Harris Isbell
Harris Isbell 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. Early work investigated aspects of physical dependence with opiates and barbiturates, while later work 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 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 published extensively on the effects of drugs 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 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 for their abuse and addiction potential, 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,
EEG studies of mental activity during drug use,
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, ways to mitigate withdrawal symptoms, the development of reliable rating methods and questionnaires for subjective drug effects, cross-drug comparisons, drug tolerance, and classification of drug groups."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 ; this fact is not documented in the published research articles. The separate living environment within the ARC for experimental subjects was also a motivation.The use of prison subjects for these sorts of experiments 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 to abstinent addicts in a treatment center is another..
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" . Subjects in some of the more extreme psychedelic experiments were all "Negro males", though this is not a regular pattern.
In spite of the risky nature of some of the experiments, 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 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, 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, and then attempting to induce addiction by regular administration of the substance of interest. Addiction was determined by the occurrence of abstinence symptoms when administration of the substance stopped. Sometimes a different substance 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, evaluating various doses to see if they
induced similar effects
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. Physical measurements included pulse, blood pressure, rectal temperature, kneejerk reflex sensitivity, and pupil diameter while LSD causes dilation ). Psychological measurements consisted of a self-evaluation form with multiple statements, as well as evaluation by experienced and trained observers. Some subjects had negative reactions to LSD, but others found the experience "pleasant", or even "dearly loved" it as long as the dosage was not too high.
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".Many opiate derivatives and synthetic opioids were tested for addiction and abuse potential.
Isbell and Vogel 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. did a controlled experiment on the effects of chronicbarbiturate 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. 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 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 occurred in 4 of the 6 subjects. Given these withdrawal symptoms, Isbell et al. make 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,
and mescaline; these substances were sometimes described as "psychotomimetic". LSD and psilocybin for many of the experiments was supplied by Sandoz Pharmaceuticals. According to a 1986 interview with Isbell, the psychedelics research was initiated by an explicit CIA request.
LSD
- Isbell et al. motivated their study of LSD by the superficial similarities between the LSD state and schizophrenia, as well as the previous findings of interactions between LSD and the endogenous neurotransmitter serotonin. A dosage of 1-2 micrograms per kilogram of body weight was determined to induce "striking effects". Four experiments then quantified tolerance effects. Experiment 4 included 77 consecutive days with doses of 1.55 micrograms/kg, although the full sequence of LSD doses was at least a week or two longer than this due to the tolerance protocol. Tolerance to LSD developed rapidly; by day 3 the subjective effects were significantly lessened, and later in the experiments subjects simply read and watched TV normally. In the middle of the experiment, even a quadruple dose had little effect. Tolerance also disappeared rapidly; after no LSD had been given for 3 days, a subsequent dose again had a large effect. There were no abstinence symptoms after LSD administration stopped.
- Isbell et al. also concluded that the LSD reaction "had only a superficial resemblance to the chronic forms of any of the major psychoses".
- Isbell and Logan reported that chlorpromazine could either block or reverse the effects of LSD. Azacyclonol had no effect, while pre-treatment with reserpine augmented the effects of LSD. Isbell et al. reported that pre-treatment with scopolamine, phenoxybenzamine or "BAS" had little effect on a subsequent LSD dose. They attempt to explain these results within the neurotransmitter knowledge of the period.
Psilocybin
- Isbell reported that psilocybin had physical and psychological effects similar to LSD, although psilocybin had a shorter duration and much less potency for a given dosage.
- Isbell et al. found that 12 days treatment with LSD induced tolerance to either LSD or psilocybin, and that psilocybin also induced tolerance to both LSD and psilocybin. This cross-tolerance supported the hypothesis that the two substances at least partially share their mechanism of action.
Other
- Wolbach et al. reported that mescaline and LSD had similar effects, that direct tolerance could be induced by mescaline, and that each substance induced cross-tolerance to the other. This was particularly interesting, since LSD are indole compounds, while mescaline is not.
- Contrasting with the psilocybin and mescaline results, Isbell et al. found that tolerance to intramuscular LSD did not provide tolerance to an intramuscular injection of the indole hallucinogen DMT.
- Isbell et al. investigated the psychological and physical effects of 13 different congeners of LSD, and correlated these effects with their potency as a serotonin antagonist in smooth muscle. With the exception of "ALD-52", all of the substances were less potent than LSD. There was low correlation between the smooth muscle and the "psychotomimetic" effects.
THC (marijuana)
- Isbell et al. reported that pure THC had marijuana-like effects, whether smoked or taken orally. A number of other isolated compounds present in marijuana did not show these effects.
- Isbell and Jasinski compared LSD and smoked THC. Physical symptoms were quite different, and tolerance to LSD did not cause tolerance to THC, suggesting different mechanisms of action. Their data do not show a statistical difference in the psychological effects of the two substances; this is somewhat surprising since cannabis is not usually considered to be a psychedelic drug. Whether this result is due to the small number of subjects, an inappropriate rating scale, the use of pure THC, or an exceedingly high THC dose is unclear.
- Jasinski, Haertzen, and Isbell describe some of the subjective and physiological effects of the synthetic cannabinoids parahexyl and dimethylheptylpyran.
However,
higher doses reliably produced what Isbell referred to as a "psychotic reaction".
Isbell also commented on the potency of
street marijuana of that time.
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 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.