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Doi:10.1016/j.coph.2004.08.010

Long-term effects of exposure to cannabisLeslie Iversen The long-term use of cannabis, particularly at high intake levels, heavy users of cannabis, or in animals treated for prolonged is associated with several adverse psychosocial features, periods with the drug. Most reports have shown that there including lower educational achievement and, in some are deficits in the performance of complex cognitive instances, psychiatric illness. There is little evidence, tasks in long-term cannabis users, although there is little however, that long-term cannabis use causes permanent evidence that these are qualitatively or quantitatively cognitive impairment, nor is there is any clear cause and effect more severe than those seen after acute drug use .
relationship to explain the psychosocial associations. Thereare some physical health risks, particularly the possibility of More controversial is the question of whether long-term damage to the airways in cannabis smokers. Overall, by cannabis use can cause irreversible deficits in higher brain comparison with other drugs used mainly for ‘recreational' function that persist after drug use stops. Human studies purposes, cannabis could be rated to be a relatively safe drug.
are fraught with difficulties, as described in detail byEarleywine Indeed, many studies have suffered from poor design. One confounding factor in human studies is University of Oxford, Department of Pharmacology, Mansfield Road, that comparisons have to be made between groups of drug Oxford OX1 3QT, UK users versus non-users; however, it is usually impossible Corresponding author: Iversen L ([email protected]) to compare the baseline performance of these groupsbefore cannabis use to see if they are properly matched.
Pope et al. for example, tested 69 early-onset heavy Current Opinion in Pharmacology 2005, 5:69–72 cannabis users (who began smoking before the age of 17) This review comes from a themed issue on in a battery of neuropsychological tests after a two-week period of abstinence. The group performed significantly Edited by Graeme Henderson, Hilary Little and Jenny Morton worse than late-onset users or controls, but also displayeda lower verbal IQ. When the data were adjusted for this, Available online 21st December 2004 all differences between early-onset users and others 1471-4892/$ – see front matter ceased to be significant.
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It is not sufficient to identify a group of cannabis users and simply to test them after stopping cannabis use. Onestudy, for example, recruited 63 current heavy users who had smoked cannabis at least 5000 times in their lives and 72 control subjects . The subjects underwent a 28-daywashout from cannabis use, monitored by urine assays. At days 0, 1 and 7, the heavy users scored significantly below Cannabis is the most commonly used illicit drug. In many control subjects on a battery of neuropsychological tests, countries, more than 50% of young people have used it at particularly in recall of word lists. However, by day 28, least once and it is widely perceived as relatively safe.
there were no differences between the groups in any of Many people believe that there are genuine medical uses the test results, and no significant association between for cannabis-based medicines and it seems likely that cumulative lifetime cannabis use and test scores. The fact such products will gain official approval in several that drug-induced effects on cognitive performance can Western countries. Concurrently, there is a move towards persist for up to a week after stopping the drug (perhaps relaxation of the criminal penalties associated with the because of the persistence of D9-tetrahydrocannabinol recreational use of cannabis — ranging from the down- [THC] in the body, or because of a subtle withdrawal grading of criminal penalties in the UK to the possibility syndrome) means that many earlier studies that did not of full legalization in Canada and Switzerland. In light of allow a sufficiently long washout period might be invalid.
these changes in attitude, it is timely to consider again theadverse effects associated with long-term cannabis use One way of assessing cognitive function is to measure IQ.
over a period of years, as no drug can ever be considered Fried et al. tested the effects of cannabis use in a group completely safe.
of 70 young people by subtracting each person's IQ scoreat nine years of age (before drug use) from their score at Effects on cognition age 17-20 years. Current cannabis use was found to be Several studies have addressed the question of whether significantly correlated in a dose-dependent manner with severe deficits in cognitive function develop in chronic a decline in IQ scores. However, no such decline was seen Current Opinion in Pharmacology 2005, 5:69–72 in subjects who had formerly been heavy cannabis users cannabis use can precipitate psychiatric illness in a vul- and had stopped taking the drug. The authors concluded nerable minority of previously well people remains unan- that cannabis does not have a long-term effect on global swered. One could equally argue that a tendency to psychotic illness might increase the likelihood of earlycannabis use . It is possible that cannabis may pre- This general conclusion was also supported by a review of cipitate schizophrenic illness earlier in vulnerable people the 40 published studies that met adequate criteria, which who exhibit ‘schizophreniform' tendencies. Such a con- failed to detect any consistent evidence of persisting clusion is supported by the results of a study of 122 newly neuropsychological deficits in cannabis users — although admitted schizophrenia patients in the Netherlands, some studies reported subtle impairments in the ability to which showed a strong association between cannabis learn and remember new information use and the age of onset of the first psychotic episodein men, with users experiencing their first psychotic Cannabis and psychiatric illness episode 6.9 years earlier than non-users There has been a long-standing concern that cannabis usemight precipitate mental illness in some users. It is clear Other studies have explored the association between that an acute schizophrenia-like psychosis can occur in cannabis use and depression. One longitudinal study in response to a high dose of cannabis , but whether Australia reported that daily use of cannabis by teenage cannabis use can cause persistent psychiatric illness in girls (but not boys) led to an approximately twofold people who had not previously shown psychotic symp- increased risk for depression/anxiety in later life A toms remains contentious. A recent re-analysis of the review of other studies of this type suggested that heavy results of a large scale study of >50 000 Swedish men cannabis use may increase depressive symptoms in some (age 18–20 years) conscripted into the Swedish army users, but whether this represents a causal relationship is between 1969 and 1970 suggested that those who had used cannabis >50 times before the age of 18 years had a6.7-fold increased risk of developing schizophrenia in Psychosocial sequelae of cannabis use later life . A review of this and four other longitudinal Apart from the potential risk of mental illness, there has cohort studies also concluded that early cannabis use been a long standing concern that adolescent use of might be a causal factor for schizophrenia-like illness cannabis could lead to reduced educational achievement in later life However, the interpretation of such and reduced motivation — sometimes referred to as an studies is fraught with many difficulties, as reviewed by ‘amotivational syndrome' Macleod et al. These authors highlighted that proofof a causal relationship is subject to many confounding Cherek et al. attempted to assess this experimentally factors. When known confounding factors were applied to in a study in which human participants earned money by the Swedish army data, for example, the odds ratio was responding on a complex lever-pressing schedule. There reduced from 6.7 to 3.1 This, in turn, suggests that was a significant reduction in the number of responses, other residual unidentified confounding factors are also time spent and money earned when the subjects were re- likely to exist. The published studies show that the tested while smoking cannabis, indicating a drug-induced existence of ‘prodromal' symptoms of psychosis clearly reduction in motivation.
increased the risk of subsequent psychiatric illness incannabis users . This factor was adequately con- Various longitudinal studies have sought to establish the trolled for in only one of the five published longitudinal relationship between cannabis use and subsequent edu- studies In this New Zealand cohort, even when cational achievement. A study of 1265 New Zealand those exhibiting prodromal symptoms of psychosis were children showed that cannabis use was dose-depen- eliminated, those who started cannabis use by age 15 dently related to an increased risk of leaving school years (but not those who started later) showed a fourfold without qualifications, failure to enter university and increase in the risk of developing schizophrenia-like ill- failure to obtain a university degree. A similar conclusion ness by age 26 years. However, the number of subjects was reached in reviews of other published studies of this involved was small (there were 26 15-year old cannabis type . The review by Macleod et al. was users, of whom three developed mental illness) so the particularly comprehensive; the authors studied 48 pub- statistical power of this study was limited. Degenhardt lished longitudinal studies on the use of cannabis, of et al. sought to test the hypothesis of a causal relation- which 16 were considered to provide the most robust ship between cannabis use and schizophrenia by a care- evidence. Their conclusions for cannabis use were, firstly, ful examination of the incidence of schizophrenia in Australia during the past 30 years. Although the preva- achievement; secondly, a consistent association with lence of cannabis use had increased markedly during this use of other drugs; thirdly, an inconsistent association period, there was no evidence of a significant increase in with psychological problems of various types; and finally, the incidence of schizophrenia. The question of whether an inconsistent association with antisocial or other Current Opinion in Pharmacology 2005, 5:69–72 Long-term effects of exposure to cannabis Iversen problematic behaviours. They concluded that ‘‘Available nity, there is no evidence that cannabis causes any other evidence does not support an important causal relation serious immunosupression in users . The authors sug- between cannabis use and psychosocial harm, but cannot gested that the effects on lung macrophages might be exclude the possibility that such a relation exists''.
related to the ability of cannabis in animal studies to causea shift from Th1 to Th2 cytokine production.
Whatever the nature of the association, it seems clear thatlong-term heavy cannabis use carries a variety of negative With increasing use of cannabis, there remains a concern attributes. A case control study compared 108 heavy-use that cannabis use during pregnancy might impair foetal long-term cannabis users, who had on average smoked development. Reviews of data from humans, however, 18 000 times, with 72 age-matched controls who had suggest that such effects are minimal for cannabis users smoked cannabis <50 times The heavy-use can- when compared with the well-documented adverse nabis smokers reported significantly lower educational effects of tobacco or alcohol use Nevertheless, attainment and lower income than did controls. When treatment of pregnant rats with high doses of THC did asked to rate the subjective effects of cannabis on cogni- lead to significant reductions in expression of neural tion, memory, career, social life, physical and mental adhesion molecule L1 in the foetal brain — a key protein health and various quality-of-life measures, a large major- for brain development ity of heavy-use cannabis smokers reported negativeeffects of their drug use.
ConclusionsA review of the literature suggests that the majority of Cannabis and substance dependence cannabis users, who use the drug occasionally rather than Although it was previously thought that cannabis was not on a daily basis, will not suffer any lasting physical or a drug of addiction, it is now recognized that cannabis use mental harm. Conversely, as with other ‘recreational' can lead to substance dependence in perhaps as many as drugs, there will be some who suffer adverse conse- 10% of regular users, according to the internationally quences from their use of cannabis. Some individuals accepted DSMIV definition of ‘substance dependence' who have psychotic thought tendencies might risk pre- . In both animals and humans, a clear withdrawal cipitating psychotic illness. Those who consume large syndrome can be identified In rodents, chronic doses of the drug on a regular basis are likely to have lower administration of THC or synthetic cannabinoids leads educational achievement and lower income, and may to downregulation and desensitization of cannabinoid suffer physical damage to the airways. They also run a CB1 receptors in the brain This might partly explain significant risk of becoming dependent upon continuing the tolerance that develops in both animals and humans use of the drug. There is little evidence, however, that on repeated use of the drug. In regular cannabis users, these adverse effects persist after drug use stops or that abstinence leads to a withdrawal syndrome characterized any direct cause and effect relationships are involved.
by negative mood (irritability, anxiety, misery), musclepain, chills, sleep disturbance and decreased appetite. A In contrast, cannabis might have beneficial effects in placebo-controlled study showed that these symptoms some medical indications. There is considerable litera- were significantly reduced by oral administration of THC, ture obtained from animal studies to suggest that cannabis suggesting that the withdrawal syndrome and underlying has analgesic effects . Until recently, however, there substance dependence were related to effects of THC on has been a dearth of controlled clinical studies to validate the cannabinoid CB1 receptor, rather than to any other such effects in patients. This has now changed, with the component of herbal cannabis .
publication in the past two years of a number of double-blind placebo-controlled trials showing the effectiveness Other potentially toxic effects of long-term of cannabinoids in relieving chronic neuropathic pain or pain associated with multiple sclerosis  Some of the most serious adverse effects of smoked . The largest of these trials involved 630 multiple cannabis are on the respiratory system. Although little sclerosis patients and showed significant pain relief after progress has been made recently in quantifying such 15 weeks of treatment with either pure THC or cannabis risks, warnings continue to be issued about the potential extract It seems likely that medicinal cannabis will for long-term damage or even malignancy in the airways re-enter the Pharmacopoeia.
It is known that lung macrophages isolated fromcannabis smokers exhibit impaired anti-bacterial activity, References and recommended reading and one experimental study showed that this might be Papers of particular interest, published within the annual period ofreview, have been highlighted as: caused, in part, by reduced expression of inducible nitricoxide synthase and decreased production of nitric oxide  of special interest of outstanding interest A review of the evidence for immunosuppressanteffects of cannabis concluded that, with the exception of Earleywine M: Understanding marijuana. Oxford: Oxford the effects of cannabis smoking on broncho-alveolar immu- University Press; 2002.
Current Opinion in Pharmacology 2005, 5:69–72 Pope HG Jr, Gruber AJ, Hudson JI, Cohane G, Huestis MA, 17. Lynskey L, Hall W: The effect of adolescent cannabis use Yurgelun-Todd D: Early-onset cannabis use and cognitive on educational attainment: a review. Addiction 2000, deficits: what is the nature of the association? Drug Alcohol Depend 2003, 69:303-310.
18. Gruber AJ, Pope HG, Hudson JI, Yurgelun-Todd D: Attributes Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D: of long-term heavy cannabis users: a case-control study.
Neuropsychological performance in long-term cannabis Psychol Med 2003, 33:1415-1422.
users. Arch Gen Psychiatry 2001, 58:909-915.
The prospects for heavy-use long-term smokers of cannabis are bleak.
Fried P, Watkinson B, James D, Gray R: Current and former 19. Sim-Selley LJ: Regulation of cannabinoid CB1 receptors in the marijuana use: preliminary findings of a longitudinal study central nervous system by chronic cannabinoids. Crit Rev of effects on IQ in young adults. CMAJ 2002, 166:887-891.
Neurobiol 2003, 15:91-119.
Gonzalez R, Carey C, Grant I: Nonacute (residual) 20. Haney M, Hart CL, Vosburg SK, Nasser J, Bennett A, Zubaran C, neuropsychological effects of cannabis use: qualitative Foltin RW: Marijuana withdrawal in humans: effects of oral THC analysis and systematic review. J Clin Pharmacol 2002, or divalproex. Neuropsychopharmacology 2004, 29:158-170.
21. Taylor DR, Hall W: Respiratory health effects of cannabis: Iversen LL: Cannabis and the brain. Brain 2003, position statement of the Thoracic Society of Australia and New Zealand. Intern Med J 2003, 33:310-313.
Comprehensive review of acute- and long-term actions of cannabis in theCNS.
22. Roth MD, Whittaker K, Salehi K, Tashkin DP, Baldwin GC: Mechanisms for impaired effector function in alveolar Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G: macrophages from marijuana and cocaine smokers.
Self-reported cannabis use as a risk factor for schizophrenia J Neuroimmunol 2004, 147:82-86.
in Swedish conscripts of 1969: historical cohort study.
BMJ 2002, 325:1199-1201.
23. Kraft B, Kress HG: Cannabinoids and the immune system.
Of men, mice and cells. Schmerz 2004, 18:203-210.
Arseneault LJ, Cannon M, Witton Murray RM: Causal association between cannabis and psychosis: examination of the 24. Park B, McPartland JM, Glass M: Cannabis, cannabinoids and evidence. Br J Psychiatry 2004, 184:110-117.
reproduction. Prostaglandins Leukot Essent Fatty Acids 2004, An important review of the evidence from longitudinal studies of a causal relationship between cannabis use and subsequent psychiatric 25. Chiriboga CA: Fetal alcohol and drug effects. Neurologist 2003, Macleod J, Oakes R, Copello A, Crome I, Egger M, Hickman M, Review of the literature concludes that there are only minimal effects of Oppenkowski T, Stokes-Lampard H, Davey Smith G: cannabis on foetal development.
Psychological and social sequelae of cannabis and other illicit 26. Gomez M, Hernandez M, Johansson B, de Miguel R, Ramos JA, drug use by young people: a systematic review of longitudinal Fernandez-Ruiz J: Prenatal cannabinoid and gene expression general population studies. Lancet 2004, 363:1579-1588.
for neural adhesion molecule L1 in the fetal rat brain.
An excellent analysis of all published longitudinal studies.
Brain Res Dev Brain Res 2003, 147:201-207.
10. Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE: 27. Iversen LL, Chapman V: Cannabinoids: a real prospect for Cannabis use in adolescence and risk for adult psychosis: pain relief? Curr Opin Pharmacol 2002, 2:50-55.
longitudinal prospective study. BMJ 2002, 325:1212-1213.
28. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U: 11. Degenhardt L, Hall W, Lynskey M: Testing hypotheses about Analgesic effects of the synthetic cannabinoid CT-3 on the relationship between cannabis use and psychosis.
chronic neuropathic pain: a randomized controlled trial.
Drug Alcohol Depend 2003, 71:37-48.
J Amer Med Assoc 2003, 290:1757-1762.
12. Veen ND, Selten JP, van der Tweel I, Feller WG, Hoek HW, 29. Wade DT, Robson P, House H, Makela P, Aram JA: A preliminary Kahn RS: Cannabis use and age of onset of schizophrenia.
controlled study to determine whether whole-plant cannabis Am J Psychiatry 2004, 161:501-506.
extract can improve intractable neurogenic symptoms.
13. Patton GC, Coffey C, Carlin JB, Degenhardt L, Lynskey M, Hall W: Clin Rehabil 2003, 17:21-29.
Cannabis use and mental health in young people. BMJ 2002, 30. Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A: Cannabinoids for treatment of spasticity and other symptoms 14. Degenhardt L, Hall W: Exploring the association between related to multiple sclerosis (CAMS study): multicentre cannabis use and depression. Addiction 2003, randomized placebo-controlled trial. Lancet 2003, The largest controlled clinical trial for cannabinoid use in multiple 15. Cherek DR, Lane SD, Dougherty DM: Possible amotivational effects following marijuana smoking under laboratoryconditions. Exp Clin Psychopharmacol 2002, 10:26-38.
31. Svendsen KB, Jensen TS, Bach FW: Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? 16. Fergusson DM, Horwood LJ, Beautrais AL: Cannabis and Randomised double blind placebo controlled crossover trial.
educational achievement. Addiction 2003, 98:1681-1692.
Br Med J 2004, 329:253-261.
Current Opinion in Pharmacology 2005, 5:69–72

Source: http://cannabiscoalition.ca/info/IversenCannabisEffects.pdf