Background

Marijuana, or cannabis, is a crude preparation of flowering tops, leaves, seeds, and stems of female plants of the Indian hemp Cannabis sativa; and it is usually smoked as a "recreational" drug. The intoxicating constituents of hemp are found in the resin exuded by the tops of the plants, particularly the females. Male plants produce only a small amount of resin. The resin itself, when prepared for smoking or eating, is known as "hashish." Various cannabis preparations are used as intoxicants throughout the world, with potency varying with the amount of resin present. The tops contain the most resin; stems, seeds, and lower leaves the least. The intoxicants in the resin are called cannabinoids, the most active of which is delta 9-tetrahydrocannabinol (THC).

Although marijuana use in the United States dates back to the 19th century, its early use was confined predominantly to certain groups such as Mexican laborers, inner city Blacks, and some "Bohemian" groups. Restricted by increasingly severe legal penalties imposed during the 1930s, its use in those relatively small groups was not a major cause for public concern. Following the widespread popularity and use of the hallucinogen LSD during the 1960s, an explosion in marijuana use took place, at first on college campuses, followed by downward spread to secondary schools and upward to portions of the middle class. Public alarm grew over the hazards to the general public posed by the rapidly growing use of marijuana and other mind-altering drugs. Marijuana, plus other drugs like heroin, had a high potential for abuse with limited or no potential for medical use, and they were designated as schedule I drugs – making their use and possession illegal.

The scheduling of dangerous drugs is done by the Drug Enforcement Administration (DEA), but only after the Food and Drug Administration (FDA) decides that a new drug is a suitable medication, albeit one needing to be scheduled because of its abuse potential. The agencies work closely together, as required by law, and a routine scheduling action cannot be taken by one of the agencies without the concurrence of the other.

Recent developments

During the past two decades in the United States, there has been a steady increase in the number of people entering treatment for marijuana related problems. According to one report, two-thirds of those admitted for treatment were young – between the ages of 12 and 25 years (1). The majority of those admissions were from either the justice or educational systems.

Marijuana use is associated with impaired educational attainment (2), reduced workplace productivity (3), and plays a major role in motor vehicle accidents (4). Marijuana is increasingly recognized as a cause, along with tobacco, of both lung cancer and emphysema (5) (6). In spite of this, an editorial in a major medical journal, the Lancet, stated as recently as 1995 that "the smoking of cannabis, even long term, is not harmful to health."(7).

In the United States, marijuana use remained stable at about 4% during the decade between 1991-1992 and 2001-2002, according to two large national surveys conducted 10 years apart (8). Marijuana use disorders among adults, however, increased significantly during that decade. The potency of THC in confiscated marijuana increased by 66% between 1992 and 2002, and this may have contributed to the problem. The disorders included marijuana abuse, that is, use under hazardous conditions or impairment in social, occupational, or educational functioning related to use. Another marijuana use disorder is dependence, defined as increased tolerance, compulsive use, impaired control, and continued use despite physical and psychological problems caused by its use.

A major focus for concern has been the extent to which marijuana use leads to the use of and dependence on "hard" drugs. There has been a longstanding debate over whether this association is due to the criminalization of marijuana use, forcing the user to seek suppliers who deal in other illicit drugs, or whether marijuana conditions the user to try other drugs.

A study was reported from Australia of a volunteer sample of 311 young, adult, monozygotic and dizygotic, same sex twins discordant for early cannabis use i.e. less than 17 years (1). The outcome measures included subsequent non-medical use of prescription sedatives, hallucinogens, cocaine or other stimulants, and opioids leading to abuse or dependence on these drugs. Abuse and/or dependence on cannabis or alcohol were also outcome measures. Twins who used cannabis by age 17 had odds of other drug use or alcohol dependence plus drug abuse from two to five times higher than those of their discordant twin. These associations did not differ between monozygotic and dizygotic twins. The findings indicate that early use of cannabis is associated with increased risks of progression to other illicit drug use. Since the subjects were twins neither genetic nor environmental factors were likely to have produced the results. However, since marijuana use is illegal in Australia the study was unable to establish whether having to obtain the drug from dealers involved with other illegal drugs exposes the marijuana user to other illicit drugs.

A similar study was conducted in the Netherlands, where out of a group of 6000 twins, 219 same sex pairs were chosen, one of whom had begun using marijuana before age 18 while the other twin had not (9). The study showed that the twin who used marijuana before the age of 18 had a significantly greater risk of using hard drugs and of drug dependence. Since marijuana is legal and widely available in the Netherlands, the findings from both studies clearly indicate that marijuana serves as a gateway for use and abuse of other addictive drugs in adolescents whose central nervous system is still not fully developed.

Marijuana and psychoses

The relationship of marijuana to the development of psychoses has been a cause for concern in recent years. Large intakes of cannabis are able to trigger acute psychotic episodes and may worsen the effects of established psychoses. Chronic daily users often report increased levels of anxiety, depression, fatigue, and low motivation (10).

A number of prospective studies have been conducted in the past decade to determine whether marijuana use is associated with psychoses. In summary the studies produced suggestive evidence of a causal link between marijuana and psychoses or psychotic behavior, but were unable to adjust for the effects of the many confounding variables in these studies.

In an effort to overcome these problems, a systematic review of a number the studies was published recently (11). The review used meta-analysis to analyze the data from cohort studies of psychosis reported in the literature. The studies were located in the United States, Germany, the Netherlands, the United Kingdom, Sweden, and New Zealand. The psychoses included schizophrenia and other types of abnormal behavior regularly classified as psychotic disorders. The presence of delusions, hallucinations, or thought disorder was a requirement for all psychosis outcomes. The analysis found that there was a 40% increase in the development of psychosis in individuals who had ever used marijuana compared to those who had never used it. Individuals who had used marijuana daily or weekly had more than an 80%, or twofold, increase in the risk of psychosis. The increased risks of psychosis persisted independent of other drug use or existing mental health problems. The evidence for affective disorders, i.e., depression or anxiety, however, was less strong. The authors state that although the individual lifetime risk of chronic psychotic disorders such as schizophrenia among marijuana users is likely to be less than 3%, even among those who use the it regularly, it can be expected to have a substantial effect on the incidence of psychotic disorders in the general population, because use of the drug is so common. No evidence was found in this review to link the development of psychosis with early use of marijuana.

The evidence from this study is compelling and can be interpreted to indicate that marijuana use has been, and will continue to be, an important factor in the large numbers of homeless, mentally ill adults in American cities. The Lancet has altered its stand on marijuana and now states that governments should invest in sustained and effective education campaigns on the risks to health posed by using cannabis (7).

Recent findings from comparative research

Work on the pharmacology of the cannabinoids has found that there are cellular receptors for these substances located on cells throughout the body. These receptors are most widely expressed in the brain, but they are also found on cells in other parts of the body—such as the cardiovascular system, the lungs, liver, kidneys, and cells of the immune system. The receptors are part of a normal system within the body and are activated by intercellular signaling molecules known as endocannabinoids. Although these molecules are unrelated to the cannabinoids produced by marijuana, they carry the name cannabinoids by virtue of their discovery through cannabis research.

The normal functions of these receptors is still incompletely understood, but experiments in animal models are beginning to show the importance of some receptors in neuronal growth and the maturation of nerve connections in the brain. Activation of these receptors by marijuana cannabinoids can interfere with their normal function (12).

A recent report indicates that THC can affect brain development and induce cognitive and behavioral deficits in prenatally exposed infants which are sustained into adolescence. These data show that maternal marijuana use may affect early neurodevelopment by interfering with immature nerve cells. (13). There is obviously much more to be learned from this type of animal research involving cannabinoid receptors and the effects of their activation by cannabinoids found in marijuana.

Marijuana as medicine

There have been a number of successful efforts, both through referenda and through legislation, to legalize the use of marijuana for medical purposes. The proponents argue that either smoked or ingested marijuana is safe and effective for the treatment of cancer chemotherapy induced nausea and vomiting and for pain associated with spinal cord injury or peripheral neuropathies. Advocates also suggested that using marijuana is effective in treatment of a variety of other conditions including malnutrition, movement disorders, epilepsy, and glaucoma. The Office of National Drug Control Policy funded a study by the Institute of Medicine to evaluate the scientific evidence for benefits and risks of using marijuana as a medicine. The report was issued in 1999, and a summary of the report was published the following year (14). The report focused principally on marijuana's use for nausea and vomiting, wasting syndrome, neurological disorders, and glaucoma. The review found a modest therapeutic potential for various cannabinoids found in marijuana, particularly for pain relief, control of nausea and vomiting, and appetite stimulation. The review stated, however, that most of the medical conditions studied already have good to excellent medications currently available. The authors went on to state that the future of cannabinoid medication would lie in the preparation of pure drugs, delivered using non-smoked means, under standard federal and state regulatory systems.

References:

1) Lynsky MT, Heath AC, Bucholz KK, et al. Escalation of drug use in early-onset cannabis users vs. co-twin controls. JAMA 2003; 289: 427-433

2) Lynsky MT, Hall W. The effects of adolescent cannabis use on educational attainment: a review. Addiction. 2000; 95: 1621-1630

3) Lehman WI, Simpson DD. Employee substance abuse and on-the-job behaviors. J Appl Psychol 1992; 77: 309-321

4) National Highway Traffic Safety Administration. Traffic Safety Facts 2001 Washington: D.C.

5) Aidington S, Harwood M, Cox B, et al. Cannabis use and the risk of lung cancer: a case-control study. European Respiratory Journal 2008; 31:280-286

6) Beshay M, Kaiser H, Niedhart D, et al. Emphysema and secondary pneumothorax in young adults smoking cannabis. European J. Cardio-Thoracic Surgery 2007; 32: 834-838

7) Editorial: Rehashing the evidence on psychosis and cannabis. The Lancet 2007; 370: 292

8) Compton WH, Grant BE, Colliver JD et al. Prevalence of marijuana use disorders in the United States 1991-1992 and 2001-2002 JAMA 2004; 291: 2114-2121

9) Lynsky MT, Vink JM, Boomsa DI Early onset cannabis use and progression to. other drug use in a sample of Dutch twins. Behav Genet 2006; 36: 195-200

10) Patton GC, Coffey CC, Carlin JB, et al. Cannabis use and mental health in young people: a cohort study BMJ 2002; 325: 1195-1198

11) Moore HM, Zammit S, Hughes AL et al. Cannabis use and risk of psychotic or affective mental health outcomes; a systematic review.The Lancet 2007; 370: 319-328

12) Stern PR NEUROSCIENCE:.Cannabis use impairs brain development. Science 2005; 309:222

13) Berghuis P, Rajnick AM, Morozov YM et al. Hardwiring the brain: endocannabinoids shape neuronal conductivity. Science 2007; 316: 1212-1216

14) Watson SJ, Benson JA, Joy JE. Marijuana and medicine: assessing the science base

Arch Gen Psychiatry 2000; 57: 547-552