This report is intended for scientific, industrial and governmental use only. It does not recommend or endorse any specific application for the chemicals discussed.
No part of this book may be reproduced by any means without the written permission of the publisher. Limited portions may be reproduced by news media or scientific journals with attribution.
Library of Congress Catalog No. 79-62920
ISBN 978-0-9796913-0-0
First Printing Feb. 1979
Printed in the United States of America.
AUTHORS
MARK NICKERSON, Ph.D., M.D., Sc.D. (Hon.), F.R.S. (C)
Professor and Past Chairman
Department of Pharmacology and Therapeutics
McGill University, Montreal, P.Q., Canada
JOHN O. PARKER, M.D., M.Sc., F.R.C.P. (C)
Professor of Medicine and Chairman
Division of Cardiology
Queen's University, Kingston, Ont., Canada
THOMAS P. LOWRY, M.D., F.A.P.A.
Assistant Clinical Professor of Psychiatry
University of California, Davis, California
EDWARD W. SWENSON, M.D., F.A.C.P., F.C.C.P.
Associate Clinical Professor of Medicine
Pulmonary Disease Division
University of California, Davis, California
PREFACE
For the past several years there has been considerable controversy regarding the use of butyl nitrite in consumer products used for odorizing purposes. This controversy accelerated in May, 1977 when the State of Connecticut proposed to ban their sale. The State claimed that there existed a reasonable probability of substantial personal injury resulting from the misuse of these products. The State's concern was the direct concentrated inhalation of these products for the purpose of obtaining a physiological effect. In view of these concerns, and the limited amount of current, consolidated information available, a research program was initiated.
Funding was obtained from Pharmex, Ltd. of San Francisco. At the outset objectives were defined, and a survey of pertinent literature was conducted. Government agencies and private companies with relevant information were questioned. When available data were doubtful or insufficient, a series of research projects was conducted under appropriate auspices.
Professor Mark Nickerson at McGill University is the retired Chairman of its Department of Pharmacology and Therapeutics. Dr. Nickerson has, for nearly forty years, been the author of the Nitrite Vasodilator chapter of Goodman & Gillman's standard textbook of pharmacology. Professor John Parker of Queen's University has been Chairman of the Division of Cardiology for more than six years. Nitrite vasodilators, including amyl, butyl and isobutyl nitrite, have been a subject of his special study. He has written numerous papers dealing with their effects on the cardiovascular system. Professor Thomas Lowry is a psychiatrist who has done extensive research into drugs and sexual behavior. Professor Edward Swenson is a specialist in pulmonary disease who has written more than 80 publications on the subject.
This project took nearly two years to accomplish and substantial resources were utilized. This expenditure of time and effort should be amply justified by this report which we believe will consolidate, clarify, and expand pharmacological, toxicological and sociological data regarding these nitrites.
Much statistical data was obtained from epidemiological records maintained by agencies of the federal government, and from the records of Burroughs Wellcome Company and Eli Lilly and Company. Our special thanks to the Pacific Western Distributing Corporation of San Francisco which provided much confidential information concerning RUSH and its other products from its files.
Our special thanks to Ms. Dee Chiavetta, who supervised the gathering of vast amounts of data, and who typed and retyped numerous drafts and manuscripts.
October 1, 1978
MARK NICKERSON
JOHN O. PARKER
THOMAS P. LOWRY
EDWARD W. SWENSON
CONTENTS
Part 1. General...........................................1
Part II. Pharmacology.................................2
Part III. Toxicology.....................................5
Part IV. Sociology & Behavioral Effects.....8
Part V. Summary and Conclusions.............12
Part VI. Appendices....................................15
Part I - GENERAL
The alkyl nitrites are aliphatic esters of nitrous acid. Those most frequently used for commercial purposes are amyl, butyl and isobutyl nitrite. While it is considered probable that numerous other aliphatic nitrites have similar potential, there is no report of their current use.
The term amyl nitrite, when used for pharmaceutical purposes, refers to a mixture of isomers containing not less than 97% of isoamyl nitrite (Merck Index). Butyl (1-nitrosoxy-butane) and isobutyl nitrite (1-nitrosoxy-2-methylpropane) are isomers having distinct physical characteristics. These nitrites are flammable, potent oxidizing materials. All alkyl nitrites are miscible with alcohol. They are very slightly soluble in water which causes decomposition.
Amyl nitrite has been used for therapeutic purposes for over a century and was reported by Sir Lauder Brunton in 1867. The volatile nitrites are used in industry as intermediates in chemical synthesis, and in the perfume industry as scent components. (Von Oettingen, 1946). They are generally manufactured by the action of sodium nitrite and sulfuric acid on the appropriate alcohol.
Since 1969, butyl and isobutyl nitrite have been used extensively as primary ingredients in products offered as room odorizers or "Liquid Incense". The most common of these is branded "RUSH" 1.
RUSH® and Liquid Incense® are trademarks of Pacific Western Distributing Corp., San Francisco.
Part II - Pharmacology
Amyl nitrite has maintained a prominent position among vasodilators used in medicine for more than 100 years. All the major pharmacological properties of the nitrites are shared qualitatively by a large number of organic nitrate esters. The similarity suggests that organic nitrates act in the body through release of nitrite ion. The nitrite esters most thoroughly studied are ethyl, butyl, isobutyl, amyl and octyl. The most commonly studied nitrate esters are nitroglycerin and isosorbide dinitrate. The major differences between the effects of nitrite and nitrate esters are due to the very transient action of the former.The basic pharmacological action of alkyl nitrites when in-haled is to relax smooth muscle. Unless another interpretation is specifically indicated, the following discussion will deal with the net changes produced by these nitrites in man under various conditions.Cardiovascular SystemThe most prominent and important actions of nitrite are on vascular smooth muscle. The dilating effect on the systemic arterioles reduces peripheral vascular resistance and this is usually associated with a decrease in systemic blood pressure. Through baroreceptor and adrenergic responses there is a transient increase in venous tone, venous return, cardiac output and a somewhat more prolonged increase in heart rate. These cardiovascular responses are substantially influenced by gravitational factors and are short-lived, usually reversed within 90 seconds. An occasional individual shows increased sensitivity to the vasodilating effects of nitrite, and more marked hypotensive responses can occur. These are usually limited to transient tachycardia, dizziness, weakness, pallor and perspiration. Occasionally nausea and vomiting occur.
The most severe effect of such vasodilatation and hypotension from nitrite is syncope, defined as transient loss of consciousness. This can occur in sensitive persons or in any individual kept in a static upright position after nitrite administration. The duration of lesser responses in humans is invariably sufficient to allow discontinuation of voluntary inhalation prior to syncope. In laboratory tests where sodium nitrite, a compound with similar but prolonged effects, was administered to subjects in the horizontal position, who were then tilted to a 75° upright position, a severe hypotensive response occurred. When the subject was re-turned to the horizontal position, all circulatory abnormalities promptly disappeared and consciousness was regained within 20 seconds (Weiss et al., 1937).Inhalation of nitrite produces a dramatic cutaneous flush of the head, neck and clavicular area blush zone) in doses that do not alter the blood pressure significantly. The meningeal vessels are effectively dilated and this is the basis for the transient pulsating headache experienced by many persons after administration of a nitrite. No direct action of nitrite on the heart has been proved. Changes in rate and in cardiodynamics are secondary to actions on vascular smooth muscle.
A great many parameters of cardiac function have been measured and calculated to characterize the effects of similar but longer acting compounds such as nitroglycerin and isosorbide dinitrate. They quite consistently show a decrease in left ventricular energy requirements.
The increased energy demand causing angina pectoris is associated with a hemodynamic pattern of left ventricular failure, and nitrates and nitrites appear to restore compensation. Even when blood pressure and coronary blood flow are considerably reduced by a nitrate or a nitrite, normal subjects, and most patients with coronary atherosclerosis, show no electrocardiographic evidence of myocardial hypoxia.
Other EffectsThe nitrites act on almost all smooth muscle structures. Bronchial smooth muscle is relaxed irrespective of the cause of the pre-existing tone. The muscles of the biliary tract are effectively relaxed and pain and other symptoms incident to increased pressure are transiently relieved. Smooth muscle of the gastrointestinal tract can be relaxed and abnormal spasm frequently reduced. Similarly, nitrite can relax ureteral and uterine smooth muscle; but, these effects are somewhat unpredictable. Nitrites are singularly devoid of actions on tissues other than smooth muscle.Absorption, Fate and ExcretionAll lower aliphatic nitrites are promptly absorbed from the lung. They are ineffective by mouth since they are promptly destroyed in the gut. They are less effective by injection than by inhalation. It appears that the nitrites are hydrolyzed in vivo to nitrite ion and the corresponding alcohol. The alcohol is then partly oxidized and partly exhaled unchanged (Sutton, 1963). The nitrite ion which is absorbed, enters the bloodstream and is removed by the kidneys and excreted in the urine. A percentage may be oxidized by the liver to nitrate which would be excreted in the same manner.ToleranceNeither tolerance to nor dependence on the volatile nitrites has been demonstrated. In contrast, tolerance to the cardiovascular effects of the nitrates can develop after only a few days of continuous exposure. No cross-tolerance has been demonstrated.
Part III - Toxicology
Untoward responses to the inhalation of nitrite are, with the exception of methemoglobinemia, secondary to actions on the cardiovascular system.
These responses are enumerated as follows: Headache is common and can be severe. It is, however, usually a short-lived phenomenon. Transient episodes of dizziness, weakness and other manifestations of the cerebral ischemia associated with postural hypotension may occasionally develop, particularly if the subject is standing immobile; and, these may rarely progress to syncope (fainting). This reaction appears to be accentuated by alcohol, which also induces vasodilatation. Even in the most severe nitrite-induced syncope, the assumption of the horizontal position, which facilitates venous return, will promptly correct the condition. No further therapeutic measures are required.
The hemodynarnic effects of amyl and isobutyl nitrite are almost identical. Following inhalation of the nitrite, blood pressure begins to fall within 10 seconds and reaches a nadir at 30 seconds. After 90 seconds following inhalation it has returned to normal (Parker, 1978, Appendix VI).
Numerous toxicology textbooks state that nitrites and organic nitrates can increase intraocular pressure and precipitate glaucoma. This statement appears to be unfounded in view of more recent work which indicates that these agents have no significant effect on intraocular pressure (Whitworth & Grant, 1964). Long term uncontrolled use of the volatile nitrites has been shown not to be associated with deterioration of ventilatory function (Swenson, 1978, Appendix VIII). Liver or kidney damage is unlikely, even with long term chronic inhalation of alkyl nitrites. The total quantity of nitrates absorbed would be insignificant when compared to the quantity absorbed from foodstuffs and rural water supplies. The compounds have minimal irritant proper-ties to the skin and mucous membranes, though contact is painful to the nasal mucosa.
Nitrite ion readily oxidizes hemoglobin to methemoglobin, both in vitro and in vivo thus inducing methemoglobinemia. While formation of large amounts of methemoglobin can seriously impair the oxygen carrying capacity of the blood, there is no evidence that the inhalation of organic nitrites can generate sufficient quantities of methemoglobin to be clinically significant.
Serious symptoms of hypoxia due to methemoglobinemia are not seen until more than one-half of total body hemoglobin has been oxidized (Goldstein et al., 1974). Experiments with dogs utilizing sodium nitrite show that ataxia occurs at 60% methemoglobinemia, salivation and prostration at 75%, loss of consciousness at 85%, and death at 95% (Vandenbelt et al., 1944; Matsumoto, et al., 1961).
Research was conducted on workers in a bottling plant where the average ambient concentrations of isobutyl nitrite in the atmosphere range from 25 to 155 ppm with the following results: Average methemoglobinemia was 5.1%; the highest value was 8.1%. There was no cumulative increase in methemoglobin levels despite exposure of eight hours per day, five days per week (Parker, 1978, Appendix V). This would confirm that there is no significant potential toxicity due to methemoglobinemia from alkyl nitrite inhalation.
Although inorganic nitrites, particularly sodium nitrite, have produced many accidental poisonings by ingestion, industrial intoxications from alkyl nitrites have not been reported. There are no reports of intoxication from amyl, butyl or isobutyl nitrite. The single critical intoxication described in the literature is a fatality attributed to ethyl nitrite. The description is limited to "a maid [Magd] was found dead in her bed after a bottle had broken the evening before, spilling about four liters [of] ethyl nitrite in her bedroom" (Lewin, 1929). No further physical or chemical details are presented, and no pathology is available. Because of the highly volatile and unstable nature of pure ethyl nitrite, it is most probable that this material was "sweet spirits of nitre," a mixture of 75% ethanol and 25% ethyl nitrite. It is impossible to reliably attribute this death to the inhalation of a volatile nitrite.
Summary: All the volatile nitrites can produce vascular dilation with consequent hypotension and headache, and insignificant degrees of methemoglobinemia. All effects are transient and can be rapidly reversed by removing subject from the area of high nitrite concentrations. There is no significant toxicity to the lungs, liver or kidneys. There are minimal irritant properties to the skin and mucous membranes, though contact is painful to the nasal mucosa. No pathological changes have been reported.
Part IV - Sociology and Behavioral Effects
Guthrie in 1859 first described the flushing of the skin of the neck and face that is observed in man following inhalation of amyl nitrite. Therapeutic inhalation of amyl nitrite has been utilized in medicine for the relief of angina pectoris since 1867. Ethyl nitrite was also used in 19th century medicine in the form of "sweet spirits of nitre" (a mixture of 25J% ethyl nitrite with 75% ethanol). This mixture was taken orally in a dosage equal to 1.90 - 3.75 cc mixed with water every three hours as a diaphoretic, diuretic or antispasmodic. Its effects, when inhaled, are described as qualitatively similar to the effects of amyl nitrite, although less intense due to the lower volatility of the mixture (U.S. Dispensatory, 18th Ed., 1899). The therapeutic use of "sweet spirits of nitre" ceased early in the 20th century when it was supplanted by more effective therapeutic agents. Amyl nitrite continues to be used on a therapeutic and diagnostic basis, although it has been largely supplanted by nitroglycerin tablets.
In recent years, increasing attention has focused upon the use of amyl, butyl, and isobutyl nitrite as "aphrodisiacs." "Aphrodisiac"is a loosely defined noun: usually "any drug that arouses the sexual instinct" (Dorland's Med. Dic.) or "an agent provocative of or exciting sexual desire" (Webster's 3rd Int.). In order to apply this term to nitrites, it would probably be necessary to de-fine aphrodisiacs to include substances which will enhance sexual desire or perception; since, there are no substances known, other than possibly urinary tract irritants, which will initiate sexual desire in an otherwise disinterested individual. Alkyl nitrites are not urinary tract irritants.
Some researchers who have studied these nitrites, even those who oppose their indiscriminate use because of a lack of toxicological data, believe that they are indeed true aphrodisiacs (Louria, 1972). If we interpret the dysphemism "abuse" and the euphemism "non-medical use" of amyl nitrite to mean use in a sexual context, then the uncontrolled use of amyl nitrite dates back at least as far as 1930 (Cohen, 1978). The earliest use was probably by medical students and allied health personnel who had ready access to the drug and a penchant for experimentation.
On September 20, 1960, the U.S. Food & Drug Administration (FDA) directed that the prescription requirement for amyl nitrite be eliminated. In 1964, an official of the New York City Health Department advised Burroughs Wellcome Co., the principal manufacturer of pharmaceutical amyl nitrite, that there was increasing "non-medical use." A New York pharmacist was de-scribed as being "deluged" with requests for this somewhat obsolete drug by healthy appearing young persons (Lubell, 1964). In 1967, the same individual then with the Bergen County (N.J.) Health Department, advised the FDA that the number of people using amyl nitrite "legitimately" was small in proportion to the total number "abusing" it. In August, 1967, in conjunction with the question of whether to remove the prescription requirement for the purchase of nitroglycerin tablets, the FDA invited public comment on the status of both drugs. Numerous pharmacists and pharmaceutical trade associations submitted comments affirming widespread "abuse," and recommending controlled status. This recommendation appeared to be based solely on moral and/or economic grounds. In 1969, the FDA returned amyl nitrite to prescription status.
Until the early 1970's, both butyl and isobutyl nitrite were relatively obscure compounds. They were used as intermediates in chemical synthesis and in the perfume industry (Von Oettingen, 1946). Both butyl and isobutyl nitrite have characteristic odors, somewhat sweet and very pungent. Coincident with the resurgence in popularity of incense in the United States in the 1960's, room odorizers (scents) in liquid form began to appear on the market. Many of these utilized the fragrance achieved from amyl, butyl or isobutyl nitrite, sometimes in combination. Directions for use, however, have cautioned in most instances against direct concentrated inhalation. The concentrations generated when these scents are used as directed produce no physiological effect (Parker, 1978, Appendix V), merely a fragrance. In the early 1970's, there was a proliferation of brand names and products. Some were adopted by various segments of society for the enhancement of sexual perceptions. These brands appear to follow the same general formulation.
Numerous articles and statements in the news media, and legal actions in Connecticut and California called attention to these scents as "aphrodisiac", an image aggressively sought by many perfume manufacturers. Thereafter their popularity increased even more rapidly and spread to a substantial segment of the population. Major brands, such as RUSH®, report sales increasing at more than 50% per year. In 1977, it is estimated that more than 4,000,000 bottles (10-15 ml) were sold (Appendix IV).
These products are currently purchased by both sexes. There are incomplete statistical data to establish the ages of consumers Everett 1975), and none to establish the percentage of consumers using them according to package instructions. Major manufacturers ban sales to minors for public relations reasons; and, one city, Houston, has enacted an ordinance along those lines.
The nitrites or "poppers" - an onomatopoetic street name derived from the sound of the breaking amyl nitrite pearl) are common in discotheques, where they are inhaled by dancers on the dance floor. There are numerous reports of males and females using them for a "lift" in work situations. Most frequent, however, is their use during the sexual act.
The nitrites may be used often during the sexual act, but most efficaciously immediately prior to orgasm. A crushed pearl ampule) or open bottle is held directly under the nose of one or both partners. Generally the nostrils are obstructed alternately while the user inhales deeply through the open nostril. Inhalers are also used for one, or both nostrils simultaneously.
The resulting action of the nitrite is probably explicable in terms of the vascular system. It may, in some males, enhance erection, a vascular phenomenon; or, in others reduce it, thus retarding orgasm. The hypotensive effects of dizziness and giddiness may be involved in the reduced social and sexual inhibition and in time sense distortion, and thus may lead to a sense of prolonged orgasm in both males and females2. No studies have been conducted to determine whether there is a measurable increase in the actual duration of orgasm. The cutaneous vasodilation may increase skin sensitivity, and the placebo effect cannot be discounted. Many researchers agree, however, that the alkyl nitrite may be a true aphrodisiac in the sense of promoting and enhancing sexual response.
2E.M. Brecher, author of the outstanding Consumers Union Report, Licit and Illicit Drugs, while stating that he personally found amyl nitrite sexually unrewarding, quoted a lady friend as follows: "For me, an orgasm is like a hippopotamus. But with amyl nitrite, it is like a whole herd of hippopotami."
Part V - Summary and Conclusions
The volatile nitrites have been in use for more than a century. During this entire period, their medical use was predominantly in patients with coronary disease. Even in this high risk group, strict control of frequency of administration was considered unnecessary.Reports of the non-medical use of the volatile nitrites date back nearly fifty years. During the past twenty years, there has been increasing and widespread uncontrolled use of these compounds.The nitrites exert short-lived physiological effects, due primarily to their relaxing effect on smooth muscle. The consequent dilating effect on vascular tissue may lead to a transient reduction in blood pressure and increase in heart rate. The unwanted effects of these agents are associated with the vascular effects, but despite the ready availability of the nitrites and their widespread distribution and use, there have been no substantiated reports of serious injury or death secondary to this uncontrolled use. There is no established relationship between the pharmacology or toxicology of the inhalation of the alkyl nitrites and the inhalation of nitrous oxide, or to the suggested carcinogenesis related to the ingestion of inorganic nitrites in foods.
Despite the substantial and increasing uncontrolled sale and use of pharmaceutical amyl nitrite during the decade of the 1960s (see Sociology), no manufacturers received reports of injuries (Appendix II). Based on statistics reported by the U.S. Government-managed Drug Abuse Warning Network (DAWN) project, during the five-year period ending June 30, 1978, more than 18,036 persons were admitted to hospitals and more than 933 died from "drug abuse" directly attributed to specific prescription drugs. Of these, three admissions and no deaths were attributed to amyl nitrite. During the same period, more than 23,666 persons were admitted to hospitals and 3,754 died from "drug abuse" directly attributed to specific non-prescription drugs ranging from aspirin to mouthwash, and consumer products ranging from glues and housekeeping aids to aerosol deodorants. Despite sales estimated at over 12,000,000 bottles during this period (Appendix IV), no one was reported injured and no fatalities were reported from consumer products (scents, odorizers) containing butyl or isobutyl nitrite (Appendix III-A).
During the same 1973-78 period, the National Electronic Injury Surveillance System (NEISS) managed by the U.S. Consumer Products Safety Commission estimated that out of 44,658,823 injuries attributable to consumer products, 698,554 injuries were caused by "Home and Family Maintainance Products". In this group, which includes household odorizers and deodorizers, there were estimated to have been 6,627 injuries from chemical deodorizers, and none from odorizers or scents including those containing butyl or isobutyl nitrite (Appendix III-B).
Amyl nitrite is among the safest medications listed in the U.S. Pharmacopeia. The pharmacology and toxicology of the other volatile nitrites, including amyl and isobutyl nitrite, which are in use in consumer or household products, is almost identical. Their regulation or control is, therefore, unnecessary for the protection of the public health. It is difficult to envision any product with a better record of public safety.
A definition of safety as being totally free of toxicity has no meaning in toxicology, as all substances are toxic at some level of use. No important acute or chronic toxic effects have been demonstrated with the volatile nitrites, and their use in an uncontrolled and unregulated fashion is safe. In view of the great toxicity of the numerous consumer products which are and may be misused as alternatives, restriction of the volatile nitrites could, contrary to the hopes of would-be regulators, ultimately prove harmful.
Reprinted with permission of Pharmex, Ltd 2007
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