Toxicology of Antidepressant Drugs

As many pharmacodynamic effects carry over from animals to man, many toxic effects may also be predicted from observations made in animals. However, some important toxic effects are not predictable from animal studies (WHO, 1966) and this limitation may apply particularly to drugs acting on the central nervous system, such as the antidepressants. Nevertheless, the recognition of species differences and similarities in responses is considered as an important means of predicting toxic effects in man. In the following, some degree of correlation is attempted by the comparison, whenever feasible, between toxicity in laboratory animals and adverse effects described in man, particularly in cases of acute intoxication. However, due to the differing amount of data that was available on various drugs and the widely varying experimental conditions employed, such a comparison may not always prove to be reliable. The following review has been restricted to antidepressants in clinical use and, as far as evidence was available from the literature, concentrated on two main categories of antidepressants, the monoamine oxidase (MAO) inhibitors and the tricyclics. The lithium salts are considered in a separate chapter of this volume. Read more […]

Toxicology of Antidepressant Drugs: Tricyclic Antidepressants

Animal Toxicity General Toxicology The LD 50 values for a number of tricyclic antidepressants, when administered to mice and rats in single oral or parenteral doses, are listed in Table Acute LD50 valuesa of some tricyclic antidepressants. Acute poisoning by tricyclic antidepressants usually leads to symptoms of central excitation followed at the higher and lethal dose levels by central inhibition. The symptomatology includes muscular weakness, twitching, stupor, respiratory disorders, ataxia, and tonic-clonic convulsions. Table Acute LD50 valuesa of some tricyclic antidepressants Imipramine Doxepine Nortriptyline Viloxazine Maprotiline Mouse i.v. p.o. 35 666 15- 20 148-178 26 327 60 1000 31 660- 900 Rat i.v. p.o. 22 625 13- 19 346-460 22 502 60-77 2000 38- 52 760-1050 a The values given are for LD50, single administration, in mg/kg body weight It is evident from Table Acute LD50 valuesa of some tricyclic antidepressants or from the reports of Pluviage () and of Ueki et al. () that no major differences in the acute toxicity of tricyclic antidepressants are apparent. Information on animal studies relating to the tolerance of tricyclic antidepressants Read more […]

The Theoretical Basis of Narcotic Addiction Treatment with Narcotic Antagonists

The theoretical basis of narcotic addiction treatment with narcotic antagonists was well stated by Martin et al. (). Briefly, outpatient maintenance of a previously detoxified opioid addict on a daily oral opioid-blocking dose of a narcotic antagonist is expected to accomplish two objectives: (a) to remove the incentive for seeking and using opioid drugs; and (b), to extinguish conditioned abstinence (including “craving”) should this phenomenon occur as a response to environmental stimuli to which unconditioned abstinence had previously become conditioned (). Needless to add, such a period of out-patient maintenance on a narcotic antagonist should be used to “rehabilitate” the patient – i.e., to train him in the skills necessary for holding a socially useful job. to form new, mutually supportive relationships with non-drug using persons, and to persuade him to give up the illegal “hustling” activities which had become self-reinforcing during previous periods of opioid addiction. Such a period of out-patient maintenance on a narcotic antagonist would have advantages over detoxification followed by enforced abstention from opioids (by prison sentences with or without a subsequent probationary period) in Read more […]

Human Dependence on Tobacco and Opioids: Common Factors

Recent years have seen increasing acceptance of the notion that tobacco is an addictive or dependence-producing substance, particularly as it is used in cigarette smoking. This idea is supported by the observations that tobacco serves as a reinforcer (i.e., it maintains behavior leading to its use) and that most people who smoke cigarettes would like to quit but cannot, even in the face of well documented health risks and economic sacrifices (Surgeon General’s Report 1979). The term “drug dependence” suggests that (1) the drug serves as a reinforcer, (2) behavior occurs which is maintained by the opportunity to take the drug, and/or (3) other reinforcers are sacrificed as a consequence of taking the drug (). Many cigarette smokers in some degree satisfy these criteria for drug dependence (). Since cigarette smoking has only recently been conceptualized as an instance of drug dependence, it should be useful to systematically compare cigarette smoking with another more thoroughly studied dependence process such as opioid dependence or narcotic addiction. At first blush, cigarette smoke and opioid drugs appear to produce vastly differing pharmacological and behavioral effects: large doses of opioids can produce Read more […]

Drug effects on behavior maintained by food, electric-shock presentation and stimulus-shock termination

Although early experiments did not find differences in drug effects depending on the type of event, more recent studies have reported several instances in which the maintaining event appeared to influence the effects of several drugs on behavior. For example, morphine, methadone, and the narcotic antagonists naloxone and nalorphine decreased responding maintained under 5-minute fixed-interval food-presentation schedules at doses that increased responding comparably maintained by the presentation of an electric shock (). Under similar schedule conditions, both amphetamine () and cocaine () increased responding maintained by these two events. However, appropriate doses of pentobarbital, ethanol, and chlordiazepoxide increased responding maintained by food, while only decreasing responding under shock-presentation schedules (). These findings suggested that there were several conditions under which certain drugs appeared to affect similar performances maintained under comparable schedules in an event-dependent manner. Further, as shown in Figure Effects of chlordiazepoxide on different control rates of responding under S-minute fixed-interval schedules of food or shock presentation. The event pen was defected downward Read more […]

Studies of Acute Alcohol Effects in Women and Animal Models

Alcohol Effects on Basal Hormone Levels Another approach to examination of alcohol’s toxic effects on reproductive function is to administer a single acute dose of alcohol to a normal healthy woman or experimental animal and measure the effects on pituitary and ovarian steroid hormones. Through a systematic manipulation of alcohol dose and changes in hormone levels, it should be possible to establish whether alcohol primarily disrupts hypothalamic, pituitary, or ovarian function. Surprisingly, studies of acute alcohol administration have shown that alcohol has minimal effects on basal hormone levels. Alcohol did not significantly suppress LH or estradiol in normal women or in female macaque monkeys. These data suggest that a single episode of intoxication is probably not sufficient to suppress normal basal hormone levels and that repeated episodes of intoxication are required to produce the hormonal correlates of amenorrhea, anovulation, and luteal phase dysfunction observed in clinical studies. One procedural difficulty affecting all investigations of acute alcohol effects on basal hormone levels is that studies have usually been conducted during the early follicular or luteal phase of the menstrual cycle, when basal Read more […]

Buprenorphine, Heroin, and Methadone: Comparison of Relative’ Reinforcing Properties

Buprenorphine is a partial agonist of the morphine type. It is both a long-acting opiate antagonist, like naltrexone, and a potent opiate agonist with respect to analgesia, physiological and subjective reactions in man (). However, buprenorphine does not induce physical dependence in several species and appears to produce only minimal physical dependence in man (). Buprenorphine’s positive morphine-like agonist effects combined with its antagonist potency, low toxicity, and minimal capacity for producing physical dependence, suggested that it should be valuable for the treatment of opiate addiction (). Clinical studies have shown that buprenorphine maintenance (8 mg/ day s.c.) significantly suppressed self-administration of heroin (21 to 40.5 mg/day) by male heroin addicts over 10 days of heroin availability in comparison to buprenorphine placebo (). Buprenorphine (0.282 to 0.789 mg/kg/day i.v.) also significantly suppressed opiate self-administration in the rhesus monkey drug self-administration model (). Recent clinical studies have shown that sublingual administration of buprenorphine (1-2 mg) should be suitable for daily maintenance for the treatment of narcotic addiction (). The opiate agonist effects of Read more […]

Physicians as Suppliers

The great economic importance to Britain and the Netherlands of the intra-Asian opium trade in the 19th century has already been discussed in post The Colonial Opium Trade. But another legal branch of the opium trade evolved in the course of the 19th century, involving the transport of smaller, but by no means negligible, opium shipments from the Levant and South-East Asia to Western Europe and the United States. In the case of the intra-Asian opium trade, the state monopolies described above disrupted the free interplay of supply and demand, but trade to Europe and the United States was initially unrestricted aside from the usual import duties. Here price mechanisms reigned supreme, and when opium cultivation intensified in the Levant and South-East Asia in the 19th century, prices fell. As the demand for opium soared, a variety of experiments were conducted with the aim of cultivating the poppies closer to the European market. In the period 1740 1870, for instance, there were countless attempts to cultivate the crop on British soil. And much later, in the early 20th century, new harvesting techniques were tried out some in Western Europe the aim being to replace the labourintensive harvesting of opium as an intermediary Read more […]

The medical regulation of opiates in the United States

In the United States, opium was supplied in three separate ‘domains’ in the 19th century. There were qualified physicians who prescribed opiates — and later morphine — for their patients. (And just as in Europe, it was primarily the welltodo who could afford to consult a physician). Secondly there was the market of patent (or secret) remedies such as Scotch Oats, which were for sale everywhere outside the control of medical practitioners or pharmacists: they were obtainable from general stores and itinerant quacks. These were used primarily by the lower classes of white immigrants. Thirdly, there was the supply of smoking opium for Chinese immigrants. It is particularly the first two of these domains which are of importance in the present context. The rivalry between American doctors and pharmacists was little different from that in the two European countries that have been considered. Their common commercial interests too were abundantly clear. Nevertheless, it took much longer in the United States for any comprehensive federal legislation to be introduced that would regulate the state supervision of medical facilities. Some states and local communities, however, formalized the medical regulation of opiates Read more […]

The Effects of Law Enforcement Activity on a Population of Opiate Abusers

This study examined the effect of police action against heroin pushers on clients of methadone programs in metropolitan Denver. On November 10, 1979, twenty suspected drug dealers and buyers were arrested and another twenty were under investigation in a vice squad operation in metropolitan Denver. The operation involved an undercover agent who mingled with addicts and bought opiates over an extended period from dealers, who were later arrested within a 48-hour period. Newspaper reports indicated that most of those arrested had been selling heroin in the vicinity of the outpatient clinic operated by Addiction Research and Treatment Services (ARTS) of the University of Colorado School of Medicine. Although linked to the clinic by the press, only two of those arrested were known to clinic personnel. In this study we examined the patterns of opiate use of the clients enrolled in that clinic as reflected by the presence of opiate metabolites in their urine samples collected before and after the drug bust. The clinical course of a sample of clients who abused opiates before, but not after the bust was examined. In addition, urine data from the other two methadone programs in the city were examined. Metropolitan Denver Read more […]