Drug Abuse

 

COMMENTARY

The human toxicity of marijuana: a critique of a review by Nahas and Latour

MCDONALD J. CHRISTIE & GREGORY B. CHESHER

Department of Pharmacology, University of Sydney, New South Wales, Australia

Abstract

A review entitled "The human toxicity of marijuana" was published in 1992 in the Medical Journal of Australia. The authors claimed that the adverse effects of cannabis use have been trivialized and that the effects are much more serious than earlier reported. We have made a careful study of this review and examined the claims made. We compared the claims of the authors with the information contained in the documents they cited and found that at least 28 of the 35 citations in this article were cited inaccurately. Five of these publications were misquoted, or the findings of the study were not fully reported. Twenty-three citations contained other errors, leaving only six to eight (two citations could not be retrieved because of their obscurity) accurate citations among 35. All of these inaccuracies operate in the direction of finding an adverse effect of marijuana. [Christie M, Chesher GB The human toxicity of marijuana: a critique of a review by Nahas and Latour. Drug Alcohol Review l994:13:209-216.]

Key words: marijuana; cannabis; THC; human toxicity; adverse effects; health effects.

introduction

It is not a pleasant task to make an open criticism of a paper by colleagues, but we feel compelled to do so in the case of a paper published in the Journal of Australia in 1992*. The paper, entitled "The human toxicity of marijuana" which purported to be a review of the most recent scientific literature on the health effects of cannabis, claimed that previous knowledge on the subject should now be revised in the light of "new evidence". However we believe that the authors of this paper were less than meticulous in their description of the work of others which they cited. We believe that the readers of this review could be confused as to the interpretation of the present state of knowledge of the human toxicity of marijuana.

Under the circumstances we feel it is of importance to publish a detailed examination, paragraph by paragraph, of the statements made by Nahas & Latour and the references cited by them in support of such statements. The review contains 18 paragraphs and six main headings. The reference numbers cited and the section headings listed here are those in the paper by Nahas & Latour.

Paragraphs 1 to 6 comprise the introduction to the review and prepare the reader for the "new" information which will demonstrate the "new" evidence for the mutagenic effects of cannabis which "have now been reported in man" (end of para 6). In paragraph 1, the authors cite a recent (widely cited) major review of the health effects of cannabis by Hollister (ref 1) as an example of how the adverse effects of cannabis have been "trivialized".

Nahas & Latour cite Hollister to claim "Because of its lack of life threatening effects, cannabis has been called a 'soft drug', no more damaging than coffee or tobacco". Hollister actually concluded: "Compared with other licit social drugs such as alcohol, tobacco, and caffeine, marijuana does not pose greater risks. One would wonder, however, if society were given a choice based on current knowledge, whether these drugs would have been granted their present status of acceptance". Contrary to the inference of Nahas & Latour, Hollister's review included the effects of long-term use and nowhere does he refer to marijuana as a "soft" drug. This citation misquoted what remains a most authoritative review of the health effects of cannabis.

To counter Hollister's review Nahas & Latour claimed that information has emerged on the damaging effects of cannabis "which have only recently been reported" (ref 2, Nahas & Latour 199l) and "which confirm experimental observations" (ref 3, Nahas 1986). In fact, ref. 2 is a symposium proceedings edited by Nahas in 1990. Many of the symposium papers are rewritten versions of other papers cited below, i.e. the findings were not new. Ref 3 was a review by Nahas published in the Medical Journal of Australia in 1986, and therefore was neither experimental nor new. Fourteen of the citations in that review (Nahas, ref 3) were traced to publications by, or in symposia proceedings organized by, Nahas. Citation of reviews and symposium proceedings might be considered reasonable when reviewing a large body of literature, but that process could not be considered in itself to provide substantial new experimental evidence. Furthermore, 12 of the references in the Nahas & Latour 1992 paper were dated between 1976 to 1985, and were all available to Hollister for his 1986 review.

In paragraphs 2 to 6 Nahas and Latour compare the properties of marijuana and tobacco smoke, and summarize some of the pharmacological properties of tetrahydrocannabinol (THC). There is no new information in these paragraphs which include only one citation, that of Turner, 1980 (ref 4).

Paragraph 6 cites two references to indicate that cannabis extracts are mutagenic (ref 5; Busch et al

1979) and that "THC and other cannabinoids impair DNA and RNA synthesis in cell cultures" (ref 6; Leuchtenberger et al 1973). It is not surprising that marijuana smoke condensates are mutagenic in Ames tests (ref 5; Busch et al), since smoke condensates of most plant materials contain carcinogens. On the other hand, the citation for ref 6 (Leuchtenberger et al), if correct, would be cause for concern, since it would indicate that the active drug (THC) and related compounds might be carcinogenic However, Leuchtenberger et al actually examined the effects of marijuana and tobacco smoke condensates on DNA and chromosomal components (not RNA) in human lung explants, and did not examine THC or other cannabinoids Per se.

"Pulmonary toxicity and carcinogenicity of the aerodigestive tract"

Paragraph 6 concludes with the statement that "such properties account for the toxicity which has now been reported in man". In paragraphs 7 and 8 the claim is made that aerodigestive cancers are common in young cannabis smokers and is supported by two references, 8 and 9, both of which are dated 1980 and therefore are not "new" evidence. Reœ 8 (Tashkin et al 1980) refers predominantly to large airways obstruction. The link between this finding and cancer implied by Nahas & Latour is speculative. Ref 9 (Tennant et al 1980) was cited to claim the identification of squamous cell hyperplasia in bronchial biopsies from heavy hashish users. In fact, the original reference concluded "chronic hashish smoking combined with cigarette smoking appear to have more deleterious pulmonary effects than either hashish or cigarettes smoked alone". Paragraph 9, it seems, provides five references as "documentation" of a link between aerodigestive tract cancer and cannabis. Of these only ref 14 (Caplan & Briham, 1990) is correctly cited; ref 10 (Donald, 1991 and is actually from ref 2) is cited by Nahas & Latour as reporting 12 cases of advanced head and neck cancer in young patients: "All had been daily marijuana or hashish users since high school, but did not smoke tobacco or use much alcohol". Perusal of the 11 cases reported in this paper revealed that six users also smoked tobacco and three reported "heavy alcohol intake". To fail to acknowledge the reported tobacco use and heavy alcohol intake gives the inaccurate implication that cannabis use was the sole risk factor in these cases.

Ref 11 (Endicott & Skipper, 1991), is from the proceedings of a symposium in Switzerland which could not be located in Australian libraries. Ref 12 (Taylor, 1988) reported 10 patients under the age of 40 years with the diagnosis of respiratory tract carcinoma. Nahas & Latour claimed that "seven had a history of daily marijuana use". The cited paper actually implied daily use for only five patients, presumably on the basis of clinicians' notes. Six of the 10 patients were tobacco smokers and six were heavy ethanol users. As with ref. 10 the omission of the reported use of other drugs could imply that cannabis use was the sole risk factor. Ferguson et al. (1989; ref 13) reported a 27 -year old man who died of metastatic lung carcinoma. Nahas & Latour claim that this man "had smoked marijuana heavily and steadily since the age of 11 years", but they omitted to report that the man had also smoked tobacco since the age of 17. The omission might be considered trivial in another context, but since it is used by Nahas & Latour to claim a special toxicity in the young, we believe it is a misrepresentation of the cited reference.

"Marijuana and leukemia"

In paragraph 10 Nahas & Latour cite ref 15 (Robison et al 1989) with these words: "The study showed there was a tenfold risk of leukemia in the offspring of mothers who had smoked just before or during pregnancy ... Children exposed to marijuana in utero developed the disease at a younger age compared with the controls (at a mean age of 19 months compared with 93 months) and showed clonal abnormalities". Nahas & Latour did not mention the qualifications expressed by the authors of the original paper in the interpretation of these data.

They pointed out that their data may have been influenced by confounding variables and, although the association was significant, the risk confidence intervals were large (95% confidence interval of risk was 1. 42 to 85.20) for all mind-altering drugs. Of greater concern, the authors pointed out that marijuana use (obtained by telephone interview) was greatly under-reported in the entire sample, questioning the validity of the data. They point out that rates of use of 5% and 0.5% were reported in the affected and control groups, respectively. Other studies of use during pregnancy report frequencies greater than 10%. The authors stressed the need to confirm this observation in a larger sample, presumably with more accurate reporting of maternal drug use. If these results were confirmed by a large, properly controlled study there would be cause for concern. However, Nahas & Latour presented this preliminary and, perhaps, erroneous, observation as an established fact. They omitted any mention of the cited authors' cautions.

"Damaging effects of marijuana on human fetal development"

Paragraph 10 begins with the assertion that "marijuana products were toxic to fetal development in all species studied: fish, birds, rodents, hamsters, rabbits, dogs and monkeys", citing ref 16 (Rosenkrantz, 1979) as the source. In fact, the sum paper, conducted exclusively in that although so me feticidal effects "No drug-related teratogenic effects were found Nahas & Latour then state "Offspring also displayed retarded development and behavioral anomalies", citing in this case ref 17 (Dalterio et al 1981). Ref 17 was actually concerned with the effects of THC on plasma testosterone concentrations in adult male mice. The experiments did not consider fetal development in any way and no reference was made, even in discussion, to 'retarded development' . No behavioral effects were examined and discussion of' behavioural anomalies' was confined to anecdotal reports of aphrodisiac effects of marijuana in humans and copulatory behavior in male mice. This section continues with the assertion that human birth defects such as "lower weight and head circumference" occur in marijuana smokers. The support for this statement was in two references, 18 and 19. Ref 18 (Qazi et al 1985) was a summary of five case reports of offspring of young women who lived in the central Brooklyn area. The authors attributed growth abnormalities to maternal marijuana use, without any substantial evidence. On the other hand, ref 19 (Hingson et al. 1982) studied 1690 mother/child pairs and concluded that marijuana use was associated with lower birth-weight infants and abnormalities designated as compatible with fetal alcohol syndrome, but they also "caution against firm conclusion that marijuana causes fetal growth retardation without consideration of other maternal behaviors such as drinking, tobacco smoking and other psychoactive drug use".

In support of their contentions Nahas & Latour also cited two subsequent studies, ref 20 (Hatch & Bracken, 1986) and ref 22 (Zuckerman et al 1989). Both studies found reduced birth-weight or small for gestational age, but Hatch & Bracken (ref 20) made no mention of head circumference. Ref 22 was from the same group of ref 19 and reported that low birth-weight and length were associated with validated cannabis use, but reduced head circumference was not, when potentially confounding variables were controlled for. This study, published in a highly respected journal, was the most thorough of those cited. As such, Nahas & Latour's claim of "lower ... head circumference" (with what we believe to be an implicit message of brain damage) could be seen as a misrepresentation of the cited refs 20 and 22.

The study cited to support "possible impairment of fetal brain development", ref 21 (Lester & Dreher, 1989), examined the cries of offspring of very heavy chronic cannabis-using mothers in Jamaica. Although the authors interpreted their findings as evidence that cannabis affected the "neurophysiological integrity" of infants the effects were not unequivocally demonstrated. The study also failed to consider direct intoxicating effects of THC on infants, many of whom were presumably consuming high concentrations of THC via maternal milk.

Regardless of how the findings of Zuckerman et al (ref 22) and others were viewed, there is concern that the major observations, of reduced birth-weight and length, may be valid. The prudent approach suggested by Hollister (ref 1) is worth noting: suggested 'While no definite clinical association has yet been made between cannabis use during pregnancy and fetal abnormalities, such events are likely to be rare at best and could easily be missed. The belated recognition of the harmful effects on the fetus of smoking tobacco and drinking alcoholic beverages indicates that the same caution with cannabis is wise" .

"Marijuana and the brain"

Nahas & Latour claim that the well recognized acute impairment of mental performance continues well beyond the period of cannabis intoxication, citing ref 23 (Soueif 1976; unrefereed conference proceedings). This information is neither new nor are the results consistent with larger studies of cannabis using populations (cf ref 1). Nahas & Latour next cite a study conducted in 1973 (ref 24; Satz et al 1973) which reports negative findings for this effect. However, they then cite a follow-up study by the same research group (ref 25; Page et al 1988), the results of which they describe in this way: "performed on the same cohort of Latin American marijuana users and on non-using controls, showed selective impairment of short-term memory skills in cannabis users, contradicting the results obtained 10 years earlier". Examination of this report (Page et al ref 25) reveals that the study actually found significant but "not particularly robust" deficits among users for three performance measures from at least 14 memory and performance tests. None of the tests showing deficits had been included in the original study, and only 57 of the original 82 subjects completed these tests. Although this second study found small effects, the authors described these as "subclinical". The authors also pointed out that their results may have been complicated by the consequences of the increased social disapproval of marijuana use in Costa Rica.

Nahas & Latour then cite a study by Varma et al (ref 26; Varma et al 1988) which they summarize as reporting "short term memory impairment in heavy marijuana smokers studied in India". Although these authors found one significant effect among 11 memory tests, they apparently dismissed it as spurious: "compared with a control group, the cannabis users were found to react slowly in perceptuomotor tasks, but did not differ in intelligence or memory tests". The cannabis use was described as 150 mg/day of THC for 5 years or more. The users also suffered disability in personal, social and vocational areas and indicated higher psychoticism and neuroticism scores. It is not clear whether these differences preceded or were a consequence of their heavy cannabis use.

The next citation was that of Schwartz et al (ref 27, 1989) which Nahas & Latour describe as "an exceptionally well controlled study which showed persistent short term memory impairment in a group of middle class American adolescents who used marijuana". Schwartz et al actually described their work as a "pilot study" and commented that "Although it was conducted in a methodologically more rigorous manner than many past efforts, some problems admittedly remained in the study design. Larger research efforts with at least 25 subjects in each group better matched for gender would have improved the results of our study".

They compared performance of six short-term memory tests between 10 patients enrolled in an out-patient drug abuse treatment program for adolescents and 17 (presumably) matched controls. Significant deficits were found for two of the six memory tests. Although Nahas & Latour reported a persistent deficit in memory tests during a 6-week drug-free period to support the notion of long-term memory impairment, this finding was a source of concern for the authors because it could have indicated initial differences (unrelated to drug use) between groups. It is nevertheless an important study which should be replicated.

In paragraph 12, Nahas & Latour seem to attempt to establish by implication that cannabis produces subtle brain damage. They first claimed (without any experimental evidence) that disruption of short-term memory produced by cannabis (which is not actually established) is similar to that found in brain-damaged patients presenting with memory disorders. We do not agree with their claim that "These memory deficits .. have been traced to impairment of the hippocampus ... " and "Impaired mental performance ... has been related to impaired turnover of acetylcholine", as these were not substantiated by any citations. They cited Herkenham et al (ref 28, 1990) who reported that THC binds to the hippocampus (as well as many other brain structures), which is thought to be involved in memory formation. However, contrary to the implications of Nahas & Latour, these observations do not in any way implicate a damaging effect of THC on this brain structure, or memory.

Nahas & Latour then cited a positron emission tomography (PET) study of glucose utilization (ref 29; Volkow et al. 1991, which is contained in ref. 2, a Nahas & Latour edited colloquium) to indicate brain regions associated with impairment. The technique examines metabolic activity in different brain regions to discover which brain regions are activated during intoxication. It does not measure impairment. The study was described by the authors as "preliminary" (six subjects) and no significant differences were actually reported for glucose utilization in any brain region. Nevertheless, Nahas & Latour concluded that "THC significantly alters glucose metabolism in the frontal and parietal lobes and cerebellum for several hours. Such metabolic changes in areas of the brain which control memory and information processing are associated with impairment in the performance of complex tasks".

Paragraph 13 cites studies of the "lingering effects of marijuana on memory and coordination" when volunteers were tested on a flight simulator. This study, (ref 30; Leirer & Yesavage, 1991) reported marginal deficits in performance eight and 24 hours after smoking. It is debatable whether they were statistically significant, since they used a single tail t-test to test an unexpected outcome; i.e. a previous flight simulator study had proven negative for the hypothesized long-term effect (cf ref 1).

"Marijuana and road accidents"

Nahas & Latour introduced this section (in paragraph 14) with the implication that impairment produced by cannabis is more serious than for alcohol. This was implied by citing a report to suggest "that THC was 4000 times more potent than alcohol in producing decrements in performance ... " (ref 31; Chesher et al 1985, unrefereed symposium proceedings). The comparison in the original study was made to indicate the differences in absolute potency of these drugs tested with a specified test battery. Doses of alcohol are measured in grams and those of THC in milligrams, so one would expect a potency ratio of this order.

Nahas & Latour then describe railway and heavy vehicle accidents and make the claim "several major railroad accidents have illustrated the impairing effects of marijuana on the performance of complex tasks". They first mention a freight train crash which occurred in January 1987 and then another crash which occurred one year later. In each case railway-men who may have been culpable in these crashes were found to have cannabinoids in their body fluids. These accident reports are not cited, so it has not been possible to check whether the investigation actually claimed a causative role for cannabis. Nahas & Latour have already noted in this review the retention of cannabinoids in the body for up to a month (paragraph 5), so the detection of cannabinoids in the body fluids of a railwayman does not provide proof of impairment at the time of the accident.

The authors maintain their implication of cause- effect in paragraph 15 in citing the February 1990 report of the National Transportation Safety Board (ref 32) when they claim that this report "has provided the most extensive evidence linking fatal accidents among truck drivers to cannabis". The report (p. 24), indicates that the study involved the investigation of 181 heavy truck accidents involving 185 case vehicles and drivers. These accidents resulted in the deaths of 207 people including 181 drivers of the heavy vehicles. The study included the analysis of blood and/or urine samples taken from the bodies of the drivers killed in the accidents. Their interpretation of the results of the drug analyses reads "One third of the victims whose bodies were examined had recently used alcohol or drugs: 12.8% had used marijuana, 12.5% had used alcohol and 8.5% had used cocaine". The Executive Summary of the report (ref 32) states on p. v "the Safety Board found that 33 percent of the fatally injured drivers tested positive for alcohol and other drugs". Since the report makes no mention of recency of drug use, this must have been determined by Nahas & Latour, but they do not state how they did so.

Marijuana and schizophrenia

Nahas & Latour cite a journal editorial (ref 33; Negrete, 1989) to support their claim that "It is well established that marijuana smoking can trigger an acute psychotic episode in schizophrenics". In fact, the editorial's main focus was to draw attention to a study of Swedish military conscripts (see ref 34; Andreasson et al 1987). The weaknesses of this study were criticized, as they have been elsewhere. (eg Johnson et al Lancet 1988;i:592 593). mentions of triggering psychotic episodes in this editorial were: "However, Andreasson et al's suggestion to the effect that cannabis use is a 'stressor' capable of triggering the psychotic breakdown, is an aspect that requires considerably more exploration and "Some clinical studies indeed found that cannabis appears to enhance or magnify the of schizophrenia-particularly those of the positive type-and it is therefore conceivable that the drug might precipitate the clinical expression of a disorder that would otherwise remain latent". Although there is general concern that cannabis might exacerbate symptoms of schizophrenia, Nahas & Latour's conclusions are not consistent with the overall emphasis and content of this editorial.

Nahas & Latour cited the study of Andreasson et al (ref 34, 1987, also rewritten in ref 2), which detected a six-fold greater incidence of schizophrenia among heavy cannabis users (use on more than 5O occasions) than in non-users. However, when the authors corrected for other variables, including previous psychiatric history, the relative risk dropped to 3.1 times (95% confidence interval: 2.1, 4.7). This was not mentioned by Nahas & Latour.

It should be noted that such studies cannot establish causality, as pointed out in 33 by Negrette and other commentaries (see above), because: (1) the authors did not establish a sequential or temporal link between cannabis use and admission for schizophrenia, (2) diagnosis was not reconfirmed and could in some cases represent toxic psychosis, (3) both cannabism and schizophrenia may result from a common predisposing condition, (4) schizophrenic breakdown may have been precipitated by other drugs, e.g. amphetamines, which were also used more frequently by cannabis subjects. These criticisms (ref 33) make Nahas & Latour' s claim that "The ability of cannabis to induce long lasting mental disturbances in Western man, now epidemiologically documented . ..", much less compelling than implied. Summaries of " older anecdotal reports" (ref 35, a monograph edited by Nahas, not retrieved) add little weight to their claims.

In the final paragraph of this review Nahas & Latour claim to have demonstrated that the animal research of the 1970s which described some of the possible areas of cannabis toxicity have actually been "good predictors of the long term pathophysiological manifestations observed 20 years later in chronic marijuana smokers". If their evidence for this statement resides in the arguments presented in their review in the Medical Journal of Australia in 1992 we cannot accept that they have proved this claim. We have described here a high incidence of inaccuracies in their description of the original data that they have cited. All these inaccuracies operate in the direction of finding an adverse effect of marijuana. These authors may hold a sincere belief that cannabis is a more dangerous drug than the scientific literature presents it to be. However, the inaccurate citation of scientific data as we have described in this analysis of their review in the Medical Journal of Australia does nothing to advance rational debate on this issue. The danger is that their review confused the thinking of very many concerned people.

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3 Nahas GG. Cannabis: toxicological properties and epidemiological aspects Med J Aust l986;145:82-7.

4 Turner CE, Elsohly MA, Boeren EG. Constituents of Cannabis sativa L. XVIl. A review of the natural constituents. J Nat Prod l980;43:69 234.

5 Busch FW, Seid DA, Wei ET. Mutagenic activity of marihuana smoke condensates. Cancer Lett l979;6:319-24.

6 Leuchtenberger C, Leuchtenberger R, Ritter U,. Effects of marijuana and tobacco smoke on DNA and chromosoma1 complement in human lung explants. Nature l973;242:403-4.

7 Cabral GA, Vasquez R. Marijuana decreases macrophage antiviral and antitumor activities. ln: Nahas GG, Latour C, editors. First lnternational Colloquium on Illicit Drngs. Advances in the biosciences. Oxford: Pergamon Press, l99l:93 105.

8 Tashkin DP, Ca1varese BM, Simmons MS, Shapiro BJ. Respiratory status of seventy four habitual marihuana smokers. Chest l980;78:699 706.

9 Tennant FS, Guerry RL, Henderson RL.Histopathologic and clinical abnormalities of the respiratory system in chronic hashish smokers. Subst Alcohol Actions Misuse l980;1:93 100.

10 Donald pJ. Marijuana and upper aerodigestive tract malignancy in young patients. ln: Nahas GG, Latour C, editors. First lnternational Colloquium on Illicit Drugs. Advances in the biosciences. Oxford: Pergamon Press, l99l:39-54.

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