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ALTHOUGH hydration by forcing of fluids and the use of pitressin has long been employed to precipitate epileptic seizures for diagnostic purposes in persons suspected of having idiopathic epilepsy,1no study has been made of the electroencephalographic changes produced by this procedure, either in normal or in epileptic subjects. A single injection of pitressin has been reported to have no effect on the electroencephalogram,2but no data have been found on the effects of water intoxication except for the statement by Allen3that some experiments of this type on dogs had been attempted. The present study was undertaken in an attempt to solve a clinical problem. A patient at the United States Public Health Service Hospital was referred for electroencephalographic study because he exhibited periodic episodes of antisocial behavior. A diagnosis of psychopathic personality had been made, but it was desired to rule out epilepsy. A routine

The research history of norcodeine as a narcotic blocking drug is presented. Because of the limitations found for norcodeine usage, naloxone, cyclazocine, and naltrexone have recently received attention, and the results of research with them are detailed.

In an attempt to ascertain the effect of retrieval cues on recall deficits which occur following intoxication with marijuana, 40 male volunteers were presented with word lists following the smoking of a single one gram marijuana (0.94% delta 9 -THC) or placebo cigarette and then were required to recall these words immediately after presentation. Recall occurred under a condition in which cues representative of to-be-remembered words were present or in an uncued condition. Results indicated that recall was depressed following marijuana administration under both cued and uncued conditions with cues being only mildly effective in reversing the recall deficit. There was no increase in the number of internal intrusions under marijuana, but the number of external intrusions was significantly elevated under the cued conditions.

The free recall of pictures and words was compared following the administration of marijuana or placebo in a multitrial free recall task. Since pictures are thought to be registered in both visual and verbal memory stores with this encoding being mediated by some form of mental imagery, it was predicted that marijuana would produce a greater deficit in word recall in comparison to picture recall because the drug has been reported to facilitate imagery. A trend in the opposite direction followed intoxication; picture recall was inferior to word recall in the later stages of acquisition. Although overall recall was inferior under marijuana, no differences were found between the treatment conditions in subjective organization as determined by a variety of clustering measures. Recall performance following marijuana intoxication was positively related to level of recall performance in the placebo condition.

Derived from the hypothesis that many alcoholics would experience autonomic "arousal" and craving for alcohol under conditions of high sensory stimulation, this study does not support prior findings.

Data in the literature indicate that conditioned responses (CRs) generated by repeated pairing of conditional stimulus (CS) with administration of a neurotropic drug may resemble its unconditional effects or they may be opposite in direction; furthermore, the CRs may change as such pairings are continued. In explanation, it is hypothesized that as in conditioning of physiological reflexes, a CS repeatedly paired with administration of a neurotropic drug eventually comes to activate central“processing” events that are evoked by the“stimulus” properties of the drug,i.e., the effects of the drug at receptor sites inside or outside the pia mater which lie in the afferent arms of“reflex” neural circuits; or, the CS comes to activate central processing events that are evoked by centripetal feedback responses to the effects of the drug at receptor sites in the processing or efferent arms of reflex neural circuits. Depending on the receptor site action of the drug, the conditioned autonomic and/or neuromuscular responses that are observed may be in the same direction as, or opposite in direction to the unconditioned effects of the drug. With continued pairings of CS and drug, the unconditioned processing events evoked by the stimulus properties of the drug, and hence the CRs also, change in consequence of compensatory (sometimes“overshooting”) biochemical alterations proximal to the receptor site of action of the drug, induced by negative or positive neuronal feedback mechanisms. These concepts are utilized in a theory of opiate addiction and relapse.

It is hypothesized that the phenomenon of "craving" for alcohol represents a psychological or cognitive correlate of a subclinical conditioned withdrawal syndrome which may be evoked by any state o...

Experimental evaluation of Wikler’s interoceptive conditioning hypothesis of relapse to opioid use in ex-addicts requires a preliminary study of the degree of physical dependence produced by two methods of drug administration. Wistar rats were made physically dependent on morphine by single daily intravenous injections or by a continuous i.v. infusion. Rats received the same total daily dose regardless of administration schedule. The initial daily morphine dose was 20 mg/kg, and was increased every fourth day by 20 mg/kg, until a dose of 200 mg/kg per day was reached. The rats were maintained at the highest dose level for 18 days, at which time morphine was discontinued. Body weight and water intake were the primary variables measured during addiction, maintenance, and abstinence phases of the study. Equivalent and parallel changes in mean weight and water intake in injection and infusion rats indicate equivalent degrees of physical dependence were developed. This finding allows separation of the contribution of conditioning factors and of protracted abstinence in facilitating opioid self-administration in formerly-dependent organisms.

In this paper, an attempt has been made to examine critically what is known concerning the mechanisms through which drugs modify personality function, in terms of subjective experience, overt performance, and neurophysiology. A study of available data and the techniques by which they have been acquired leads to several important general conclusions: (1) Not only is there a considerable degree of incommensurability between "subjective" and "objective" data, but also between data in either category that are acquired with different techniques. (2) The "organism" can never be separated from its " environment," and the 2 can be described only in terms of mutual interaction. (3) A "stimulus" cannot be defined in terms of its own properties alone, since its capacity to evoke responses is determined in part by antecedent events, and by particular experimental arrangements. These conclusions can be reconciled with a monistic theory of "mind" and "body" (43). However, it may be questioned whether concepts such as "...

The testing of analgesics, especially morphine, has yielded a great deal of conflicting evidence concerning the effects of drugs on pain perception. The recent reviews by Wikler (1) and Edwards (2), and the monograph by Wolff and Wolf (3), cover thoroughly the studies that have attempted to measure changes in the pain perception threshold. Although many investigators have reported rises in the pain perception threshold of some of their subjects following the administration of morphine, the majority have obtained variable results. Wolff, Hardy, and Goodell (4) found consistent rises following the administration of morphine under certain conditions. Using the same technique, Andrews (5), Isbell (6), Denton and Beecher (7), and Chapman and Jones (8) found, following morphine, that the pain perception threshold might be elevated, lowered or unchanged. Similar results were obtained by Isbell and Frank (9) in studies on the effect of analgesics on tooth pain perception thresholds. It would seem that the discrepancies were not due to faulty apparatus or lack of objectivity in handling the data. Rather, the reasons appear to lie in conditions that were not held constant or that were beyond the control of the experimenters. One such variable that has been mentioned in several studies as possibly contributing to unpredictability of results is the "emotional" status of the subject at the time the experiment is performed. Included would be such factors as response of the subject to the experimental room, to the complex apparatus, to the attitude of the experimenter, and to the expected painful stimuli. The uncontrolled variable in the subject's behavior would then seem to comprise that class of responses which is termed anticipatory, i.e., especially effectively toned responses that are anticipatory of pain. This, of course, is one type of fear or "anxiety." Isbell and Frank (9) also studied the effect of morphine on the ability of subjects to estimate intensities of painful stimuli. In their investigation, the pulp nerve of a tooth containing a silver amalgam filling was stimulated electrically at intensities three times the absolute perception threshold value. These stimuli, which served as standards, were definitely painful. After morphine the subjects were required to manipulate rheostat knobs on the stimulating apparatus until the test stimuli were reported as being equal to the standard. (The apparatus was so adjusted that turns of the knob did not correspond with the intensity of stimuli or with dial scale readings.) No change in the accuracy of estimation of painful stimuli was observed following the administration of morphine. However, analysis of the conditions under which the studies were conducted indicates that considerable effort was expended to reduce anxiety in the subjects; they were given considerable control of the experimental situation since they manipulated the stimulator knob themselves and applied the electrode to their own tooth fillings. In addition they were trained in estimating intensities of painful stimuli for approximately one week prior to testing. In view of conditions and results discussed! in published studies on pain perception thresholds, it might be expected that if conditions had been favorable for enhancement of anxiety (anticipatory responses to expected unpleasant stimuli), Isbell and Frank would have obtained different results. The present investigation is an attempt to determine the extent to which anxiety and morphine alter pain intensity estimation. The experiment was designed to investigate the effect of controlled variations in the experimenter's treatment of the subject on estimation of pain intensities, while the number, the order, and the intensity of the stimuli were kept constant for all groups. If it could be

Viewing the development of drug cults as a conditioning process, examples are given of specific effects of alcohol, barbiturates, opioids, amphetamines, cocaine, marihuana, LSD and other psychotomimetic drugs that can reinforce continued use of the drug in question through facilitation of specific patterns of behavior that serve to gratify specific biological and socio-culturally generated human needs. It is hypothesized that, through repeated temporal contiguity between such primary reinforcement and the performance of rituals prescribed by those who are already members of the drug cult, novitiates eventually learn to perceive the magical drug-effects defined by the cult and to experience them even without benefit of the drug when the rituals are performed (secondary reinforcement), thereby becoming a new, full-fledged member of the cult. It is suggested that the maintenance of secondarily reinforced behavior in the absence of further programmed reinforcement by the drug is a consequence of previous classical conditioning of primary drug effects and possibly, of interoceptive conditioning. Some therapeutic applications of conditioning theory are indicated, with special reference to the possible use of specific drug antagonists to facilitate extinction of drug-seeking behavior. Expansion of basic psychopharmacological research as well as of educational and social ameliorative efforts are stressed as desiderata for eventual control of the problem of drug abuse.

1. On 9 nights (2000-0800) over a 25-day period, an anise-flavored aqueous solution of etonitazene, 5 mcg/ml, was provided as the sole drinking fluid for one group of physically dependent rats (MFETZ) maintained on morphine, 200 mg/kg i.p. once daily at 0800 (hence acutely abstinent each night) and for one group of saline-injected rats (SFETZ), while only anise-flavored water was available to comparable physically dependent (MFH2O) and saline-injected (SFH2O) groups. 2. Beginning 3 days after abrupt and permanent termination of morphine or saline injections, all rats were tested at intervals over a period of 287 days on nocturnal (2000-0800) choice drinking from 2 tubes (positions alternated), one contained anise-flavored water and the other, plain water. 3. Analyses of variance on the mean volumes of each of the two fluids consumed by each rat over blocks of choice-drinking tests revealed that through the VIIth test (137th post-injection day), MFETZ drank more anise-flavored water than any other group while there were no significant differences among the groups as regards consumption of plain water. 4. The evidence indicates that the potency of secondary reinforcers so generated can persist long after morphine withdrawal. Some implications for problems of relapse and treatment of opioid addicts are discussed.

1. Correlative data on EEG changes, behavioral alterations and variations in blood alcohol level were obtained in 3 former narcotic addicts, without anamnestic, neurological or EEG evidence of central nervous system disorder, who received averages of 458-489 cc. of 95% ethyl alcohol daily for 48-55 days, followed by abrupt withdrawal of the drug, under controlled experimental conditions. 2. During chronic alcoholic intoxication, blood alcohol levels varied with particular procedures that were carried out, but were maintained for long periods at about 200 mg. %. Initially, EEG's were diffusely slowed, and this change persisted in milder degree during the remainder of the chronic intoxication period. However, EEG evidence of partial, though precarious, "metabolic" and "tissue" tolerance was obtained, which corresponded roughly to variations in degrees of behavioral intoxication. 3. By the 15-19th hour of abstinence, blood alcohol levels had fallen to zero. Anxiety, tremulousness, weakness and profuse perspi...

Rats were trained in a straight runway on a non-spatial single alternation (NSSA) which involved presentation of reward (R) and nonreward (N) in a fixed repeating sequence (i.e. R-N-R-N ...). Patterned running results since rats learned to run fast on R trials and slow on N trials. This task can be regarded as an animal analog of the goal directed serial alternation task employed with humans. After patterned running was well established the effects of graded doses of δ9-THC, LSD and scopolamine were delineated. Although all drugs modified alternation performance, each agent produced distinctly specific effects on the different components of NSSA. δ9-THC disrupted alternation by decreasing running speed on R trials and increasing running speed on N trials. Lower doses of LSD increased running speed on N trials while leaving R trial speeds unchanged. At the highest dose, LSD decreased running speed on R trials while leaving N trial speeds only slightly elevated from baseline. Scopolamine disrupted alternation solely by decreasing speed on R trials. The results were discussed with reference to the effects of these drugs on internal inhibition, registration and recall of internal cues and timing behavior.

T HE term “drug addiction” refers to a group of behavior patterns which differ from each other in many ways but have as a common characteristic the compulsive use of chemical agents which are harmful to the individual, society or both. It is possible to describe aspects of this group of behavior problems from various sociological, psychologic, physiologic and biochemical points of view, and these are all interrelated because, in the last analysis, the phenomena observed involve the integrated organism in its total environment. However, for present purposes discussion of “drug addiction” will be limited to those aspects of the problem that can be described in “psychodynamic” terms, i.e., by the use of concepts derived from observation of the verbal and nonverbal goal-directed behavior of patients who are or have beenaddicted to certain drugs. Several alternative formulations of the psychodynamics of drug addiction can be made on the basis of such observations, depending on the “frame of reference” used by the investigator. Their relative validity has not yet been established because of inherent difficulties that beset the solution of many problems in psychiatry, namely, in applying the test of predictive utility to the assessment of the relative importance of various concurrent processes that occur in individuals suffering from the condition under investigation, l Therefore it appears desirable to present in this paper, three formulations of the psychiatric aspects of drug addiction and to discuss briefly the kinds of investigation that will be necessary for evaluating the usefulness of each approach.

The effects of large doses of morphine in nontolerant and tolerant rats as well as the effects of abruptly withdrawing morphine in rats experimentally addicted to large doses of morphine have been studied on body weight, temperature, metabolic rate, respiratory rate, water consumption and various forms of motor activity and behavior. In confirmation of many early reports, tolerance develops to certain depressant actions of large doses of morphine and the effects of morphine in the tolerant rat are primarily excitatory, consisting of an increase in body temperature, metabolic rate and motor activity. The abstinence syndrome of rats addicted to large doses of morphine seems to have two phases: (1) An early phase, which has been called “primary abstinence” consists of weight loss, an increased number of “wet dog” shakes, increased activity, and a fall in body temperature and metabolic rate. The primary abstinence syndrome becomes clearly manifest within 8 to 16 hours following the last dose of morphine and persists for approximately 72 hours. (2) The secondary abstinence syndrome emerges thereafter and consists of a rapid gain in body weight, elevated body temperature and metabolic rate and an increase in water consumption. The secondary abstinence syndrome is protracted and small differences have been seen between addicted and control animals as long as four to six months after withdrawal of morphine.

1. In two experiments, using a cross-over design, the development of “direct” tolerance to LSD and psilocybin was measured after 10 (Experiment I) or 9 (Experiment II) volunteers had taken LSD in doses increasing to 1.5 meg/kg over the course of 6–7 days (Experiment I) or 13 days (Experiment II). On another occasion, the same patients received psilocybin in doses increasing to 150 mcg/kg over the course of 6–7 days (Experiment I) or 210 mcg/kg over the course of 13 days (Experiment II). 2. The development of “cross” tolerance to psilocybin in patients “directly” tolerant to LSD was measured by “challenging” the patients, after they had received LSD chronically, with 150 mcg/kg (Experiment I) or 210 mcg/kg (Experiment II) of psilocybin. “Cross” tolerance to LSD was evaluated by “challenging” the patients, after they had received psilocybin chronically, with 1.5 meg/kg of LSD. 3. A high degree of “direct” tolerance to LSD developed in both experiments, as manifested by statistically significant reductions in six of the seven parameters of response. Patients “directly” tolerant to LSD were also “cross” tolerant to psilocybin on five (Experiment I) or four (Experiment II) parameters. 4. Definite “direct” tolerance also developed after chronic administration of psilocybin in both experiments, but statistically significant reductions occurred in fewer parameters of response (four in Experiment I and three in Experiment II) than was the case with LSD. Patients chronically treated with psilocybin were also “cross” tolerant to LSD on four (Experiment I) or three (Experiment II) measurements. The degree of “direct” tolerance to psilocybin was less than the degree of “direct” tolerance to LSD. 5. The development of “cross” tolerance between LSD and psilocybin reinforces the idea that these two drugs cause psychic disturbances by acting on some common mechanism, or on mechanisms acting through a common final pathway.

In a two phase design, an attempt was made to differentiate the effect of marijuana on the storage and retrieval of prose material. In the first phase, 40 male subjects were administered a single 500 mg marijuana cigarette containing 2.1%delta9-THC or a placebo cigarette. Fifteen minutes after smoking, they listened to and at the same time read a narrative passage of approximately 200 words in length. Subsequently, an immediate free recall test was given in which subjects were required to write down as much of the story as they could remember. The second phase was conducted 24h later. Marijuana and placebo subjects were randomly subdivided into four groups with half of the subjects participating in the same drug condition as occurred on day one while the others switched drug state. Fifteen minutes after smoking, all subjects recalled the passage presented on day one and then were given 24 questions concerning facts and events in the story which could be answered in a few words. These questions served as retrieval cues. Following this, a new passage was presented in the same manner as occurred on day one. After an immediate free recall test, another cued recall test was administered. Results indicated that marijuana reduced immediate recall under both cued and uncued conditions incomparison to placebo. No relative cued recall advantage was found in the marijuana groups for the old or new story and marijuana produced only a moderate decrement in recall of the old story on day two. However, marijuana given in the second phase significantly reduced memory for items recalled in the initial phase irrespective of drug or cueing condition in phase one, suggesting that retrieval was also affected. Some decrement in recall of the new story did occur as a function of drug state change in group M-P. This effect was related to the serial position of input items. Serial position did not interact with drug state under any other recall condition.

The World Health Organization Expert Committee on Addiction-Producing Drugs (1964) defined drug dependence as ... a state of psychic or physical dependence, or both, on a drug, arising in a person following administration of that drug on a periodic or continuous basis. The characteristics of such a state will vary with the agent involved, and these characteristics must always be made clear by designating the particular type of drug dependence in each specific case; for example, drug dependence of the morphine type, of cocaine type, of cannabis type, of barbiturate type, of amphetamine type, etc. Common to all of these types of drug dependence is the concept of “psychic” or “psychological” dependence, which is defined as a drive that requires administration of the drug to produce pleasure or to avoid discomfort (Eddy et al., 1970). Psychic dependence is usually distinguished from “physical” dependence, which is inferred from the appearance of drug-specific, transient abstinence phenomena (autonomic and behavioral) when the drug is withdrawn abruptly. However, as Eddy et al. (1970) pointed out, physical dependence is a powerful factor in reinforcing the influence of psychic dependence. It would seem that the main distinction between psychic and physical dependence is that the former is a vaguely defined cluster of inferences derived from subjective reports of the subject, while the latter is inferred from objective changes in his autonomic nervous system and his behavior.

In man, the presence of pain is inferred by the observer from the verbal reports of the subject and/or certain behavioral characteristics expressing his or her emotional state, and from evidence, actual or presumed, of tissue injury. Given the same or equivalent degrees of tissue injury, the severity of pain and demands for its relief vary widely. For example, Beecher (1956, 1968) noted that at the Anzio Beachhead in World War II, 150 soldiers with severe war wounds (trauma to bones, intrathoracic and intra-abdominal trauma) complained far less of pain, and only 32% wanted a narcotic within 7.2–12.5 hr after the trauma, compared with 150 males who had sustained comparable injuries in civilian disasters, 83% of whom wanted a narcotic within 3.0–4.4 hr after the trauma. In animals, pain is inferred by the observer from certain “nociceptive” reflexes and behaviors (attempts to escape, struggling, attacking, vocalizing). Yet here, too, the manifestations of pain, given the same or equivalent degrees of injury, are not invariable. Thus, Pavlov (1927) reported an experiment by Erofeeva in which she used strong electric (faradic) stimulation of the skin (which normally evokes vigorous unconditioned defense reflexes) as the conditioned stimulus for the formation of an alimentary conditioned reflex, by repeatedly pairing the former with presentation of food to the food-deprived dog.

The diagnosis of physical dependence on opioids can be established only by the demonstration of typical opioid-abstinence phenomena, either by isolating the patient without abstinence-suppressing medication for at least 48 hr and observing the development of pupillary dilatation, frequent yawning, lacrimation, rhinorrhea, piloerection, sweating, restlessness, vomiting, and rise in pulse rate, respiratory rate, and rectal temperature, or by administering a narcotic antagonist and observing the appearance of such opioid-abstinence signs within a few minutes. For this purpose, either nalorphine (Nalline) or naloxone (Narcan) may be used. As a narcotic antagonist, naloxone is about 10 times as potent as nalorphine, which also possesses some opioid-agonist properties. An experienced physician may administer the narcotic antagonist (1-4 mg of nalorphine or 0.1—0.4 mg of naloxone) slowly by intravenous injection, constantly observing the patient for early opioid-abstinence signs such as pupillary dilatation, increase in respiratory rate, lacrimation, rhinorrhea, and sweating. The appearance of these signs establishes the diagnosis of physical dependence on opioids, and further intravenous injection of the narcotic antagonist should be stopped, as it may precipitate a more severe and potentially dangerous abstinence syndrome. For less experienced physicians, the subcutaneous route is safer.

According to Ariens et al. (1964b), the concept of receptors was first proposed by J. N. Langley in 1905 to account for the actions of nicotine and curare at the myoneural junction, and by P. Ehrlich in 1906 to account for specific interactions between antigens and antibodies and for the selectivity of dyes for certain components of living cells. On the basis of his research, Ehrlich (1913) concluded that “If the law is true in chemistry that ‘corpora non agunt nisi liquida,’ then for chemotherapy the principle is true that ‘corpora non agunt nisi fixata”’ (substances do not act unless they are fixated). In modern drug-receptor interaction theory, reversible “fixation” of the drug to the receptor is held to produce the pharmacological effect, and drug-receptor interactions are viewed as analogous to substrate-enzyme interactions (Michaelis & Menten, 1913). In this view, subject to some qualifications expressed by Ariens et al. (1956), the receptor concentration is regarded as if it were an enzyme concentration, the drug concentration as if it were a substrate concentration, and the pharmacological effect of the drug-receptor combination as if it were the initial reaction velocity of the enzyme-catalyzed substrate change. On the basis of these and some other assumptions, the dose-effect relationships of agonists, partial agonists, and antagonists, as well as their intrinsic activities (efficacies) and affinities, have been calculated. The term agonist implies that a given pharmacological effect of a drug increases with its dose (or its concentration) up to a maximum.

Twelve experienced marijuana users received marijuana cigarettes containing 10 mg Δ 9 -THC or placebo in two experimental sessions each separated by a one week interval. The effects of both treatments on pulse rate, subjective estimates of intoxication, multiple measures of memory including free, serial and delayed recall, final free recall, and recognition memory were assessed. Pulse rate and subjective ratings were elevated significantly following intoxication with active marijuana in comparison to placebo. Each of the three types of recall were significantly reduced following intoxication with marijuana but no differential effects of drug on recall condition were noted. Intrusion errors were elevated on the final free recall test following intoxication but recognition memory was unaffected.

By opioid is meant any drug, regardless of chemical structure, that acts like morphine. The term opioid is preferred to the older term, opiate, for two reasons: first, because opiate implies presence in or derivation from opium, which indeed contains the analgesic drugs morphine and codeine but also contains thebaine, a strong stimulant (convulsive) drug with minimal analgesic properties, and also papaverine and noscapine, which have no analgesic actions; and second, because of a host of purely synthetic drugs with actions qualitatively similar to those of morphine and codeine that, unlike the analgesics found in opium or derived therefrom, lack the phenanthrene nucleus (e.g., methadone, meperidine, d-propoxyphene). Opium is prepared from the sap of the poppy Papaver somniferum and contains about 10% by weight of morphine and about 0.5% by weight of codeine. Analgesic compounds that are derived from morphine and that retain the phenanthrene nucleus and are classed as opioids include heroin (diacetylmorphine), hydromorphone (Dilaudid), oxymorphone (Numorphan), and oxycodone (Percodan). Purely synthetic analgesic compounds that lack the phenanthrene nucleus but are classed as opioids include methadone (Dolophine), meperidine (Demerol), d-propoxyphene (Darvon), levorphanol (Levo-Dromoran), and phenazocine (Prinadol). In man, the analgesic potencies of these drugs relative to morphine (all drugs given subcutaneously) are codeine, one-twelfth; heroin, 2–3 times; hydromorphine, 6–8 times; oxymorphone, 7–10 times; oxycodone, two-thirds to equipotent; methadone, equipotent; meperidine, one-tenth to one-eighth; levorphanol, 2–3 times; and phenazocine, 3 times. By the oral route, 65 mg of d-propoxyphene is equivalent to 32–45 mg of codeine for analgesia, but 32 mg of d-propoxyphene may be no more effective than placebo. A newer synthetic compound, pentazocine (Talwin), exerts some morphinelike effects (analgesia, respiratory depression, sedation) in doses of 30–50 mg given parenterally (equivalent to 10 mg of morphine) or of 50 mg given orally (equivalent to 60 mg of codeine); at higher doses, pentazocine also produces dysphoric and psychotomimetic effects that can be reversed by naloxone, but not by nalorphine. In addition, pentazocine has weak opioid-antagonistic actions and can precipitate abstinence phenomena in morphine-dependent individuals. Though not in clinical use, etorphine (Immobilon), an opioid derived from oripavine and ultimately from thebaine, is of interest because of its extreme potency. In man, it is about 400 times as potent as morphine, though its duration of action is much shorter; in animals, its potency is even greater than in man, and it is used for immobilizing large game animals (Harthoorn & Bligh, 1965). Although of all these opioid analgesics, heroin is the most widely abused in the United States, its pharmacological effects (including the development of tolerance and physical dependence) do not differ qualitatively from those of morphine. The same is true also of hydromorphone, oxymorphone, oxycodone, levorphanol, phenazocine, and methadone, but the pharmacological effects of meperidine, d-propoxyphene, and pentazocine present more prominent differences with regard to “toxicity” and/or physical dependence. The pharmacological effects of morphine serve here as a prototype of the actions of opioids in general, and deviations from this prototype are noted for some particular opioid analgesics.

Though under certain conditions (see below), tolerance to opioids can develop without concomitant physical dependence, the two phenomena will be considered together inasmuch as most explanatory theories postulate common mechanisms and assume that one sort or another of “counteradaptation” to the agonistic actions of opioids develops during repeated drug administration (accounting for tolerance); this results in “latent hyperexcitability” of the central nervous system, which is suppressed as long as opioids are administered; when opioids are abruptly withdrawn, or when a narcotic antagonist is administered, the latent hyperexcitability becomes manifest as the opioid-abstinence syndrome (indicative of physical dependence).

Sober alcoholics are presumed to be more susceptible to relapse during states of emotional dysphoria. A prior study investigating situations most conducive to craving for alcohol reveals that 93% of alcoholics claim to experience craving when depressed, 90% when nervous, 88% when worried, 78% when feeling bad, 77% when under stress and 72% after failure: in contrast, only 35% of alcoholics claim craving when successful, 30% when happy, 23% when feeling good and 18% when relaxed (Ludwig and Stark, 1974). Toker, et al., 1973, similarly report that alcoholics, in comparison to normal controls, are most likely to go to the bar, drink, smoke and take pills whenever they feel helpless, depressed, angry and anxious. While these findings are hardly surprising, it is necessary to point out that such claims by alcoholics have never been tested adequately under laboratory conditions.

Tolerance at all levels of complexity in the brain involves "learning" in the sense of the acquisition of compensatory adaptations to the consequences of the presence of a drug-produced disturbance in function. Depending on the function, species, and dose of cannabis, "tissue tolerance," behaviorally augmented (to provide the presence of the disturbed function) or not, develops at different rates or not all (e.g., to impairment of the logical sequence of thoughts, to which no tolerance has yet been demonstrated). "Dispositional tolerance" (increased rate of metabolism of delta 9-THC due to enzyme induction) may play a role in the development of tolerance or "reverse tolerance" to cannabis in man. There is evidence that for the label "high," placebo effects may account for the "reverse tolerance" seen in experienced users on smoking (but not on ingestion of delta 9-THC or placebo) along with evidence of residual tolerance to other not-so-labeled effects of the drug. Dependence on cannabis, in the sense of abstinence phenomena on abrupt withdrawal of delta 9-THC, has been demonstrated in monkeys made tolerant to delta 9-THC given four times daily for about 1 month. In man, physiologic marijuana abstinence signs have not been demonstrated, but behavioral (and some physiologic) abstinence phenomena have been reported in heavy users of hashish or ganja. The between-dose hyperirritability and dysphoria reported to occur in experimental studies on chronic marijuana intoxication may actually be early and short-lived abstinence changes. In the West, where marijuana with relatively low delta 9-THC content is widely smoked, dependence in the sense of drug-seeking behavior appears to be less a function of any pharmacologic reinforcing properties the drug may have than of secondary (conditioned) reinforcement derived from the social milieu in which the marijuana is smoked. In cultures where marijuana of higher delta 9-THC content, hashish, or ganja is used, pharmacologic reinforcement (through suppression of abstinence changes) may play a greater role in maintaining drug-seeking behavior.

34 experienced marijuana users were divided into four equated groups of eight subjects each based on recognition memory test performance. One week later each group was retested following administration of marijuana containing 0, 5, 10 or 15 mg delta9-tetrahydrocannabinol. A dose-related effect of marijuana on pulse rate and subjective measures of potency and pleasantness occurred. Ratings of potency and changes in pulse rate were highly correlated, but this relationship did not hold within a given dosage group as determined by partial correlations. No effect of marijuana on the distribution of hit and false alarm rates or confidence ratings during the recognition memory test was noted.

Although conditioning may play a role in the development of tolerance to opioids (see Chapter 6), this phenomenon and physical dependence are basically unconditioned; that is, they can be demonstrated in animal preparations virtually incapable of acquiring classically conditioned responses. Thus, Wilder and Frank (1948) reported the development of tolerance to the depressant effects of morphine and methadone on the flexor reflex in the chronic spinal dog, as well as well-defined abstinence syndromes after abrupt withdrawal of these drugs (hyperexcitability of the flexor reflex and spontaneous “running” movements of the paralyzed hind limbs). Earlier, Shurrager and Culler (1938, 1940) and Shur-rager and Shurrager (1946) reported that a semitendinosus twitch could be conditioned in acute spinal preparations; Dykman and Shurrager (1956) also described spinal conditioning in chronic preparations. However, Kellogg et al. (1947) and Deese and Kellogg (1949) were unable to obtain spinal conditioning in recent chronic preparations. Reinvestigating this question, Lloyd et al. (1969) were unable to demonstrate classical conditioning of the flexor reflex in three drug-free chronic spinal dogs even after a maximum of 2500 conditioning and 500 test trials; they concluded that at least in the adult dog, classical conditioning of a skeletal motor response requires the functional integrity of supraspinal as well as intraspinal pathways. Hence, classical conditioning could have played no role in the development of tolerance to and physical dependence on morphine or methadone in chronic spinal dogs.

Abuse of and dependencies on drugs of all sorts (notably alcohol, cannabis, sedatives, stimulants, and tobacco), though varying in kind and in degree, are worldwide. For a sampling of drug problems through the world, the reader is referred to Peterson (1978) and to Austin et al. (1978). This chapter is concerned with problems of opioid and other drug dependencies in the United States.

In a study of men alcoholics, cortical average evoked response proved to be a good indicator of subsequent alcohol acquisition and consumption behavior in the laboratory.

• This study evaluates the ability of alcoholics to regulate their blood alcohol levels (BAL) within a designated range by relying primarily on interoceptive cues. Forty male alcoholics and 20 control subjects were exposed to an initial training session in which they received sufficient ethanol to maintain them within a designated BAL range over a 21/2-hour period. They were then exposed to two experimental sessions, one providing "overfeedback" and one "underfeedback." During each session, subjects had ten drinking decisions to make with respect to regulation of their BAL. The results indicated that alcoholics displayed greater "loss-of-control" than control subjects. This finding supported the hypothesis that alcoholics may possess a neurophysiologic feedback dysfunction that contributes to their relative inability to regulate ethanol intake.

Summary1. Rats, maintained at 70% of satiation weight, were conditioned to press a bar at a rapid and constant rate in a modified Skinner Box. After about 15 days of training when this behavior had been thoroughly established, a method for producing conditioned anxiety was introduced. Shortly after each animal began the daily bar-pressing session a 60-cycle tone, which sounded for 4 minutes, was terminated by the application of a strong: electrical shock. After several days of conditioning this procedure produced almost complete cessation of bar-pressing during the tone period. In testing the effect of a known analgesic the administration of graded doses of morphine (4-11 mg/kg) produced proportional restoration of the inhibited bar-pressing. 2. The reduction or elimination of inhibition by morphine was considered to be a reduction of anxiety associated with anticipation of noxious stimuli. The results parallel in all essential details previous methodological work on man, and strongly suggest that the pre...

Psychometric, neurological, and EEG studies were made of 24 children with scholastic-behavioral problems but no classical evidence of neurological disease and of 24 matched controls. Differences between the two groups were significant in all three measures, giving evidence of brain dysfunction in the groups with scholastic-behavioral problems. Two subgroups—hyperactive and nonhyperactive—each with characteristics suggesting a different syndrome, are described.

IN PREVIOUS studies * it was demonstrated that well-defined abstinence syndromes ensue when opiates are withdrawn abruptly after a period of addiction in long-surviving dogs without neocortex and in chronic spinal dogs. These, and other, data3indicated that the opiate abstinence syndrome involves the entire neuraxis, that, at least in part, its genesis is related to factors of little or no symbolic significance, and that the neurophysiological mechanisms that contribute to its development consist primarily of cyclic depression and excitation of certain internuncial neuron systems, with progressive augmentation of the latter process, which becomes manifest on abrupt withdrawal of the drug. However, direct transfer of such conclusions to the explanation of drug addiction in man could be made only with reservations because of possible species differences. Studies on the effects of bilateral frontal lobotomy in man4revealed that interruption of thalamofrontal fiber systems reduces markedly the craving for narcotics