ATrain Education

 

Continuing Education for Health Professionals

Cannabis (Marijuana) for Medical Use

Module 4

Cannabis as Medication

Cannabis seems unique in its wide array of indications for use. The newly discovered ECS not only adds to our understanding of human physiology but also helps us understand how and why cannabis is safe and effective for so many indications. This section reviews the safety profile of cannabis and discusses its potential risks. Then it outlines the therapeutic effects and indications for use and presents information about dosage and administration. Cannabis seems to work synergistically with opioids, and most patients with chronic pain significantly reduce or eliminate their use of opioids; thus, cannabis can be viewed as an opiate-sparing medication (Abrams, 2010). Finally, the section ends with some case examples of patients using medicinal cannabis.

Safety Profile

“In its natural form, marijuana is one of the safest substances known to man.” That statement was made by the DEA’s Administrative Law Judge, Francis Young, after reviewing more than 5000 pages of evidence during the hearings to reschedule marijuana in 1988. He also stated that “It would be unreasonable, arbitrary, and capricious for the DEA to continue to stand between those sufferers and the benefits of this substance in light of the evidence in this record” (Young, 1988). Note that he drew these conclusions in 1988, even before researchers discovered the endocannabinoid system.

By trial and error over centuries of use, humans have learned how to use many herbal plants as medication. With more modern research, physicians have moved from using botanicals to specific chemicals within those plants or synthetic versions of those chemicals. In research studies it is much easier to focus on a particular chemical; however, although these specific chemicals may have stronger and more direct effects, they can come with stronger and sometimes-toxic side effects.

Today clinicians are taught to rely on the scientific method, and double-blind placebo-controlled studies are the gold standard. To safeguard the public, the Food and Drug Administration allows new drugs on the market only after they have met basic safety studies and have been shown to have therapeutic value in clinical trials. This research takes years to come to fruition and, even then, some drugs have been allowed on the market and found to have dangerous side effects or adverse reactions when consumed by a larger population.

This course is about the medicinal use of a plant called cannabis. What’s so different about cannabis?

Cannabis is an ancient drug that has been used by countless individuals over the centuries. It is not a new drug. As noted earlier, cannabis was a very popular medication in early American history. Included on numerous bottles of medicinal cannabis would be the claim that it was “guaranteed under the Pure Food and Drugs Act of June 30, 1906.” This was the forerunner of our FDA process today. Many of our early medications (eg, aspirin) had been found to be safe for medical use based on their historical record, and so they were grandfathered in to the list of FDA-approved drugs. Had it not been for the politically driven reefer madness campaign of the 1930s, cannabis would have also been grandfathered in as an approved medication based on its safety record and efficacy.

 

Package Label from Eli Lilly, 1913

image: photo of cannabis package label from 1913

Note that this preparation was “guaranteed” under the Food and Drugs Act of 1906. Source: Courtesy of Patients Out of Time. Used by permission.

 

Throughout centuries of use there has never been a recorded human death as a result of cannabis consumption. It has a remarkably wide margin of safety. The median lethal dose or LD-50 (dose at which 50% of rats using a drug will die from overdose) of oral THC was 800 to 1900 mg/kg for rats, depending on sex and strain. No cases of death due to toxicity followed a maximum THC dose in dogs (up to 3000 mg/kg) and monkeys (up to 9000 mg/kg) (Grotenhermen, 2007). Stated another way, humans would have to consume 1500 pounds in 15 minutes to induce death. In other words, it is nearly impossible to overdose on this herbal plant. Compare that record to the fact that approximately 120 persons die each year from the use of aspirin or that high doses of acetaminophen that can lead to liver damage and death.

Thousands of studies have been funded by the National Institute on Drug Abuse (NIDA) to determine the harmful effects of marijuana. In fact, researchers cannot get federal funding or approval for a study through NIDA if the purpose is to determine its safety or efficacy as a medication (Holland, 2010). Numerous claims have been made, such as marijuana causes cancer, it destroys the immune system, it’s the gateway drug that leads to heroin, it kills brain cells, during pregnancy it will result in fetal abnormalities, and on and on.

Upon taking a closer look, many of these studies have been exposed for their flawed methodology, or the dosage was dramatically increased in an attempt to create a negative outcome. For example, there were early claims of marijuana use causing brain damage based on a study of monkeys that were exposed to cannabis smoke. However, it was discovered that the monkeys were forced to breathe only cannabis smoke for a period of time, and the damage was more likely caused by asphyxiation than cannabis smoke. No subsequent study showed such damage. Another early published study on THC and the immune system managed to show negative results but the dosage used on the rats were extremely high (Zimmer & Morgan, 1997).

In 1974, at Virginia Commonwealth University, research was conducted on rats under the theory that cannabis was carcinogenic. Rather than causing cancer, it was discovered that cannabis was effective in killing the lung-cancer cells. The funding was discontinued and the study was never published in the literature (Munson et al., 1975; Cushing, 2001). Early studies by pulmonologist Donald Tashkin of UCLA found that one cannabis cigarette had the same amount of carcinogenic material in its smoke as four tobacco cigarettes (Wu et al., 1988). The federal government held fast to this claim, but neglected to keep up with Tashkin’s work. Admittedly surprised, Tashkin completed a longitudinal study on thousands of subjects and found no pulmonary disease (Tashkin, 2008).

In 1999 the Institute of Medication (IOM) completed an 18-month study on the medical value of cannabis and found that cannabis is not highly addictive, is not a gateway drug, and is safe for medical use. Specifically the IOM stated that “except for the harms associated with smoking, the adverse effects of marijuana use are within the range of effects tolerated for other medications.” At that time, the study panel maintained some concern regarding administration of cannabis by smoking, yet they clearly noted that for patients suffering from cancer or AIDS the pulmonary risks were inconsequential compared to the disease being treated. For all other patients, the IOM panel found cannabis to be safe enough to allow physicians to conduct “n of 1” (individual case) studies. For example, if a glaucoma patient’s intraocular pressure could not be controlled by standard pharmaceuticals, the physician should be allowed to use cannabis as an individual case study with that patient (Joy et al., 1999).

Health Risks Related to Cannabis

No drug is without risks, and no drug works for everyone. However, given the long recorded history of cannabis used as medication and the inability to find clear evidence of harmful effects despite decades devoted to that goal, unadulterated cannabis can be said to present low risk as a medication.

Risks Related to Cannabis Prohibition

Over the past several decades Congress and state legislatures have passed numerous laws in the name of the war on drugs, including mandatory minimum prison sentences and asset forfeiture. In addition, a felony conviction of cannabis “manufacturing” or possession can lead to collateral damage, including revocation of professional licenses, loss of employment, loss of federal grant funding for colleges and universities, loss of child custody, and bars on voting, adoption, receiving food stamps, and living in public housing. For some patients, just admitting cannabis use to their healthcare provider or testing positive for THC in a urine drug screen may result in denial of healthcare services.

Despite the fact that cannabis is an illegal drug and wrongfully placed in Schedule I (forbidden medication) so that healthcare providers cannot legally prescribe it, patients throughout the country willingly take the legal risks because of the beneficial effects on their health.

Although cannabis is easy to grow, it requires knowledge and experience to grow medicinal-grade cannabis. If a patient grows it outdoors, the plants must be kept out of sight of prying eyes. If a patient grows it indoors, the plants require extra equipment and a dedicated room that must be protected from visitors. Most patients don’t have this knowledge or, due to their illness, are not able to properly tend to the plant, so they depend on an outside source. Often family members will grow it for the patient or procure it from an outside source, putting themselves in legal jeopardy as well.

When patients must obtain cannabis from an outside source they have no guarantee of the quality of their medication (eg, contamination with pesticides, heavy metals, mold). This is one of the problems of using a Schedule I drug and the cost can be extreme with no insurance coverage. And, of course, as an illegal substance, patients who use cannabis as medication do not receive the basic education about safe administration from healthcare professionals that they do with other medications.

Risks Related to Smoking Cannabis

How many times have you heard someone justify the cannabis prohibition by declaring “We cannot approve of patients smoking their medication”? Actually, before the cannabis prohibition there were several “cigarette” preparations of cannabis developed to treat patients with asthma. We now know that there are cannabinoid receptors in the bronchi and that cannabinoids help to dilate the airways.

Cannabis smoke does contain tar and other carcinogenic materials and, from a health perspective, it makes sense to avoid this route of administration. Donald Tashkin is the leading U.S. researcher on the clinical effects of smoking cannabis. In his extensive longitudinal study, Tashkin followed thousands of patients for years and evaluated their pulmonary status. He looked at three groups of individuals: cannabis-only smokers, cannabis-and-tobacco smokers, and tobacco-only smokers. To his surprise, the tobacco-only and cannabis-and-tobacco smokers had higher incidences of COPD or lung cancer, but the cannabis-only smokers did not. Tashkin concluded that, although the smoke itself may contain carcinogens, the cannabinoids counter the harmful effects of the smoke (Tashkin, 2008).

A large epidemiologic study of a Los Angeles population looked at 1,212 cancer cases and 1,040 cancer-free controls; they found no positive relationship between smoking cannabis and the investigated cancer types, which included mouth, larynx, lung, and pharynx (Hashibe et al., 2006).

In 2001 Ethan Russo led a team that conducted a thorough study of the longitudinal effects of cannabis on the health of four patients in the Compassionate IND program (referred to as the Missoula Study). These four patients had been receiving cannabis from a known source from 11 to 27 years and, although they were theoretically in a research program, no one had been tracking their health status over the years. It is important to note that these patients had been using the government-issued cannabis that was grown on the farm at the University of Mississippi, then shipped to North Carolina for rolling into cigarettes and packaging them in labeled canisters that held approximately 300 cigarettes. The label identified the THC level of the cannabis and the date of processing.

The patients received low-grade medicinal cannabis containing from 2% to 4% THC and some of their shipments were up to 13 years old. The quality was poor and even included stems and seeds. At the time, Irv Rosenfeld received and consumed up to 13 ounces over a 3-week period. A complete set of pulmonary function tests was conducted on each of these patients and no long-term pulmonary damage or disease was noted except for mild bronchitis (Russo et al., 2002).

Other Potential Risks Related to Medicinal Cannabis

Healthcare professionals are well aware of the possibility of health risks related to medications even when used under medical supervision. When using any medication, the goal is for the benefit (reason for use) to outweigh the risks (side effects and/or adverse reactions). The usual side effects that accompany the use of cannabis include a mild tachycardia, injected conjunctivae (red eye), dry mouth, short-term memory loss, relaxation, sedation, euphoria (sense of well-being), dizziness, and an increased appetite (“the munchies”). Cannabis is not a hallucinogen, but users may experience an alteration of time perception and/or an increased sensory perception.

A side effect for one patient may be a desired effect for another patient. A cancer patient may use cannabis to control the nausea and increase the appetite (for the benefit or desired effect), yet may also experience the side effects of euphoria (not generally a negative effect) and sedation. Dry mouth may be an undesired side effect for many patients, but a desired effect for ALS patients who have difficulty managing their oral secretions. The tachycardia is usually of little concern to most patients, but could be a risk to persons with cardiac disease. Many pain patients have reported that they never experience the euphoria or “high” that is sought by recreational users.

While cannabis is often used as an anti-anxiolytic medication, one of the most common adverse psychic effects is an acute panic reaction, which usually occurs with novice or inexperienced users or with high doses of THC (as in dronabinol or a high-THC strain of cannabis). This rarely requires any pharmacologic intervention and treatment includes a quiet, relaxing environment with reassurance that the patient is fine and the effects will soon wear off.

Psychotic symptoms have been described following acute cannabis consumption and claims have been made that cannabis may cause schizophrenia. Recent reports affirmed that cannabis did not “cause” schizophrenia, but its use was associated with earlier onset of symptoms and more severe psychosis, especially paranoia. Yet some schizophrenic patients report a reduction in their symptoms with the use of cannabis. Although an association has been noted, no causal relationship has been determined (Macleod et al., 2006).

As cannabis use has increased in some populations, there has been no corresponding increase in the incidence of schizophrenia, which would be expected if cannabis was a causal factor. It is of interest to note that, independent of cannabis use, there are more cannabinoid receptors in the brains of patients with schizophrenia that in normal individuals.

In Brazil researchers at two separate laboratories have been conducting research with CBD as an antipsychotic medication (Crippa, 2010; Takahashi, 2010). Remember that CBD is non-psychoactive and when taken with THC it will dampen the psychoactive effects of THC. Could it be that the use of high-THC-content cannabis by patients prone to schizophrenia may trigger the onset of schizophrenia, while high-CBD content cannabis may help manage the symptoms? More research is needed in this area and, until then, patients with a family history of schizophrenia may be cautioned against the use of medicinal cannabis.

THC can impair perception and psychomotor performance, which means that patients may be at increased risk for accidents if operating equipment (eg, driving a vehicle). With chronic use, many patients develop tolerance to the effects that may contribute to impaired driving. For some patients, cannabis is necessary to control their symptoms so they can drive more safely.

The low risk of any serious adverse event occurring with initial use of cannabis makes it an ideal first trial medication (if it were legal) for many patients. No medication works for everyone, and if cannabis is not helpful to an individual patient there is essentially no harm done in trying it. If cannabis is an effective medication, then the clinician and patient need to know the potential risks related to chronic use of this herbal medication.

The primary purpose of the Missoula Study was to determine what, if any, were the negative effects of chronic use of smoking cannabis. In addition to the pulmonary function tests, this study of the four long-term federally supplied cannabis patients included exams such as a complete physical exam, chest x-ray, MRI of the brain, neuropsychological testing, hormone and immunological assays, and an EEG. The overall conclusions were that cannabis provided these patients with symptomatic relief from pain, muscle spasms, and intraocular pressure, helped reduce their use of other prescription medications, produced no long-term sequelae, and improved their quality of life. Obviously these four patients are a small sample size, but each of these patients is convinced that cannabis is an essential medication for them (Russo et al., 2001).

Long-term use of cannabis has not been associated with increased mortality in animals or humans. In an animal study, rats were administered 50 mg/kg of THC for a period of 2 years and at the end of the observation the survival rate was higher among the treated rats than in the controls (a higher incidence of cancer was noted in the control rats) (Chan et al., 1996). A longitudinal study of 65,171 Kaiser Permanente Medical Care Program enrollees found no relationship between cannabis use and mortality (Sidney et al., 1997).

Some studies have shown a reduction in sperm count with chronic cannabis use, but it is reversible if cannabis is discontinued. Studies are inconclusive regarding the effects of cannabis on male and female sterility. THC readily crosses the placenta, but it appears unlikely that cannabis causes fetal abnormalities. When socioeconomic variables have been accounted for, there appear to be no significant fetal problems related to cannabis use by the mother (Dreher, 1997).

Much research has been conducted on the effects of THC or cannabis on the immune system, and the negative effects seem to be dose-related, with negative findings associated with excessive dosage. In clinical studies of HIV-infected men, the use of cannabis was not associated with the onset of AIDS, and no negative drug interactions were found with the use of cannabis in HIV-positive adults taking protease inhibitors (Abrams et al., 2003). There has been some evidence that cannabis use is a risk factor for the progression of fibrosis in chronic hepatitis C patients (Herzode et al., 2005); however, cannabis use improved retention and virologic outcomes in patients treated for hepatitis C with interferon and ribavirin (Sylvestor et al., 2006). A recent study warned of a possible risk of heart attack with acute cannabis intoxication, yet chronic cannabis use has not been associated with cardiovascular risk factors such as blood triglyceride levels and blood pressure in the longitudinal CARDIA study, which began in 1986 (Grotenhermen, 2007).

Risks Related to Abuse and Addiction

Since marijuana is commonly referred to as a drug of abuse, the risk of tolerance, dependence, and addiction should be addressed. Tolerance is defined as the need to increase the dose with chronic use to in order to get the same effects. Healthcare professionals commonly see this with the use of opioids for chronic pain; over time patients develop a tolerance and require higher doses to manage their pain. When used medicinally on a regular basis over a period of time, patients who use cannabis often develop a tolerance to the cognitive and psychomotor impairment as well as the psychological “high,” yet they do not develop a tolerance to its medicinal benefits.

The first patient admitted into the Compassionate IND program, Robert Randall, consumed 10 cannabis cigarettes per day for years to control his intraocular pressure. One month, he seemed to be going through his supply faster than usual. Upon further investigation he discovered that his federal prescription had been changed without his or his physician’s knowledge. Each of his cannabis cigarettes contained 0.8 grams of cannabis rather than the usual 1 gram. Not realizing this decrease in dosage, he simply smoked more cigarettes to continue with his daily requirements. Once discovered, his physician complained and the correct dosage was provided in his next cannabis shipment (Randall and O’Leary, 1998). On the other hand, patients have noticed a tolerance to the therapeutic effects with the use of dronabinol (synthetic THC).

Dependence is a term often misused as a synonym for addiction, but the two terms are not synonymous. Dependence (also referred to as physical dependence) is the result of continued regular use of a drug that produces a physiologic change in the central nervous system to the extent that abrupt cessation of the drug causes withdrawal symptoms.

The seriousness of the withdrawal symptoms depends upon the drug being used and the extent of its use (risks increase with higher doses over long periods of time). For those drugs that do produce physical dependence, there is an expected physiologic response that would occur in anyone who used the drug on a regular basis, but this is not by itself indicative of addiction. For some drugs, such as alcohol or benzodiazepines, withdrawal symptoms can be serious and life-threatening. Opioids can cause withdrawal symptoms similar to a severe case of the flu. However withdrawal from cannabis is generally mild in comparison. Cannabis withdrawal symptoms may include irritability, restlessness, difficulty sleeping, decreased appetite, anxiety, anger, and strange dreams. Less common symptoms include headaches, sweating, chills, stomach pain, and general discomfort.

Most of the cannabis withdrawal symptoms begin within 24 hours following abrupt cessation, are most severe 2 to 4 days later, and last 1 to 2 weeks. Withdrawal from cannabis is generally uncomfortable but not dangerous and does not require medical management. Not all persons complain of withdrawal when discontinuing use. A large survey in Australia found approximately 30% of current marijuana users reported withdrawal symptoms when they stopped using cannabis (Teesson et al., 2002).

It seems important to note that some patients begin using cannabis to manage what some researchers consider withdrawal symptoms. Patients have used cannabis as a sleep aid, appetite stimulant, relaxant, and calming agent. If they stop using cannabis, are their initial reasons for use simply reemerging or are they experiencing true withdrawal symptoms?

Cannabis abuse is a very ambiguous and value-laden term and therefore its use is questionable. “Drug abuse” has often been defined as use of a drug without a prescription or use of an illegal drug. Those notions are not very helpful. Some persons or cultures may not accept the paternalistic notion that only a physician can decide whether a person should use a drug, when to use it, or how often to use it. And the idea that drugs are legal or illegal leads many people to believe that the legal drugs are good and the illegal drugs are bad. Drugs are not inherently good or bad but, as Andrew Weil noted years ago, it is their manner of use that is either bad or good (Weil and Rosen, 1993).

Addiction (sometimes referred to as psychological dependence) is defined as a pattern of drug abuse characterized by an overwhelming preoccupation with the compulsive use of a drug and securing its supply, and a high tendency to relapse if the drug is taken away. Tolerance and dependence are common results of addiction, but are not necessary components of addiction. The new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of the American Psychiatric Association (APA) has been developed with the input of thousands of expert psychiatrists over several decades to classify and characterize human mental health disorders, including substance-use disorders. To provide some continuity in the concept/diagnosis of cannabis addiction, clinicians can use the criteria set up in the DSM (as reported in the APA, 2013):

According to the DSM-5, substance use disorders has replaced the terms abuse or addiction and they are identified by drug type, so here we use the term cannabis use disorder, and depending upon the number of positive criteria, the person is diagnosed with a mild, moderate or severe cannabis use disorder. Below is a list of the 11 criteria of which at least 2 must be met within a 12 month period:

  1. Cannabis is often taken in larger amounts or over a longer period than was intended.
  2. There is a persistent desire or unsuccessful efforts to cut down or control cannabis use.
  3. A great deal of time is spent in activities necessary to obtain cannabis, use cannabis, or recover from its effects.
  4. Craving, or a strong desire or urge to use cannabis.
  5. Recurrent cannabis use resulting in a failure to fulfill major role obligations at work, school, or home.
  6. Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis.
  7. Important social, occupational, or recreational activities are given up or reduced because of cannabis use.
  8. Recurrent cannabis use in situations in which it is physically hazardous.
  9. Cannabis use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by cannabis.
  10. Tolerance, as defined by either of the following: (a) A need for markedly increased amounts of cannabis to achieve intoxication or desired effect or (b) markedly diminished effect with continued use of the same amount of cannabis.
  11. Withdrawal, as manifested by either of the following: (a) The characteristic withdrawal syndrome for cannabis (the following symptoms develop within a week of cessation of cannabis: irritability, anger or aggression; nervousness or anxiety; sleep difficulty; decreased appetite or weight loss; restlessness; depressed mood; and at least one of the following physical symptoms: abdominal pain, shakiness/tremors, sweating, fever, chills, or headache. (b) Cannabis (or a closely related substance) is taken to relieve or avoid withdrawal symptoms.

Addiction to cannabis rarely occurs because, in general, persons who have problems with drug addiction usually prefer more potent psychoactive drugs and caution should be used in making a cannabis use disorder diagnosis to ensure that the problems come from the use of cannabis rather than from the prohibition of cannabis. When dronabinol was initially approved as a medication it was placed in Schedule II of the CSA. After several years on the market, it was down-regulated to Schedule III because of the lack of diversion and little evidence of addiction. Initially, animal studies are used to evaluate the abuse potential of drugs, with the understanding that these do not necessarily reflect similar outcomes in humans. It is important to note that numerous studies have concluded that while cannabis may produce a feeling of euphoria in humans, in general animals will not self-administer THC (DSM-V, 2013).

In 1994 Jack E. Henningfield, of the National Institute on Drug Abuse (NIDA), and Neal L. Benowitz, of the University of California at San Francisco (UCSF), ranked six commonly used drugs by five criteria: withdrawal symptoms (dependence), reinforcement (craving), tolerance, dependence (addiction) potential, and intoxication. They ranked the six drugs from 1 as the most serious to 6 as the least serious. Cannabis (marijuana) was ranked lowest for withdrawal symptoms, tolerance, and dependence (addiction) potential; it ranked close to caffeine in the degree of reinforcement and higher than caffeine and nicotine only in the degree of intoxication (Henningfield & Benowitz, 1994).

 

Ranking scale: 1= Most serious 6 = Least serious
Explanation of terms:

Withdrawal (physical dependence). Presence and severity of characteristic withdrawal symptoms.
Reinforcement. Substance’s ability, in human and animal tests, to get users to take it repeatedly, and instead of other substances.
Tolerance. Amount of substance needed to satisfy increasing cravings and level of plateau that is eventually reached.
Dependence (addiction). Difficulty in ending use of substance, relapse rate, percentage of people who become addicted, addicts self-reporting of degree of need for substance, and continue use in face of evidence that it causes harm.
Intoxication. Level of intoxication associated with addition, personal, and social damage that substance causes.

Source: Henningfield and Benowitz, 1994.

Ranking of Six Commonly Used Drugs

 

Withdrawal

Reinforcement

Tolerance

Dependence

Intoxication

 

NIDA

UCSF

NIDA

UCSF

NIDA

UCSF

NIDA

UCSF

NIDA

UCSF

Nicotine

3

3

4

4

2

4

1

1

5

6

Heroin

2

2

2

2

1

2

2

2

2

2

Cocaine

4

3

1

1

4

1

3

3

3

3

Alcohol

1

1

3

3

3

4

4

4

1

1

Caffeine

5

4

6

5

5

3

5

5

6

5

Marijuana

6

5

5

6

6

5

6

6

4

4

 

Also in 1994, the U.S. National Comorbidity Study found that 9% of lifetime cannabis users met the DSM-R-III criteria for dependence at some time in their life, compared to 32% of tobacco users, 23% of opiate users, 17% of cocaine users, and 15% of alcohol users (Anthony, Warner and Kessler, 1994). It does appear that early onset of first use of cannabis is associated with an increased risk of later developing addiction.

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