction techniques in relation to clinical cannabis consumption are well advanced (Russo 2001; Grottenherman 2001a, 2001b). Particular attention is merited to vaporization techniques that provide cannabinoid and turpiniod component administration to prospective clinical cannabis patients without pyrolysis (Gieringer 1996a; Gieringer 1996b; Gieringer 2001). Sublingual administration of cannabis extracts is another most promising technique of clinical cannabis administration (Wittle, Guy, and Robson 2001).

3 of the 4 study subjects have employed Marinol, and found it inadequate or a poor substitute for cannabis in symptomatic relief of their clinical syndromes.

CONCLUSIONS AND RECOMMONDATIONS

  1. Cannabis smoking, even of a crude low-grade product, provides effective symptomatic relief of pain, muscle spasms, and intraocular pressure 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.
  4. The side effect profile of NIDA cannabis in chronic usage suggest some mild pulmonary risks.
  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 exstaneous, inert fibrous matter.
  9. It is the authors' opinion that the Compassionate IND program should be reopened and extended to 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.