Harris Isbell
Harris Isbell (June 7, 1910 – December 23, 1994) was an American pharmacologist and the director of research for the NIMH Addiction Research Center at the Public Health Service Hospital in Lexington, Kentucky from 1945 to 1963. He did extensive research on the physical and psychological effects of various drugs on humans (imprisoned narcotics offenders, see below). Early work investigated aspects of physical dependence (an important aspect of drug addiction) with opiates and barbiturates, while later work (at least partially funded by the Central Intelligence Agency as part of the MKUltra project) investigated psychedelic drugs, including LSD. The research  was extensively reported in academic journals such as the "Journal of Pharmacology and Experimental Therapeutics", "Psychopharmacologia", and the AMA "Archives of Neurology and Psychiatry". Biography. He was born on June 7, 1910 in Arkansas to Francis Taylor Isbell and Celeste Mathews. He received his M.D. from Tulane University School of Medicine in 1934, and held various research positions before becoming head of the Addiction Research Center (ARC) in 1945. He was awarded the US Public Health Service Meritorious Service Award in 1962; Attorney General Robert F. Kennedy praised him as "an extraordinarily able director and coordinator of multidisciplinary research" and  an outstanding investigator in his own right whose work in clinical pharmacology has exerted far-reaching influences on medical practice. After leaving the ARC in 1963, he became Professor of Medicine and Pharmacology at the University of Kentucky School of Medicine. Isbell and his associates (including Abraham Wikler) published extensively on the effects of drugs (including opiates, synthetic opioids, barbiturates, alcohol, amphetamine, ibogaine, multiple psychedelics, and THC) on human subjects, with over 125 publications. Among their experimental results were the qualitative and quantitative documentation of physical dependence on barbiturates, physical dependence on alcohol, tolerance to amphetamine, the clinical use of  opiate antagonists (e.g., nalorphine/Nalline and naloxone/Narcan) as treatment for opiate overdoses, the ability of methadone to alleviate opiate withdrawal symptoms, rapid tolerance but lack of physical dependence with LSD, cross-tolerance between LSD and psilocybin, and the ability of pure THC to cause marijuana-like effects. New pharmaceutical substances were assayed (in the prisoner population) for their abuse and addiction (substance dependence) potential (medications for pain, cough, and diarrhea were of particular concern), and this information was utilized by groups such as the World Health Organization. Other work at the ARC during Isbell's tenure included psychological aspects  of human opiate addiction (e.g., re-arousal of craving after abstinence upon return to the addiction environment, i.e. a "conditioned" response), EEG studies of mental activity during drug use (including mescaline), and animal studies. Isbell died on December 23, 1994 in Lexington, Kentucky. Research. Areas of interest described in Isbell's published work include physical and psychological effects of individual substances (including potential for dependence and addiction), ways to mitigate withdrawal symptoms (e.g., methadone therapy), the development of reliable rating methods and questionnaires for subjective drug effects (the Addiction Research Center Inventory), cross-drug comparisons, drug tolerance, and classification of  drug groups (based on both the physiological and the subjective effects of a drug, as well as its cross-tolerance with other drugs). Section::::"Volunteer" subjects. The subjects in Isbell's experiments are described as "volunteers"; they were recruited from the associated Lexington Public Health Service Hospital. The hospital was a US Government facility for treating drug abuse; some patients were sentenced drug offenders, while others voluntarily entered for treatment. The subjects in ARC experiments were all incarcerated male narcotics offenders with a history of drug addiction; subjects signed a simple "Consent Form". Subjects were motivated by payment in the form  of drugs (usually opiates); this fact is not documented in the published research articles. The separate living environment within the ARC for experimental subjects (e.g., the possibility of having a small private room) was also a motivation. The use of prison subjects for these sorts of experiments (and the nature of payment) would be difficult or impossible to justify by current human subjects and informed consent standards. The potential for coercion in a prison environment is one concern; providing drugs (whether as experimental substances or as payment) to abstinent addicts in a treatment center is another. (See Campbell (2007) for  a detailed discussion of ethical and historical aspects of the ARC subject protocols.) Subjects in the experiments are described as physically healthy former drug addicts who were not psychotic, although they often were described as having "character disorders or inadequate personalities" (this diagnosis appears to be based on MMPI test evaluation). Subjects in some of the more extreme psychedelic experiments (LSD doses for 77 days in a row) were all "Negro males", though this is not a regular pattern (e.g., the 5 subjects in the similarly extreme 1950 barbiturate study described below were all white males). In spite of the  risky nature of some of the experiments (e.g., inducing addiction to opiates, alcohol, barbiturates, or new minimally tested pharmaceuticals, and then forcing immediate and severe withdrawal), there were apparently no fatalities, though there was at least one close call. Subjects sometimes dropped out in the middle of an experiment, although in one reported case a subject who wished to drop out after a severe negative reaction to a 180 microgram LSD dose ("He felt that he would die or would become permanently insane") required "considerable persuasion" to continue. General methodology. The studies took place in a dedicated experimental ward. Given  the hospital context, medical personnel were readily available. In general, the methodology appears scientifically sound (e.g., proper balancing of experimental conditions, within-subjects designs, single (sometimes double) blind procedures as appropriate, placebo conditions, careful documentation of the experimental procedures, appropriate awareness of potential confounding factors, etc.), although the small number of subjects in some of the experiments is a statistical concern. The general methodology for the addiction studies consisted of first getting subjects drug-free (with apparent exceptions for cigarettes and coffee), and then attempting to induce addiction by regular administration (orally or injected) of the substance of interest. Addiction  was determined by the occurrence of abstinence symptoms when administration of the substance stopped. Sometimes a different substance (e.g., methadone) would be administered at the peak of withdrawal to determine if it alleviated symptoms. Following the evaluation of this cold turkey withdrawal, subjects were then usually more gradually weaned off of the substance being tested. Isbell also evaluated the "euphoric" effect of various drugs (typically opioids), evaluating various doses to see if they induced similar effects (e.g., talkativeness, comfort in the experimental situation, sedation in high doses) as 30 mg of morphine. The ability to induce euphoria is sometimes/often  considered to be a component of addiction liability. In the psychedelic studies, subjects had the choice of staying in an individual room or mingling with other subjects in a common area. Observations and measurements were taken before the substance of interest was ingested, and hourly thereafter (following a 10-minute rest in bed). Physical measurements included pulse, blood pressure, rectal temperature, kneejerk reflex sensitivity, and pupil diameter (opiates cause constriction (miosis) while LSD causes dilation (mydriasis)). Psychological measurements consisted of a self-evaluation form with multiple statements (e.g., "I am confused"), as well as evaluation by experienced and trained observers . Some subjects had negative reactions to LSD (as noted above), but others found the experience "pleasant", or even "dearly loved" it as long as the dosage was not too high (less than 2 micrograms per kilogram of body weight). Opioids. Isbell and associates published a number of studies on morphine, methadone and assorted analgesics; much of this work was motivated by the search for a "nonaddicting analgesic" (that is, a compound with the pain-relieving capabilities of morphine, but without the opioid dependence issues). Many opiate derivatives and synthetic opioids were tested for addiction and abuse potential. Isbell and Vogel  (1949) investigated methadone, a synthetic opioid developed in Germany in 1937. They found that intravenous methadone had similar subjective effects as morphine and heroin, and induced physical dependence with chronic use. However, the withdrawal symptoms were significantly milder than with morphine. Administration of methadone during morphine withdrawal alleviated withdrawal symptoms, and methadone was reasonably effective when taken orally. This combination of characteristics led them to propose methadone administration as a way of facilitating morphine withdrawal. Barbiturates. Isbell "et al". (1950) did a controlled experiment (no other drugs involved, and proper nutrition) on the effects of chronic barbiturate administration. 5 non -epileptic subjects were given slowly increasing doses of secobarbital, pentobarbital, or amobarbital to a point of obvious intoxication over a period of more than 73 days. Both the nature of the intoxication and the nature of the withdrawal symptoms are described as similar to chronic alcohol use. Intoxication symptoms included confusion, poor judgment, hostility, and motor incoordination. Upon abrupt withdrawal of barbiturates, initial symptoms included tremor, anxiety, weakness, and vomiting, followed by convulsion, delirium, and hallucinations. Alcohol. Isbell "et al". (1955) demonstrated that alcohol causes physical dependence; that is, cessation of alcohol consumption in a chronic user can cause significant  physical withdrawal symptoms. Subjects were abstinent drug addicts; some but not all had a history of heavy alcohol use. Out of 10 initial subjects, 6 subjects were successfully kept in a state of constant moderate intoxication (still able to walk) for a period from 48–87 days. Subjects were given controlled oral doses of alcohol throughout the day from 6am until midnight, and a booster dose around 3am; the total consumption per subject was in the range of a quart of 80-proof liquor per day. All subjects were provided with a healthy diet in addition to the alcohol . Withdrawal of alcohol at the end of the intoxication period produced tremors and weakness in all 6 subjects. Two subjects suffered convulsions, and delirium or hallucinations (audio or visual) occurred in 4 of the 6 subjects. Given these withdrawal symptoms, Isbell "et al". (1955) made some proposals for safely managing alcohol withdrawal. Psychedelics. Starting in 1956, Isbell and associates published studies on LSD, psilocybin, psilocin, DMT, bufotenine, morning glory seeds (ololiuqui), and mescaline; these substances were sometimes described as "psychotomimetic". LSD and psilocybin for many of the experiments was supplied by Sandoz Pharmaceuticals (both of these substances were legal at  the time). According to a 1986 interview with Isbell, the psychedelics research was initiated by an explicit CIA request. THC (marijuana). Starting in 1967, Isbell and associates published a few studies on THC and marijuana (cannabis). Isbell also investigated dosage effects of THC, and reported that low doses (4–6 mg) produced a pleasurable state (euphoria, perceptual distortion, and change of mood); this dosage was described by subjects as "good reefer". However, higher doses (18 milligrams of THC) reliably produced what Isbell referred to as a "psychotic reaction" (e.g., "all of a sudden [the subject] was on a trip and watching  his own burial. The smoker will swear that what hit him never came from marijuana"). Isbell also commented on the potency of street marijuana of that time ("the local grass is probably pretty weak stuff"). Drug policy. In 1951 Isbell testified to Congress before the passage of the Boggs Act of 1952 that "smoking marijuana has no unpleasant aftereffects, no dependence is developed on the drug, and the practice can easily be stopped at any time." Isbell (1971b) (p 903) provides a liberal view of drug policy. He observes that the drug laws of the time are "excessively rigid and  extremely punitive", and have not had any proven effect on the drug problem. He then states that "simple possession of a drug for one's own use should be a civil offense punishable only by a fine", and suggests the possibility that marijuana of low or moderate potency could be legalized and regulated like tobacco, while also observing that maintenance on barbiturates, cocaine, or amphetamine would not be "pharmacologically sound". However, Isbell rejected removing controls on marijuana, which would "open the way to more potent stuff" such as hashish, with the consequent risk of high-dose effects. Harris Isbell Harris