Normal Skin Test Responses in Chronic Marijuana Users Abstract. The cell-mediated immunity of 22 chronic marijuana smokers showed no difference from that of normal controls when evaluated by in vivo skin testing with 2,4-dinitrochlorobenzene. However, a significant difference was seen between these chronic marijuana users, all of whom could be sensitized to 2,4-dinitrochlorobenzene, and age-matched cancer patients, who showed a decreased capacity to be sensitized. In a study of 51 subjects, Nahas (1) suggested that cellular immunity may be impaired by the chronic use of marijuana. His in vitro studies showed that lymphocyte blastogenesis in response to allogeneic cells (mixed lymphocyte culture) and in response to the mitogen phytohemagglutinin was decreased to levels comparable to those of patients with a known impairment of cellular immunity (cancer, uremia, and kidney transplant patients), and that this depression was statistically different from that of normal controls. However, in vivo skin testing with the foreign antigen 2,4-dinitrochlorobenzene (DNCB) and with a battery of common antigens may be a better gauge of overall immunocompetence than any currently used in vitro lymphocyte function test, because skin testing closely correlates to clinical prognosis in cancer patients (2). Since 96 percent of the normal population can be sensitized to DNCB (2, 3), we tested the capacity of chronic marijuana users to develop a delayed cutaneous hypersensitivity response to DNCB and thus grossly evaluated, in vive, their immunologic competence. For this study, the chronic marijuana user was defined as one who regularly smoked marijuana a minimum of three times per week for at least 6 months (4). Tobacco smoking and alcohol were allowed but the regular or frequent use of other drugs disqualified the subject from the study. Skin testing with DNCB was performed in a standard fashion (2) on 22 healthy males ranging in age from 21 to 30 years. After the skin was cleansed with acetone, a sensitizing dose of 2000 "g of DNCB dissolved in 0.1 ml of acetone was applied to the skin of the upper arm. A 100-pg dose was applied at the same time to the ipsilateral forearm to test for previous sensitization. After 14 days, the subjects were challenged on the ipsilateral forearm with 100, 50, and 25 g of DNCB as well as with a cutaneous irritant, croton oil. as a check for an intact inflammatory response. On the same day. four common antigens in doses of 0.1 ml were injected intradermally in the contralateral forearm. The antigens were monilia (Hollister-Stier, 2 units), mumps (Lilly, 2 units), purified protein derivative (Connaught, 5 units, intermediate strength), and Varidase (Lederle, 10 units). All positive reactions were scored as 1+ (erythema and induration of less than half the diamete, of the tout site), 2+ (measurable skin reaction over at least half of the test site), 3+ (reaction covering the entire test site), or 4+ (bullac formation). All 22 subjects reacted to 50 μg of DNCB (21 were either 3+ or 4+), and 21 reacted to 25 ug of DNCB (14 were either 3+ or 4+). Seventeen subjects reacted to two or more common antigens, three subjects reacted to only one common antigen, and two subjects failed to react to any of them. The failure of two DNCB-positive subjects to respond to any of the common antigens is probably not indicative of a defect in immunologic memory. In this age group, unresponsiveness is probably due to lack of exposure to these antigens. The results of the DNCB skin testing are summarized in Table 1 and are compared with combined data from published evaluations of DNCB skin testing in normal subjects and cancer patients (2. 3). In order to obtain an age-matched control group with probable immunodepression, we reviewed the skin test records of 60 consecutive cancer patients between the ages of 21 and 30 years from the Division of Oncology, University of California, Los Angeles. These patients, who were not under drug treatment at the time of testing, were tested by the identical procedure in the same institution as the marijuana users and represent a concurrent control group. Twelve (20 percent) were DNCB-negative. Thus, this DNCB procedure can detect a defective immune response. When our group of 22 DNCB-positive, chronic marijuana users was compared to the control group of 279 normal subjects, there was no statistical difference (5, 6). It appears that the chronic use of marijuana does not decrease the capacity of a subject to become sensitized and to develop delayed cutaneous hypersensitivity when challenged with the hydrocarbon hapten DNCB. However, when the marijuana ༈ ལྕན། ༩,1es eers compared with either cancer group (all ages (5, 7) or ages 21 ta. 30 (5, 8)]. a statistical difference was found. The 10 percent difference in DNCB positivity between all cancer patients and the age-matched cancer patients. although not significant (5, 9). may be due to the fact that many patients in the age-matched group had early, localized disease. Immunocompetence appears to decrease with increas.ag age and extent of neoplastic disease Prolonged immunosuppression profound implications. Patient, with congenital immunodeficiencies ard those with iatrogenic immunosuppression (such as renal transplant pation >) develop cancer at rates at least 3 times that of the general population (10). However, there is no clinical or epi demiologic evidence to suggest that chronic marijuana users might be more prone to the development of neoplastic or infectious processes. In vivo skin testing has proved to be a valuable tool in the gross evaluation of the immune system because a delayed cutaneous hypersensitivity response requires the participation of a number of components of cell-mediated immunity. Since responses were normal in the chronic marijuana users we tested, it would appear that chronic marijuana smoking does not produce a gross cellular immune defect that can be detected by skin testing. Further study is needed to evaluate chronic marijuana use and its effect, if any. on the immune system. MELVIN J. SILVERSTEIN PHYLLIS J. Lessin Department of Surgery, Division of Oncology, and Department of Psychiatry, Center for the Health Sciences, University of California. Los Angeles 90024 References and Notes 1. G. G. Nahas, N. Suciu-Foca, J.-P. Armand, A. Morishuma, Science 183, 419 (1974). 2. F. R. Filber and D. L. Morton, Cancer 25, 362 (1970). 3. W. J. Catalona and P. B. Chretien, ibid. 31, 353 (1973); R. C. Chakravorty, H. P. Curutchet. F. S Coppolly, C. M Park, W. K Blaylock, W Lawrence, Surgery 73, 740 (1973). YNT, FC Sparks. I R Filber, DL Morton, Proc, James Ewing Soc. 27, 24 (1974) 4. Marijuana smoking ranged from three times per week to several times per div. No mat juana was administered by us to these subjects, so the specific disure levels or percentage of tetrahydrocannabinol of the marijuana smoked is not known Senator SCHWEIKER. In your prepared statement you relate marihuana smoking to possible precancerous lesions in the lungs. You do not comment on how that would compare to regular cigarette smoking. Referring again to your testimony, is it very similar to cigarette smoking or is it more advanced than cigarette smoking? Give us some benchmark in relation to cigarette smoking. Dr. DUPONT. In the Leuchtenberger studies they suggested that marihuana had a more powerful effect in lung tissue culture than did cigarette smoking. But again this is a tissue culture study and not a clinical study. We had no evidence of an association between marihuana smoking and lung cancer in human populations at this point. Senator SCHWEIKER. Was this done with a mouse lung tissue? Dr. DUPONT. And human lung tissue, but both were tissue cultures. Senator SCHWEIKER. Tissue only. In your statement you also talk about driving. Senator Javits and Senator Randolph asked you a little bit about that.. One thing I was not clear on is the comparison, in this case, to alcoholism. I think Senator Javits was asking you a question about the incidence of usage. My question is, again, what benchmark, in terms of level of intensity or level of performance, can you indicate from your studies regarding alcohol versus marihuana usage? Dr. DUPONT. For both substances, the effect on driving is dose related. It depends on how much of the substance the individual uses. Individuals who use very small quantities of alcohol often do not show reductions in their driving skills until the dose goes up. A similar doseresponse relationship occurs with marihuana. The effect depends on the dose that the individual is using. There is no dose equivalency of marihuana and alcohol so you cannot now compare the two, except to say in each category the effect is dose related. Senator SCHWEIKER. Can you give us some layman's demarcation, in the case of joints, before you would be intoxicated in terms of impairing your driving? I am talking marihuana. Forget the alcohol for the moment. Dr. DUPONT. The problem with the joints is, of course, that they have a very uncertain amount of THC. I am not sure what specific level of THC was used in the studies I referred to in my statement. Senator SCHWEIKER. The study would certainly have some index. Dr. DUPONT. It is in the study. Senator SCHWEIKER. Would you please furnish that for the record? Dr. DUPONT. Dr. Peterson points out that the cigarettes used in the study contained 4 milligrams and 8 milligrams of THC which is a fairly modest dose. The NIDA official marihuana content of THC for cigarettes is 20 milligrams, that is they are of higher potency than those used in this study. The dose used in this study is more equivalent to the street level of one marihuana cigarette. Senator SCHWEIKER. You also say that the single most significant factor related to the cessation of marihuana use by former college users has been found to be development of commitment to nonstudent roles, including family and job responsibilities. Are you saying there is essentially a student phenomenon that when they get on to other things, the use factor declines markedly? Is that what you are telling us? Dr. DUPONT. I do not know that it is just students. I think one of the problems in this field has been that so many of the surveys have been conducted among students, that the general public has the impression that marihuana use is student related phenomenon. I tried to point out in testimony that our new evidence shows that marihuana use occurs in nonstudents at about the same rate as among age-matched students. We do find that the level of marihuana use is higher in youth oriented groups. For example, students and military are two examples of groups that are predominantly comprised of young people, and both show high rates of marihuana use. In work situations which usually involve exposure to a far greater age range we find lower rates of marihuana use. When youth get out of the youth dominated situations, where there is a higher social acceptance of marihuana use, then we find a higher rate of cessation of marihuana use. I do not want to emphasize that too much because, of course, many individuals who go into work settings do continue to use marihuana. It is not a 1-to-I relationship. There is just a higher rate for giving it up among people who go into work settings than for those who stay in youth-oriented activities. Senator SCHWEIKER. The youth culture is what you are talking about, whether it is the student or nonstudent variety? Dr. DUPONT. If the peer reference group is predominantly youthoriented, there is a higher incidence of continued use. Senator SCHWEIKER. You go on to say that these changes also reflect an increasing social isolation from other marihuana users. I am not quite sure what you mean by that. Dr. DUPONT. What I mean is that when an individual finds himself in a new social setting where there are fewer marihuana users, he is less likely to use marihuana and more likely to give it up. That sentence, as I intended it, was to reinforce the previous point. Senator SCHWEIKER. Could we not make the same observations about alcohol? Dr. DUPONT. Yes, I think it is true for most behavior. When we find ourselves in settings where many other people are exhibiting a particular behavior, the behavior is likely to continue. And when we find ourselves in situations where other people are not carrying on a particular behavior, we are likely to stop. Senator SCHWEIKER. Now, you say that you would like to set the record straight about reports of your statement last week. You say you did not call for decriminalization. I am not clear what you are saying you did do last week. Dr. DUPONT. What I did do was to review the medical evidence with respect to the problems of marihuana use and emphasize that it supported an effort to discourage marihuana use. I also said that it seemed to me we could develop and support a policy of legal discouragement that did not rely on criminal penalties. I carried that through at some length to point out how that this could be done. I did not go the next step and say, therefore, that it should be done. I also pointed out that the possession offense itself is now primarily a State and local issue, and it is not primarily a Federal problem. The Federal possession offense was made a misdemeanor in 1970 by the Controlled Substances Act. We have only about 1,500 Federal arrests for possession of marihuana last year out of 420,000 total arrests, so the vast majority, 99-plus percent, are State and local arrests. The Federal Government is watching with interest what the States are doing with respect to how they handle the marihuana possession offense. My own view is that we have to look very carefully at the noncriminal sanctions. One thing which is of great concern to me in this field is that when people talk about removing criminal sanctions, they immediately jump to the conclusion that, in fact, we are removing all sanctions. This is not the case. One example that is very significant to me is how people respond to a stop sign when they are driving. You can sometimes come up to a stop sign and see that there is no traffic coming, and you pull through it with very low risk, and yet our law says you must stop. The vast majority of people accept that almost all of the time. If you are caught going through a stop sign, of course you are penalized by a "noncriminal" penalty-a ticket-that people accept. The sanction does influence behavior without the threat of prison. Too many people now assume that if we do not have a criminal sanction against the possession of marihuana, then we have no sanction at all. What I pointed out in that speech was that there is a great and growing area of the law which involves noncriminal sanctions called "violations." This is the area where the Oregon statute places the marihuana possession offense. I am looking at that with great interest. The Federal Government is looking at that approach with sympathy. But we are not saying this is what everybody ought to do. That is the distinction, admittedly it is a fine line, but it is an important one. Senator SCHWEIKER. Just one last question. You mentioned that you are a moderate user of alcohol and a most infrequent user of marihuana. I am just wondering, as a doctor, is the effect the same? In other words, for the people who use both-this is just an observation, I realize is the ultimate effect the same in terms of whatever they are getting from both drugs? Dr. DUPONT. No. The effects are different. There are some similarities. They both are central nervous depressants. But marihuana is less of a general depressant and more of a selective depressant. At higher doses marihuana, THC, is mildly hallucinogenic which is not true of alcohol. From the user's point of view, there are some similarities and some differences. I would point out another finding which is of great concern to me. Many people in public discussion of marihuana assume we are talking about either alcohol use or marihuana use. They assume that if young people are using marihuana they are not using alcohol, and vice versa. They assume that there is some fixed need in the public, or in an individual, for a recreational mind-affecting substance. The evidence is clearly to the contrary. The evidence is that the use of alcohol and marihuana go together. In fact, the evidence is that the use of all drugs, licit and illicit, is positively associated, one drug with another. Similarly the giving up of one drug is associated with an increased likelihood of giving up of other drugs. This is a fundamentally important point when we consider a policy of relaxing our disapproval of any drug. We do not achieve a reduc |