Pubdate: Wed, 22 May 2002 Source: Journal of the American Medical Association (US) Vol: 287 No. 20, May 22/29, 2002 Copyright: 2002 American Medical Association. Contact: http://jama.ama-assn.org/ Details: http://www.mapinc.org/media/219 Note: References in [ ] authors shown below their letters DOES MARIJUANA USE CAUSE LONG-TERM COGNITIVE DEFICITS? To the Editor: Dr Solowij and colleagues  concluded that their findings "confirm that long-term heavy cannabis users show impairments in memory and attention that endure beyond the period of intoxication." In his accompanying Editorial, Dr Pope  pointed out that this study could not establish a causal relationship between use of marijuana and later declines in cognitive performance. Neither Solowij et al nor Pope, however, referred to laboratory studies designed to assess causality, such as ours, which evaluated the effects of acute marijuana administration on complex cognitive performance in regular marijuana smokers.  Unlike the subjects of Solowij et al, these individuals were not seeking treatment and had heavier marijuana use, averaging 24 marijuana cigarettes per week. Participants smoked a single marijuana cigarette during 3 separate outpatient sessions containing varying amounts of tetrahydrocannabinol, which had minimal effects on cognitive functioning. Chait  reported similar findings. Both of these laboratory studies found minimal cognitive deficits after marijuana administration in experienced users and suggest that recent marijuana use is a minimal confounder in experienced marijuana users. Data from well-controlled laboratory studies in combination with data from retrospective studies can ultimately provide a more comprehensive view of marijuana-related effects on human cognitive performance. Erik W. Gunderson, MD; Suzanne K. Vosburg, PhD; Carl L. Hart, PhD; Department of Psychiatry, Division on Substance Abuse, New York State Psychiatric Institute and College of Physicians and Surgeons of Columbia University, New York 1. Solowij N, Stephens RS, Roffman RA, et al, for the Marijuana Treatment Project Research Group. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA. 2002;287:1123-1131. ( http://www.mapinc.org/drugnews/v02/n395/a10.html ) 2. Pope HG Jr. Cannabis, cognition, and residual confounding. JAMA. 2002;287:1172-1174 ( http://www.mapinc.org/drugnews/v02/n396/a01.html ) 3. Hart CL, van Gorp W, Haney M, et al. Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology. 2001;25:757-765. 4. Chait LD. Subjective and behavioral effects of marijuana the morning after smoking. Psychopharmacology (Berl). 1990;100:328-333. - ---------------------------------------------------------------------- To the Editor: While the study of Dr Solowij and colleagues  demonstrates a significant difference in cognitive function between long-term users and short-term/nonusers of marijuana, I am concerned about possible selection biases. Because all the marijuana users in this trial were actively seeking assistance with reduction or cessation, the sample may be biased toward those individuals who feel they have a substance use problem so severe it requires treatment. Michael Watson, MC, USNR, Department of Family Practice, Naval Hospital, Jacksonville, Fla 1. Solowij N, Stephens RS, Roffman RA, et al, for the Marijuana Treatment Project Research Group. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA. 2002;287:1123-1131. ( http://www.mapinc.org/drugnews/v02/n395/a10.html ) - ---------------------------------------------------------------------- To the Editor: I would like to point out 2 defects in the study of Dr Solowij et al. First, it does not control for age-related differences in cognitive function, which could potentially cause the differences between the long- and shorter-term user groups. Second, cannabinoids are present for many days after ingestion. Age-related differences in excretion may also explain the apparent difference in function between long- and shorter-term users of marijuana. Julia R. Nyquist, MD; San Anselmo, Calif - ---------------------------------------------------------------------- In Reply: Dr Gunderson and colleagues refer to controlled laboratory studies that found minimal cognitive deficits in experienced users after acute marijuana administration. These findings support our interpretation that the observed long-term effects were unlikely to be confounded by residual effects of recent cannabis use. Our study was designed specifically to investigate chronic effects, with years of use as our variable of interest. By requiring several hours abstinence prior to testing, we induced an unintoxicated cognitive state that long-term users typically operate in for substantial periods in their daily life. We showed that impairments were generally unrelated to withdrawal and recent use. We concluded that a probable causal relationship exists because we controlled for potential confounding factors. It should be noted that the experienced cannabis users in these laboratory studies did not approach the long-term durations reported by participants in our study, and that the potency of cannabis smoked in the community is generally greater than that administered in the laboratory. Nevertheless, we agree that controlled laboratory studies provide a valuable complement to naturalistic studies like ours. Just as acute effects of cannabis differ in experienced vs naive subjects, long-term effects vary with the frequency and duration of cannabis use. This and the mechanisms involved in the development of tolerance to the acute effects of cannabinoids on cognition are complex issues that require further research. Dr Watson expresses concern about selection bias. Although the participants in this study were seeking treatment, their impairments were related specifically to the number of years that cannabis had been used, replicating our previous findings in cannabis users not seeking treatment.  Thus, regardless of treatment seeking, there is good evidence for a neurobiological explanation underlying cognitive impairments that develop over many years of exposure to cannabis. Dr Nyquist claims that there was a lack of control for age differences between groups. We included age as a covariate in analyses where it correlated with test performance and we performed semipartial correlations to examine the unique contributions of age and duration of cannabis use to the variance in cognitive test performance (reported in Table 4). Because age and duration of cannabis use are so inextricably linked, isolation of effects associated with years of cannabis use relies on statistical control methods; our results showed a greater unique contribution from the years of cannabis use. We ensured that the control group did not differ in age from the overall cannabis user sample prior to their division into long- and shorter-term user groups. Our previous studies1 have shown cognitive impairments in long-term cannabis users compared with age-matched controls. We are unaware of any literature showing age-related differences in excretion of cannabinoid metabolites. Nadia Solowij, PhD; National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia; Department of Psychology, University of Wollongong, Wollongong, Australia Thomas Babor, PhD, MPH; Department of Community Medicine, University of Connecticut Health Center, Farmington Robert Stephens, PhD; Department of Psychology, Virginia Polytechnic Institute and State University, Blacksburg Roger A. Roffman, DSW; Innovative Programs Research Group, School of Social Work, University of Washington, Seattle, for the Marijuana Treatment Project Research Group 1. Solowij N. Cannabis and Cognitive Functioning. Cambridge, United Kingdom: Cambridge University Press; 1998. - ---------------------------------------------------------------------- To the Editor: In his Editorial accompanying our paper on cognitive functioning in long-term heavy cannabis users,  Dr Pope  makes inferences that question the validity of our findings. We point out that the possible confounding factors that Pope alludes to were in fact controlled in our study. We also wish to clarify other issues that he brings up. First, we did not claim that the cognitive impairments associated with long-term heavy cannabis use in our study were irreversible; we only showed no performance differences between those abstaining for less than or more than 17 hours (range, up to 240 hours). A reversible deficit need not necessarily be due to a residue of cannabinoids or to withdrawal, which our data did not support. These impairments could be interpreted in terms of a gradual adaptation of the nervous system to prolonged exposure to exogenous cannabinoids, possibly resulting in altered functioning of the endogenous cannabinoid or other neuromodulator systems. After prolonged abstinence, these systems may well return to healthy function. Future analyses from this study will investigate recovery of function in the same sample 4 months after cessation or reduction of cannabis use. Second, Pope suggests that our results may have been influenced by residual confounding. Our screening of participants was very thorough: there was no greater incidence among the cannabis users of head injury, concussion, hospitalization, treatment seeking for psychological or emotional problems, or use of prescription medications. Data (not reported in the article) showed no association between performance on the cognitive tests and psychological distress as measured by the Beck Depression Inventory, State-Trait Anxiety Inventory, and Brief Symptom Inventory, on which shorter-term users generally had the highest scores yet did not differ from controls in cognitive performance. Similarly, no site differences were found in either sociodemographics or cognitive test performance. The sex ratio did not differ between any of our groups but since Pope and Yurgelun-Todd had previously reported sex differences in cognitive effects of cannabis,  we also investigated these and found none. Contrary to Pope's assertion that the results may be explained by differences in prior abuse of other substances, we showed that significant memory impairment was evident in the long-term users after excluding participants with previous histories of other substance use. We also reported analyses that countered the hypothesis that these effects might be due to age or to recent use of cannabis. The results replicate findings from our earlier studies that used different cognitive tests and measures of brain electrical activity  to show that cognitive impairments worsen with the number of years of cannabis use. Few studies have investigated the effects of duration of cannabis use. Of course, there may be unknown influences affecting associations of this kind but the evidence from our study supports the most parsimonious conclusion that it is the years of cannabis use that produces the impairment. Nadia Solowij, PhD; National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia; Department of Psychology, University of Wollongong, Wollongong, Australia Robert Stephens, PhD; Department of Psychology, Virginia Polytechnic Institute and State University, Blacksburg Roger A. Roffman, DSW; Innovative Programs Research Group, School of Social Work, University of Washington, Seattle Thomas Babor, PhD, MPH; Department of Community Medicine, University of Connecticut Health Center, Farmington for the Marijuana Treatment Project Research Group 1. Solowij N, Stephens RS, Roffman RA, et al, for the Marijuana Treatment Project Research Group. Cognitive functioning of long-term heavy cannabis users seeking treatment. JAMA. 2002;287:1123-1131. 2. Pope HG Jr. Cannabis, cognition, and residual confounding. JAMA. ( http://www.mapinc.org/drugnews/v02/n396/a01.html ) 3. Pope HG Jr, Yurgelun-Todd D. The residual cognitive effects of heavy marijuana use in college students. JAMA. 1996;275:521-527. 4. Solowij N. Cannabis and Cognitive Functioning. Cambridge, United Kingdom: Cambridge University Press; 1998. - ---------------------------------------------------------------------- In Reply: Dr Solowij and colleagues provide reassurance regarding their extensive efforts to control for possible confounds. Our similar study  of equally long-term cannabis users agrees with theirs in finding cognitive impairment hours to days after discontinuing cannabis. However, our studies still disagree on one important point: Solowij et al found increasing cognitive impairment with increasing duration of cannabis use, whereas we did not. I still believe that the most parsimonious explanation for this discrepancy is residual confounding, either from inadequate adjustment for measured confounders or (perhaps more likely) from the presence of unmeasured confounders. This is because both studies depend heavily on the assumption that, after appropriate statistical adjustments, longer- and shorter-duration cannabis users are comparable on all factors, other than the amount of exposure, that would influence the outcome. [2, 3] Such comparability may be almost impossible to achieve in a retrospective study, particularly since preexposure cognitive function and latent vulnerability to neuropsychiatric disorders (either unexpressed or only partially expressed) may predispose to duration of cannabis use and may influence outcome. Even in seemingly well-matched groups, minor confounders can substantially alter estimated effects. One cannot exclude the possibility that among cannabis users spontaneously seeking psychiatric treatment for their drug use, subtle neuropsychiatric factors, not induced by cannabis, may affect cognitive performance despite the best efforts to control for such factors. The most that can be concluded is that the effect sizes observed in our 2 studies are simultaneously consistent either with no duration-associated deficits at all (all observed differences being due to residual confounding) or with a substantial association of possible clinical importance. Therefore, I stand by my conclusion that we must live with uncertainly. Harrison G. Pope, Jr, MD; Biological Psychiatry Laboratory, McLean Hospital, Harvard Medical School, Belmont, Mass 1. Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D. Neuropsychological performance in long-term cannabis users. Arch Gen Psychiatry. 2001;58:909-915. 2. Greenland S, Robins JM. Identifiability, exchangeability, and epidemiologic confounding. Int J Epidemiol. 1986;15:412-418. 3. Little RJ, Rubin DB. Causal effects in clinical and epidemiologic studies via potential outcomes: concepts and analytical approaches. Annu Rev Public Health. 2000;21:121-145.