726
mg/dl. Urinalysis, blood urea nitrogen, creatinine, electrolytes, blood-glucose, serum calcium and magnesium levels, bloodammonia level, chest X-ray, electroencephalogram, computerised tomography scan, and cerebrospinal fluid examination normal. Blood and urine toxin screens disclosed small, non-toxic amounts of pethidine and diazepam metabolites. All drugs were discontinued. Over the subsequent twenty-four hours she returned to her normal level of responsiveness and the abnormal c.N.s. signs resolved. She was discharged four days later. It is impossible to prove that cimetidine caused this child’s transient encephalopathy. The fact that she received other drugs with potential c.N.s. toxicity makes the relationship less clear. Nonetheless, because toxic levels of these drugs were not identified and because the child’s c.N.s. abnormalities closely resembled those described in adults, we warn that cimetidine use in children, particularly in combination with drugs which act on the C.N.S., may result in an encephalopathy similar to that reported in adults. were
Divisions of Pediatric Neurology and Pediatric Gastroenterology, University of Utah Medical Center, Salt Lake City, Utah 84132, U.S.A.
JAMES F. BALE, JR CHARLES ROBERTS LINDA S. BOOK
DUODENAL EROSIONS DURING CIMETIDINE THERAPY
may not be the same condition, even though they appear be related. Therefore, at this stage in our knowledge (or rather in the lack of it) it seems more accurate to consider the development of erosions in the distal stomach or proximal duodenum (or lower oesophagus) to be an event in the natural history of the "duodenal-ulcer syndrome" rather than a druglinked effect. The association with cimetidine treatment may well be fortuitous.
they to
District General Hospital, Rotherham S60 2UD
CIMETIDINE FOR PRURITUS can be a debilitating symptom accompanyand myeloproliferative disorders. The report of the use of a histamine (Hz) antagonist cimetidine producing relief from pruritus in a patient with polycythasmia vera prompted us to try this drug in a patient with a myelodysplastic disorder. A 70-year-old woman presented in March, 1978, with tiredness, palpitations, and ankle swelling. On examination she appeared anaemic but no lymphadenopathy or hepatosplenomegaly was present. Laboratory investigations, including peripheral blood smear and bone-marrow studies, suggested a preleukaemic myelodysplastic disorder (refractory anasmia with
SIR,—Pruritus
ing lymphomas
excess
SIR,—Dr Al-Nakib’s letter (March 17,
p.
607) and two ear-
lier reports on duodenal erosions and cimetidine1,2 prompt me to put forward four observations made whilst treating over 250 duodenal-ulcer patients with cimetidine during the past three years. In a study on the intermittent treatment of duodenal ulcer, I treated the patients with cimetidine until healing was complete or very nearly so, as judged by endoscopy every 4-6 weeks. A common finding was that the ulcer(s) would disappear but that erosions would persist or appear for the first time. Most of these patients required treatment for a further 4-12 weeks before the erosions healed, but in a few, the lesions cleared spontaneously.3 In a current study, patients whose ulcer(s) have healed on cimetidine are being maintained on this drug or on placebo. Endoscopy is done periodically on all patients, even when symptom-free. Recurrence of an ulcer is frequently preceded by the appearance of erosions, which in turn is preceded by, or coincides with, an increase in duodenitis (oedema, congestion, and granularity of the mucosa as judged by endoscopic appearance). (Erosions or ulceration not uncommonly precede the return of prominent symptoms by weeks or months.) Symptoms of reflux are common in duodenal ulcer and several patients have associated erosive cesophagitis. This cesophagitis generally improves as the ulcer heals on cimetidine. However, in some patients subsequently put on low-dose cimetidine maintenance, the symptoms of reflux return. Whilst in a proportion this is associated with a recurrence of the ulcer, in others there is a return of erosive cesophagitis, with or without an increase in duodenitis, but not of the ulcer. In the remainder there is no significant change. This is paradoxical since cimetidine is commonly used in the treatment of reflux
cesophagitis. Prepyloric
oedema and congestion are not uncommon in patients with duodenal ulcer. This is usually diffuse or multifocal, with or without erosions. Whilst these changes generally regress as the ulcer heals on cimetidine, occasionally these erosions persist or, more rarely, appear for the first time. Duodenal ulcer and duodenal erosions frequently coincide; 1. 2. 3.
Linaker, B. D., Hughes, S. Br. med. J. 1978, ii, 1278. Webster, J., Petrie, J. C., Mowat, N. A. G. ibid. 1978, i, 20. Bardhan, K. D. in Cimetidine (edited by C. Wastell and P. Lance), p. 31. Edinburgh, 1978.
K. D. BARDHAN
blasts).
given frequent blood-transfusions for anaemia. In September, 1978, she presented with severe generalised pruritus exacerbated by skin contact with water. No basophils were identified in the peripheral smear or in buffy-coat slides stained She
was
with toluidine-blue. 2 months later she was put on cimetidine 300 mg three times a day, and within 24 h the pruritus had resolved. When admitted to hospital for coronary insufficiency a month later the cimetidine was discontinued, and the pruritus returned the following day. It did not respond to diphenhydramine, an H, receptor antagonist, but when the cimetidine was re-started 2 days later the pruritus again resolved within 24 h. The dose of cimetidine has been reduced to 300 mg twice a day, and the pruritus continues to be controlled. There are at least two types of histamine receptor (H! and H,). Antihistamines diminish the effects of histamine by occupying receptor sites in the target cells. The well-known association of allergic reactions and histamine release suggests a role for receptor antagonists since pruritus is a common symptom in hayfever and urticaria. Increased histamine levels have been found in the serum and urine of patients with myeloproliferative disorders who complain of pruritus. Increased basophil-counts have also been found in some of these patients, although the correlation between histamine level and basophil-count is not striking. Cyproheptadine, an H,-receptor antagonist, produced relief from pruritus in twelve of sixteen patients.’ This symptomatic improvement was not accompanied by any lowering of serum or urinary histamine levels. The use of metiamide, an Hz-receptor antagonist closely related to cimetidine, did not lower serum or urine histamine levels in a patient with chronic myeloid leukxmia. The local ædema produced by the injection of histamine has been blocked by burimamide,3another Hz-receptor antagonist. The Hz receptor seems to be an important component of the inflammatory reaction which seems related to the local production of histamine that produces pruritus. Both Hj and H2 receptor4antagonists have been successful in alleviating the symptoms of pruritus in patients with myeloproliferative disorders. The cells responsible for histamine 1. 2. 3. 4.
Easton, P., Galbraith, P.R. New Engl. J Med. 1978, 299, 1134 Harriet, S., Warner, R. R. P., Wasserman, L. R. Blood, 1966, 28, 795. Rosenthal, S., Schwartz, J. H., Canellos, G. P Br.J. Hæmat. 1977, 36, 367 Beaven, M. A. New Engl. J. Med. 1976, 294, 320.
727 release and resultant pruritus may well have a combination of H, and Hz receptors and antagonism of one group of these receptors is, in some cases, enough to alleviate symptoms. DAVID V. SCHAPIRA
JOHN M. BENNETT
CADMIUM TOXICITY
SIR,—We support the view of Dr Harvey and his co-workers (March 10, p. 551) that the results of their pilot study at Shipham are broadly reassuring. We have studied a group of forty-five men age 18-55 years (mean 34) occupationally exposed for up to 9 years to cadmium pigments during various stages of their manufacture, whose exposure, we believe, has been greatly in excess of that of the Shipham inhabitants. The mean liver cadmium of these men was higher than that at Shipham-19.4 parts per million (range 0—40). There was no correlation between exposure (measured in µg-years) and liver cadmium (r=0.13). Within the group we surveyed we can find no evidence of renal tubular dysfunction. We
----
plan
to
publish
____
____.
detailed results elsewhere.
Johnson, Matthey & Co. Ltd., Southgate, London N14 6ET
E. G. HUGHES MORAG STEWART
WARFARIN AS TERATOGEN
SIR,—The complications to the fetus arising from the use of warfarin in pregnancy fall into two main categories-serious hxmorrhage if the drug is administered close to the time of deliveryl.2 and nasal hypoplasia with or without the radiological appearance of chondrodysplasia punctata.3-6 We. describe here a fetus with nasal hypoplasia and large spontaneous subdural hxmorrhages before 32 weeks’ gestation. An 18-year-old woman had had her mitral valve replaced at the age of 16 years and had been treated postoperatively with warfarin. During her second pregnancy she was first seen at 32 weeks when hydramnios was noted and ultrasound examination demonstrated a biparietal diameter of 10.4 cm (>90th centile, mean at 32 weeks 8-0 cm). This measurement suggested hydrocephalus. Prothrombin ratio was 1 2. Spontaneous labour and delivery occurred at 33 weeks. The infant weighed 2.70 kg, the occipitofrontal circumference was 35 cm, and gestational assessment 35 weeks. There was marked nasal hypoplasia, apparent hypertelorism, and widely separated sagittal and lambdoid sutures. Pallor was extreme, with tachycardia, hepatomegaly, and generalised cedema. The child died at 3 h. Post-mortem examination demonstrated large bilateral subdural haemorrhages. Warfarin is a potent teratogen, and this case adds further support to this view. The hxmorrhagic complications have previously been thought avoidable provided warfarin is discontinued 4 weeks before delivery.7,8However, in this case fetal hxmorrhage developed before the 32nd week. We feel that warfarin should be used in pregnancy only when there are very definite indications for its administration. Women of childbearing age should be warned of the teratogenic risk. In the series reported so far the risk has been low,8,9 though the number of women reported who were receiving warfarin at conception is too small to permit accurate assessment of the risk. St. Thomas’ Hospital, London SE1 7EH
use and of its of cannabis used in terms of milligrams of material of a specified percentage of A-9-tetrahydrocannabinol concentration that have been smoked. When the drug is administered in the laboratory by smoking, details oi the inhalation pattern, including the length of time the smoke is retained in the lungs, are usually specified. By contrast, studies of chronic cannabis use generally specify only the approximate amounts smoked and the range of A-9-tetrahydrocannabinol level to be found in typical "street" samples. This is true of recent work in Jamaica, Greece, and Costa Rica done under more rigorous scientific conditions than is typical of most research on chronic "traditional" use.I-3 Thus, virtually all studies of longer term chronic cannabis use have ignored a factor which has now been demonstrated to be of considerable importance m determining the effects of tobacco smokingnamely, the role of inhalation patterns, including depth of inhalation. There is good experimental evidence that blood levels of nicotine and carboxyhsemoglobin (COHb) are profoundly affected by inhalation. Feyerabend et al .4 and Armitage et al.5 have demonstrated differences as great as fifteen-fold between the plasma-nicotine levels of inhaling and non-inhaling cigarette smokers. Castleden and Cole6 found that COHb levels in venous blood. also varied significantly between primary pipe and cigar smokers (i.e., those who have never smoked cigarettes habitually) and secondary pipe and cigar smokers (those who formerly smoked cigarettes). Turner et al. also found that plasma-nicotine levels of ex-cigarette smokers smoking a cigar were about nine times as great as for cigar smokers who had never smoked cigarettes. These findings suggest that inhalation patterns may persist even when the smoker attempts to alter his usual mode of use or inhalation pattern. It is generally conceded that the much more serious health consequences of cigarette versus pipe and cigar smoking are the result of the difference in inhalation which typically accompanies these varying modes of tobacco use. If variation of inhalation patterns is of similar importance with respect to cannabis use-a not unreasonable assumption-plasma-cannabinoid levels might be expected to vary strikingly, depending on the depth and pattern of inhalation. Health implications, especially for the lung, would also be expected to vary with inhalation. One apparent characteristic of the newer American and European use of marihuana and hashish is the habit of deep inhalation, the smoke being retained in the lung for several seconds. Although it does not seem to have been specifically investigated, this habit of very deep inhalation and smoke retention may be less common in countries in which cannabis has been traditionally available at relatively low cost. If this difference in mode of use is confirmed, it might well explain the relatively benign consequences of chronic cannabis use found in the Jamaican, Greek, and Costa Rican studies1-3 which are in some contrast with other observations on "newer" non-traditional use by young people. Henderson et al. 8 found pulmonary complaints and evidence of bronchial tissue changes in American soldiers stationed in Europe following much briefer periods of exposure to cannabis than is usual in chronic, traditional users. Tashkin et
SIR,-Most human studies of marihuana
effects
University of Rochester Cancer Center, Strong Memorial Hospital, Rochester, N.Y. 14642, U. S. A.
....
IMPORTANCE OF INHALATION PATTERNS IN DETERMINING EFFECTS OF MARIHUANA USE
M. F. SMITH
M. D. CAMERON
1 Villa Sante, V. Am J. Obstet. Gynec 1965, 33, 142. 2 Beller, F. K Clin. Obstet Gynec 1968, 11, 290. 3 Becker, M. H., and others Am. J. Dis. Child 1975, 129, 356. 4 Shaul, W. L., Emery, H., Hall, J G. ibid 1975, 129, 360. 5 Abbott, A., Sibert, J. R., Weaver,J B Br. med. J. 1977, i,1639. 6 Kari, O., Raivio, E. K , Saarikoski, S. Acta pædiat. scand. 1977, 7. Bloomfield, D. Am. J. Obstet Gynec. 1970, 107, 883. 8 Hirsh, J, Cade, J. F , O’Sullivan, E. F. Br. med J. 1970, i, 270. 9 Fillmore, S. J., McDevitt, S. Ann. intern Med 1970, 73, 731.
66, 735
specify the
amounts
Comitas, L. Ganja in Jamaica: the effects of marihuana. New York, 1976. 2. Stefanis, C., Cornbush, R., Fink, M. (editors). Hashish: studies of long-term use. New York, 1977. 3. Coggins, W. J. in Pharmacology of Marihuana (edited by M. C. Braude and S. Szara); p. 667. New York, 1976. 4. Feyerabend, T., Levitt, T., Russell, M. A. H. J. Pharm. Pharmac. 1975, 27, 1. Rubin, V.,
434. 5. Armitage, A. K., Dollery, C. T., George, C. R., Houseman, T. H., Lewis, P. J., Turner, D. M. Br. med. J. 1975, iv, 313. 6. Castleden, C. M , Cole, P. V. Lancet, 1973, ii, 21. 7. Turner, J. A. McM., Sillett, R. W., McNicol, M. W Br med. J 1977, ii, 1387. 8. Henderson, A. A., Tennant, F. S., Guerney, R. Archs Otolary. 1972, 95, 248.
mg/dl. Urinalysis, blood urea nitrogen, creatinine, electrolytes, blood-glucose, serum calcium and magnesium levels, bloodammonia level, chest X-ray, electroencephalogram, computerised tomography scan, and cerebrospinal fluid examination normal. Blood and urine toxin screens disclosed small, non-toxic amounts of pethidine and diazepam metabolites. All drugs were discontinued. Over the subsequent twenty-four hours she returned to her normal level of responsiveness and the abnormal c.N.s. signs resolved. She was discharged four days later. It is impossible to prove that cimetidine caused this child’s transient encephalopathy. The fact that she received other drugs with potential c.N.s. toxicity makes the relationship less clear. Nonetheless, because toxic levels of these drugs were not identified and because the child’s c.N.s. abnormalities closely resembled those described in adults, we warn that cimetidine use in children, particularly in combination with drugs which act on the C.N.S., may result in an encephalopathy similar to that reported in adults. were
Divisions of Pediatric Neurology and Pediatric Gastroenterology, University of Utah Medical Center, Salt Lake City, Utah 84132, U.S.A.
JAMES F. BALE, JR CHARLES ROBERTS LINDA S. BOOK
DUODENAL EROSIONS DURING CIMETIDINE THERAPY
may not be the same condition, even though they appear be related. Therefore, at this stage in our knowledge (or rather in the lack of it) it seems more accurate to consider the development of erosions in the distal stomach or proximal duodenum (or lower oesophagus) to be an event in the natural history of the "duodenal-ulcer syndrome" rather than a druglinked effect. The association with cimetidine treatment may well be fortuitous.
they to
District General Hospital, Rotherham S60 2UD
CIMETIDINE FOR PRURITUS can be a debilitating symptom accompanyand myeloproliferative disorders. The report of the use of a histamine (Hz) antagonist cimetidine producing relief from pruritus in a patient with polycythasmia vera prompted us to try this drug in a patient with a myelodysplastic disorder. A 70-year-old woman presented in March, 1978, with tiredness, palpitations, and ankle swelling. On examination she appeared anaemic but no lymphadenopathy or hepatosplenomegaly was present. Laboratory investigations, including peripheral blood smear and bone-marrow studies, suggested a preleukaemic myelodysplastic disorder (refractory anasmia with
SIR,—Pruritus
ing lymphomas
excess
SIR,—Dr Al-Nakib’s letter (March 17,
p.
607) and two ear-
lier reports on duodenal erosions and cimetidine1,2 prompt me to put forward four observations made whilst treating over 250 duodenal-ulcer patients with cimetidine during the past three years. In a study on the intermittent treatment of duodenal ulcer, I treated the patients with cimetidine until healing was complete or very nearly so, as judged by endoscopy every 4-6 weeks. A common finding was that the ulcer(s) would disappear but that erosions would persist or appear for the first time. Most of these patients required treatment for a further 4-12 weeks before the erosions healed, but in a few, the lesions cleared spontaneously.3 In a current study, patients whose ulcer(s) have healed on cimetidine are being maintained on this drug or on placebo. Endoscopy is done periodically on all patients, even when symptom-free. Recurrence of an ulcer is frequently preceded by the appearance of erosions, which in turn is preceded by, or coincides with, an increase in duodenitis (oedema, congestion, and granularity of the mucosa as judged by endoscopic appearance). (Erosions or ulceration not uncommonly precede the return of prominent symptoms by weeks or months.) Symptoms of reflux are common in duodenal ulcer and several patients have associated erosive cesophagitis. This cesophagitis generally improves as the ulcer heals on cimetidine. However, in some patients subsequently put on low-dose cimetidine maintenance, the symptoms of reflux return. Whilst in a proportion this is associated with a recurrence of the ulcer, in others there is a return of erosive cesophagitis, with or without an increase in duodenitis, but not of the ulcer. In the remainder there is no significant change. This is paradoxical since cimetidine is commonly used in the treatment of reflux
cesophagitis. Prepyloric
oedema and congestion are not uncommon in patients with duodenal ulcer. This is usually diffuse or multifocal, with or without erosions. Whilst these changes generally regress as the ulcer heals on cimetidine, occasionally these erosions persist or, more rarely, appear for the first time. Duodenal ulcer and duodenal erosions frequently coincide; 1. 2. 3.
Linaker, B. D., Hughes, S. Br. med. J. 1978, ii, 1278. Webster, J., Petrie, J. C., Mowat, N. A. G. ibid. 1978, i, 20. Bardhan, K. D. in Cimetidine (edited by C. Wastell and P. Lance), p. 31. Edinburgh, 1978.
K. D. BARDHAN
blasts).
given frequent blood-transfusions for anaemia. In September, 1978, she presented with severe generalised pruritus exacerbated by skin contact with water. No basophils were identified in the peripheral smear or in buffy-coat slides stained She
was
with toluidine-blue. 2 months later she was put on cimetidine 300 mg three times a day, and within 24 h the pruritus had resolved. When admitted to hospital for coronary insufficiency a month later the cimetidine was discontinued, and the pruritus returned the following day. It did not respond to diphenhydramine, an H, receptor antagonist, but when the cimetidine was re-started 2 days later the pruritus again resolved within 24 h. The dose of cimetidine has been reduced to 300 mg twice a day, and the pruritus continues to be controlled. There are at least two types of histamine receptor (H! and H,). Antihistamines diminish the effects of histamine by occupying receptor sites in the target cells. The well-known association of allergic reactions and histamine release suggests a role for receptor antagonists since pruritus is a common symptom in hayfever and urticaria. Increased histamine levels have been found in the serum and urine of patients with myeloproliferative disorders who complain of pruritus. Increased basophil-counts have also been found in some of these patients, although the correlation between histamine level and basophil-count is not striking. Cyproheptadine, an H,-receptor antagonist, produced relief from pruritus in twelve of sixteen patients.’ This symptomatic improvement was not accompanied by any lowering of serum or urinary histamine levels. The use of metiamide, an Hz-receptor antagonist closely related to cimetidine, did not lower serum or urine histamine levels in a patient with chronic myeloid leukxmia. The local ædema produced by the injection of histamine has been blocked by burimamide,3another Hz-receptor antagonist. The Hz receptor seems to be an important component of the inflammatory reaction which seems related to the local production of histamine that produces pruritus. Both Hj and H2 receptor4antagonists have been successful in alleviating the symptoms of pruritus in patients with myeloproliferative disorders. The cells responsible for histamine 1. 2. 3. 4.
Easton, P., Galbraith, P.R. New Engl. J Med. 1978, 299, 1134 Harriet, S., Warner, R. R. P., Wasserman, L. R. Blood, 1966, 28, 795. Rosenthal, S., Schwartz, J. H., Canellos, G. P Br.J. Hæmat. 1977, 36, 367 Beaven, M. A. New Engl. J. Med. 1976, 294, 320.
727 release and resultant pruritus may well have a combination of H, and Hz receptors and antagonism of one group of these receptors is, in some cases, enough to alleviate symptoms. DAVID V. SCHAPIRA
JOHN M. BENNETT
CADMIUM TOXICITY
SIR,—We support the view of Dr Harvey and his co-workers (March 10, p. 551) that the results of their pilot study at Shipham are broadly reassuring. We have studied a group of forty-five men age 18-55 years (mean 34) occupationally exposed for up to 9 years to cadmium pigments during various stages of their manufacture, whose exposure, we believe, has been greatly in excess of that of the Shipham inhabitants. The mean liver cadmium of these men was higher than that at Shipham-19.4 parts per million (range 0—40). There was no correlation between exposure (measured in µg-years) and liver cadmium (r=0.13). Within the group we surveyed we can find no evidence of renal tubular dysfunction. We
----
plan
to
publish
____
____.
detailed results elsewhere.
Johnson, Matthey & Co. Ltd., Southgate, London N14 6ET
E. G. HUGHES MORAG STEWART
WARFARIN AS TERATOGEN
SIR,—The complications to the fetus arising from the use of warfarin in pregnancy fall into two main categories-serious hxmorrhage if the drug is administered close to the time of deliveryl.2 and nasal hypoplasia with or without the radiological appearance of chondrodysplasia punctata.3-6 We. describe here a fetus with nasal hypoplasia and large spontaneous subdural hxmorrhages before 32 weeks’ gestation. An 18-year-old woman had had her mitral valve replaced at the age of 16 years and had been treated postoperatively with warfarin. During her second pregnancy she was first seen at 32 weeks when hydramnios was noted and ultrasound examination demonstrated a biparietal diameter of 10.4 cm (>90th centile, mean at 32 weeks 8-0 cm). This measurement suggested hydrocephalus. Prothrombin ratio was 1 2. Spontaneous labour and delivery occurred at 33 weeks. The infant weighed 2.70 kg, the occipitofrontal circumference was 35 cm, and gestational assessment 35 weeks. There was marked nasal hypoplasia, apparent hypertelorism, and widely separated sagittal and lambdoid sutures. Pallor was extreme, with tachycardia, hepatomegaly, and generalised cedema. The child died at 3 h. Post-mortem examination demonstrated large bilateral subdural haemorrhages. Warfarin is a potent teratogen, and this case adds further support to this view. The hxmorrhagic complications have previously been thought avoidable provided warfarin is discontinued 4 weeks before delivery.7,8However, in this case fetal hxmorrhage developed before the 32nd week. We feel that warfarin should be used in pregnancy only when there are very definite indications for its administration. Women of childbearing age should be warned of the teratogenic risk. In the series reported so far the risk has been low,8,9 though the number of women reported who were receiving warfarin at conception is too small to permit accurate assessment of the risk. St. Thomas’ Hospital, London SE1 7EH
use and of its of cannabis used in terms of milligrams of material of a specified percentage of A-9-tetrahydrocannabinol concentration that have been smoked. When the drug is administered in the laboratory by smoking, details oi the inhalation pattern, including the length of time the smoke is retained in the lungs, are usually specified. By contrast, studies of chronic cannabis use generally specify only the approximate amounts smoked and the range of A-9-tetrahydrocannabinol level to be found in typical "street" samples. This is true of recent work in Jamaica, Greece, and Costa Rica done under more rigorous scientific conditions than is typical of most research on chronic "traditional" use.I-3 Thus, virtually all studies of longer term chronic cannabis use have ignored a factor which has now been demonstrated to be of considerable importance m determining the effects of tobacco smokingnamely, the role of inhalation patterns, including depth of inhalation. There is good experimental evidence that blood levels of nicotine and carboxyhsemoglobin (COHb) are profoundly affected by inhalation. Feyerabend et al .4 and Armitage et al.5 have demonstrated differences as great as fifteen-fold between the plasma-nicotine levels of inhaling and non-inhaling cigarette smokers. Castleden and Cole6 found that COHb levels in venous blood. also varied significantly between primary pipe and cigar smokers (i.e., those who have never smoked cigarettes habitually) and secondary pipe and cigar smokers (those who formerly smoked cigarettes). Turner et al. also found that plasma-nicotine levels of ex-cigarette smokers smoking a cigar were about nine times as great as for cigar smokers who had never smoked cigarettes. These findings suggest that inhalation patterns may persist even when the smoker attempts to alter his usual mode of use or inhalation pattern. It is generally conceded that the much more serious health consequences of cigarette versus pipe and cigar smoking are the result of the difference in inhalation which typically accompanies these varying modes of tobacco use. If variation of inhalation patterns is of similar importance with respect to cannabis use-a not unreasonable assumption-plasma-cannabinoid levels might be expected to vary strikingly, depending on the depth and pattern of inhalation. Health implications, especially for the lung, would also be expected to vary with inhalation. One apparent characteristic of the newer American and European use of marihuana and hashish is the habit of deep inhalation, the smoke being retained in the lung for several seconds. Although it does not seem to have been specifically investigated, this habit of very deep inhalation and smoke retention may be less common in countries in which cannabis has been traditionally available at relatively low cost. If this difference in mode of use is confirmed, it might well explain the relatively benign consequences of chronic cannabis use found in the Jamaican, Greek, and Costa Rican studies1-3 which are in some contrast with other observations on "newer" non-traditional use by young people. Henderson et al. 8 found pulmonary complaints and evidence of bronchial tissue changes in American soldiers stationed in Europe following much briefer periods of exposure to cannabis than is usual in chronic, traditional users. Tashkin et
SIR,-Most human studies of marihuana
effects
University of Rochester Cancer Center, Strong Memorial Hospital, Rochester, N.Y. 14642, U. S. A.
....
IMPORTANCE OF INHALATION PATTERNS IN DETERMINING EFFECTS OF MARIHUANA USE
M. F. SMITH
M. D. CAMERON
1 Villa Sante, V. Am J. Obstet. Gynec 1965, 33, 142. 2 Beller, F. K Clin. Obstet Gynec 1968, 11, 290. 3 Becker, M. H., and others Am. J. Dis. Child 1975, 129, 356. 4 Shaul, W. L., Emery, H., Hall, J G. ibid 1975, 129, 360. 5 Abbott, A., Sibert, J. R., Weaver,J B Br. med. J. 1977, i,1639. 6 Kari, O., Raivio, E. K , Saarikoski, S. Acta pædiat. scand. 1977, 7. Bloomfield, D. Am. J. Obstet Gynec. 1970, 107, 883. 8 Hirsh, J, Cade, J. F , O’Sullivan, E. F. Br. med J. 1970, i, 270. 9 Fillmore, S. J., McDevitt, S. Ann. intern Med 1970, 73, 731.
66, 735
specify the
amounts
Comitas, L. Ganja in Jamaica: the effects of marihuana. New York, 1976. 2. Stefanis, C., Cornbush, R., Fink, M. (editors). Hashish: studies of long-term use. New York, 1977. 3. Coggins, W. J. in Pharmacology of Marihuana (edited by M. C. Braude and S. Szara); p. 667. New York, 1976. 4. Feyerabend, T., Levitt, T., Russell, M. A. H. J. Pharm. Pharmac. 1975, 27, 1. Rubin, V.,
434. 5. Armitage, A. K., Dollery, C. T., George, C. R., Houseman, T. H., Lewis, P. J., Turner, D. M. Br. med. J. 1975, iv, 313. 6. Castleden, C. M , Cole, P. V. Lancet, 1973, ii, 21. 7. Turner, J. A. McM., Sillett, R. W., McNicol, M. W Br med. J 1977, ii, 1387. 8. Henderson, A. A., Tennant, F. S., Guerney, R. Archs Otolary. 1972, 95, 248.
