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Cannabis Research - Institute of Medicine

Institute of Medicine Report

Marijuana and Medicine: Assessing the Science Base

1999 - National Academy of Sciences

 

Withdrawal/Dependence

Withdrawal symptoms can be observed in animals but appear mild compared with those of withdrawal from opiates or benzodiazepines, such as diazepam (Valium). (Ch.2, IOM, 1999)

although few marijuana users develop dependence, some do. But they appear to be less likely to do so than users of other drugs (including alcohol and nicotine), and marijuana dependence appears to be less severe than dependence on other drugs. (Ch.3, IOM, 1999)

because underage smoking and alcohol use typically precede marijuana use, marijuana is not the most common, and is rarely the first, "gateway" to illicit drug use. There is no conclusive evidence that the drug effects of marijuana are causally linked to the subsequent abuse of other illicit drugs. (E.S. , IOM, 1999)

Decriminalization and Increased Use

Monitoring the Future, the annual survey of values and lifestyles of high school seniors, revealed that high school seniors in decriminalized states reported using no more marijuana than did their counterparts in states where marijuana was not decriminalized. (Ch.3, IOM, 1999)

Despite the greater increase among decriminalized states, the proportion of marijuana users among ER patients by 1978 was about equal in states that had and states that had not decriminalized marijuana. That is because the non-decriminalized states had higher rates of marijuana use before decriminalization. In contrast with marijuana use, rates of other illicit drug use among ER patients were substantially higher in states that did not decriminalize marijuana use. Thus, there are different possible reasons for the greater increase in marijuana use in the decriminalized states. On the one hand, decriminalization might have led to an increased use of marijuana (at least among people who sought health care in hospital ERs). On the other hand, the lack of decriminalization might have encouraged greater use of drugs that are even more dangerous than marijuana. (Ch.3, IOM, 1999)

The authors of this study conclude that there is little evidence that the Dutch marijuana depenalization policy led to increased marijuana use, although they note that commercialization of marijuana might have contributed to its increased use. Thus, there is little evidence that decriminalization of marijuana use necessarily leads to a substantial increase in marijuana use. (Ch.3, IOM, 1999)

Finally, there is the broad social concern that sanctioning the medical use of marijuana might lead to an increase in its use among the general population. No convincing data support that concern. (Ch.3, IOM, 1999)

there is a broad social concern that sanctioning the medical use of marijuana might increase its use among the general population. At this point there are no convincing data to support this concern. The existing data are consistent with the idea that this would not be a problem if the medical use of marijuana were as closely regulated as other medications with abuse potential. (E.S. , IOM, 1999)

Amotivational Syndrome

One of the more controversial effects claimed for marijuana is the production of an "amotivational syndrome." This syndrome is not a medical diagnosis, but it has been used to describe young people who drop out of social activities and show little interest in school, work, or other goal-directed activity. When heavy marijuana use accompanies these symptoms, the drug is often cited as the cause, but no convincing data demonstrate a causal relationship between marijuana smoking and these behavioral characteristics. (Ch.3, IOM, 1999)

Immunity

Despite the many claims that marijuana suppresses the human immune system, the health effects of marijuana-induced immunomodulation are still unclear. (Ch.3, IOM, 1999)

The short-term immuno-suppressive effects are not well established; if they exist at all, they are probably not great enough to preclude a legitimate medical use. The acute side effects of marijuana use are within the risks tolerated for many medications. (Ch.3, IOM, 1999)

Cancer

There is no conclusive evidence that marijuana causes cancer in humans, including cancers usually related to tobacco use. (Ch.3, IOM, 1999)

Terminal cancer patients pose different issues. For those patients the medical harm associated with smoking is of little consequence. For terminal patients suffering debilitating pain or nausea and for whom all indicated medications have failed to provide relief, the medical benefits of smoked marijuana might outweigh the harm. (Ch.4, IOM, 1999)

Tolerance

Tolerance can appear after a few days of frequent daily administration (two or three doses per day) of oral THC or marijuana extract, with heart rate decreasing, reclining blood pressure falling, and postural hypotension disappearing.73 Thus, the intensity of the effects depends on frequency of use, dose, and even body position. (Ch.3, IOM, 1999)

Cardiovascular

The cardiovascular changes have not posed a health problem for healthy, young users of marijuana or THC. (Ch.3, IOM, 1999)

Reproduction/Pregnancy

The presence of cannabinoid receptors in sperm suggests the possibility of a natural role for anandamide in modulating sperm function during fertilization. However, it remains to be determined whether smoked marijuana or oral THC taken in prescribed doses has a clinically significant effect on the fertilizing capacity of human sperm. (ch. 3, IOM, 1999)

Like tobacco smoke, marijuana smoke is highly likely to be harmful to fetal development and should be avoided by pregnant women and those who might become pregnant in the near future. Nevertheless, although fertility and fetal development are important concerns for many, they are unlikely to be of much concern to people with seriously debilitating or life-threatening diseases. The well-documented inhibition of reproductive functions by THC is thus not a serious concern for evaluating the short-term medical use of marijuana or specific cannabinoids. (Ch.3, IOM, 1999)

The results of studies of the relationship between prenatal marijuana exposure and birth outcome have been inconsistent (reviewed in 1995 by Cornelius and co-workers30). Except for adolescent mothers, there is little evidence that gestation is shorter in mothers who smoke marijuana. (Ch.3, IOM, 1999)

In a study of neonates born to Jamaican women who did or did not ingest marijuana during pregnancy, there was no difference in neurobehavioral assessments made at three days after birth and at one month. (Ch.3, IOM, 1999)

The children in the different marijuana exposure groups showed no lasting differences in global measures of intelligence, such as language development, reading scores, and visual or perceptual tests. Moderate cognitive deficits were detectable among these children when they were four days old and again at four years, but the deficits were no longer apparent at five years. (Ch.3, IOM, 1999)

Despite the uncertainty as to the underlying causes of the effects of prenatal exposure to cannabinoid drugs, it is prudent to advise against smoking marijuana during pregnancy. (Ch.3, IOM, 1999)

Safety

Marijuana is not a completely benign substance. It is a powerful drug with a variety of effects. However, except for the harm associated with smoking, the adverse effects of marijuana use are within the range tolerated for other medications. Thus, the safety issues associated with marijuana do not preclude some medical uses. (Ch.3, IOM, 1999)

The side effects of cannabinoid drugs are within the acceptable risks associated with approved medications. Indeed, some of the side effects, such as anxiety reduction and sedation, might be desirable for some patients. As with many medications, there are people for whom they would probably be contraindicated. (Ch.3, IOM, 1999)

 

Pain and Movement

…basic biology indicates a role for cannabinoids in pain and control of movement, which is consistent with a possible therapeutic role in these areas. The evidence is relatively strong for the treatment of pain and, intriguing although less well established, for movement disorders. (Ch.2, IOM, 1999)

Pain

There have not been extensive clinical studies of the analgesic potency of cannabinoids, but the available data from animal studies indicate that cannabinoids could be useful analgesics. (Ch.4, IOM, 1999)

In a later larger single-dose study, the same investigators reported that the analgesic effect of 10 mg of THC was equivalent to that of 60 mg of codeine; the effect of 20 mg of THC was equivalent to that of 120 mg of codeine.139 (Note that codeine is a relatively weak analgesic.) The side effect profiles were similar, though THC was more sedating than codeine. In a separate publication the same authors published data indicating that patients had improved mood, a sense of well-being, and less anxiety. (Ch.4, IOM, 1999)

The results of the studies mentioned above on cancer pain are consistent with the results of using a nitrogen analogue of THC. Two trials were reported: one compared this analogue with codeine in 30 patients, and a second compared it with placebo or secobarbital, a short-acting barbiturate.175 For mild, moderate, and severe pain, the THC analogue was equivalent to 50 mg of codeine and superior to placebo and to 50 mg of secobarbital. (Ch.4, IOM, 1999)

Clinical studies should be directed at pain patients for whom there is a demonstrated need for improved management and where the particular side effect profile of cannabinoids promises a clear benefit over current approaches. The following patient groups should be targeted for clinical studies of cannabinoids in the treatment of pain:

  • Chemotherapy patients, especially those being treated for the mucositis, nausea, and anorexia.
  • Postoperative pain patients (using cannabinoids as an opioid adjunct to determine whether nausea and vomiting from opioids are reduced).
  • Patients with spinal cord injury, peripheral neuropathic pain, or central poststroke pain.
  • Patients with chronic pain and insomnia.
  • AIDS patients with cachexia, AIDS neuropathy, or any significant pain problem. (Ch.4, IOM, 1999)

In conclusion, the available evidence from animal and human studies indicates that cannabinoids can have a substantial analgesic effect. (Ch.4, IOM, 1999)

Nausea and Vomiting

In studies that compared THC with a placebo, THC was usually found to possess antiemetic properties. (Ch.4, IOM, 1999)

Delta8-THC is less psychoactive than THC151 but was found to completely block both acute and delayed chemotherapy-induced emesis in a study of eight children, ages 3-13 years.2 Two hours before the start of each cancer treatment and every six hours thereafter for 24 hours, the children were given Delta8-THC as oil drops on the tongue or in a bite of bread (18 mg/m2 body surface area). The children received a total of 480 treatments. The only side effects reported were slight irritability in two of the youngest children (3.5 and 4 years old). (Ch.4, IOM, 1999)

The evidence from the well-conducted trials indicate that cannabinoids reduce emesis in about one-fourth of patients receiving cancer chemotherapy. (Ch.4, IOM, 1999)

studies of the effects of adjunctive cannabinoids on chemotherapy-induce, IOM, 1999d emesis are worth pursuing for patients whose emesis is not optimally controlled with other agents. (Ch.4, IOM, 1999)

in patients already experiencing severe nausea or vomiting, pills are generally ineffective because of the difficulty in swallowing or keeping a pill down and slow onset of the drug effect. Thus, an inhalation (but preferably not smoking) cannabinoid drug delivery system would be advantageous for treating chemotherapy-induced nausea. (Ch.4, IOM, 1999)

It is possible that the harmful effects of smoking marijuana for a limited period of time might be outweighed by the antiemetic benefits of marijuana, at least for patients for whom standard antiemetic therapy is ineffective and who suffer from debilitating emesis. (Ch.4, IOM, 1999)

Wasting Syndrome

Anecdotes abound that smoked marijuana is useful for the treatment of HIV-associated anorexia and weight loss.23,62 Some people report a preference for smoked marijuana over oral THC because it gives them the ability to titrate the effects, which depend on how much they inhale. In controlled laboratory studies of healthy adults, smoked marijuana was shown to increase body weight, appetite, and food intake. (Ch.4, IOM, 1999)

cannabinoids could be used as appetite stimulants, in patients with diminished appetite who are undergoing resistance exercises or anabolic therapy to increase lean body mass. They could also be beneficial for a variety of effects, such as increased appetite, while reducing the nausea and vomiting caused by protease inhibitors and the pain and anxiety associated with AIDS. (Ch.4, IOM, 1999)

The profile of cannabinoid drug effects suggests that they are promising for treating wasting syndrome in AIDS patients. Nausea, appetite loss, pain, and anxiety are all afflictions of wasting, and all can be mitigated by marijuana. (Ch.4, IOM, 1999)

for cases in which symptoms are multifaceted, the combination of THC effects might provide a form of adjunctive therapy; for example, AIDS wasting patients would likely benefit from a medication that simultaneously reduces anxiety, pain, and nausea while stimulating appetite. (E.S. , IOM, 1999)

Cachexia

The only cannabinoid evaluated for treating cachexia in cancer patients is dronabinol, which has been shown to improve appetite and promote weight gain. (Ch.4, IOM, 1999)

such cannabinoids as THC might prove useful as part of a combination therapy as an appetite stimulant, antiemetic, analgesic, and anxiolytic, especially for patients in late stages of the disease. (Ch.4, IOM, 1999)

MS

Compared to the currently available therapies, the long half-life of THC might allow for a smoother drug effect throughout the day. The intensity of the symptoms resulting from spasticity, particularly in MS, can rapidly increase in an unpredictable fashion such that the patient develops an "attack" of intense muscle spasms lasting minutes to hours. An inhaled form of THC (if it were shown to be efficacious) might be appropriate for those patients. (Ch.4, IOM, 1999)

Parkinson's Disease

Theoretically, cannabinoids could be useful for treating Parkinson's disease patients because cannabinoid agonists specifically inhibit the pathways between the subthalamic nucleus and substantia nigra and probably also the pathways between the subthalamic nucleus and globus pallidus (these structures shown in Figure 2.6).165,169 The latter effect was not directly tested but is consistent with what is known about these neural pathways. Hyperactivity of the subthalamic neurons, observed in both Parkinson's patients and animal models of Parkinson's disease, is hypothesized to be a major factor in the debilitating bradykinesia associated with the disease.36 Furthermore, although cannabinoids oppose the actions of dopamine in intact rats, they augment dopamine activation of movement in an animal model of Parkinson's disease. This suggests the potential for adjunctive therapy with cannabinoid agonists. (Ch.4, IOM, 1999)

Movement Disorders

The abundance of CB1 receptors in basal ganglia and reports of animal studies showing the involvement of cannabinoids in the control of movement suggest that cannabinoids would be useful in treating movement disorders in humans. Marijuana or CB1 receptor agonists might provide symptomatic relief of chorea, dystonia, some aspects of parkinsonism, and tics. (Ch.4, IOM, 1999)

Alzheimer's Disease

Eleven Alzheimer's patients were treated for 12 weeks on an alternating schedule of dronabinol and placebo (six weeks of each treatment). The dronabinol treatment resulted in substantial weight gains and declines in disturbed behavior.190 No serious side effects were observed. One patient had a seizure and was removed from the study, but the seizure was not necessarily caused by dronabinol. Recurrent seizures without any precipitating events occur in 20% of patients who have advanced dementia of Alzheimer's type.189 Nevertheless, these results are encouraging enough to recommend further clinical research with cannabinoids. (Ch.4, IOM, 1999)

Glaucoma

Marijuana and THC have been shown to reduce IOP by an average of 24% in people with normal IOP who have visual-field changes. In a number of studies of healthy adults and glaucoma patients, IOP was reduced by an average of 25% after smoking a marijuana cigarette that contained approximately 2% THC--a reduction as good as that observed with most other medications available today. (Ch.4, IOM, 1999)

In summary, cannabinoids and marijuana can reduce IOP when administered orally, intravenously, or by inhalation but not when administered topically. (Ch.4, IOM, 1999, IOM, 1999)

Cannabis Medications

Advances in cannabinoid science of the past 16 years have given rise to a wealth of new opportunities for the development of medically useful cannabinoid-based drugs. The accumulated data suggest a variety of indications, particularly for pain relief, antiemesis, and appetite stimulation. For patients such as those with AIDS or who are undergoing chemotherapy, and who suffer simultaneously from severe pain, nausea, and appetite loss, cannabinoid drugs might offer broad-spectrum relief not found in any other single medication. (Ch.4, IOM, 1999)

Until a nonsmoked rapid-onset cannabinoid drug delivery system becomes available, we acknowledge that there is no clear alternative for people suffering from chronic conditions that might be relieved by smoking marijuana, such as pain or AIDS wasting. (Ch.4, IOM, 1999)

The accumulated data indicate a potential therapeutic value for cannabinoid drugs, particularly for symptoms such as pain relief, control of nausea and vomiting, and appetite stimulation. The therapeutic effects of cannabinoids are best established for THC, which is generally one of the two most abundant of the cannabinoids in marijuana. (Cannabidiol is generally the other most abundant cannabinoid.) (E.S., IOM, 1999)

The combination of cannabinoid drug effects (anxiety reduction, appetite stimulation, nausea reduction, and pain relief) suggests that cannabinoids would be moderately well suited for particular conditions, such as chemotherapy-induced nausea and vomiting and AIDS wasting. (E.S., IOM, 1999)

Scientific data indicate the potential therapeutic value of cannabinoid drugs, primarily THC, for pain relief, control of nausea and vomiting, and appetite stimulation; smoked marijuana, however, is a crude THC delivery system that also delivers harmful substances. (E.S., IOM, 1999)

for certain patients, such as the terminally ill or those with debilitating symptoms, the long-term risks are not of great concern. Further, despite the legal, social, and health problems associated with smoking marijuana, it is widely used by certain patient groups. (E.S., IOM, 1999)

it will likely be many years before a safe and effective cannabinoid delivery system, such as an inhaler, is available for patients. In the meantime there are patients with debilitating symptoms for whom smoked marijuana might provide relief. The use of smoked marijuana for those patients should weigh both the expected efficacy of marijuana and ethical issues in patient care, including providing information about the known and suspected risks of smoked marijuana use. (E.S., IOM, 1999)

Until a nonsmoked rapid-onset cannabinoid drug delivery system becomes available, we acknowledge that there is no clear alternative for people suffering from chronic conditions that might be relieved by smoking marijuana, such as pain or AIDS wasting. (E.S., IOM, 1999)