[18][19] 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),[20] EEG studies of mental activity during drug use (including mescaline),[21][22] and animal studies.

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.

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"[14] (this diagnosis appears to be based on MMPI test evaluation).

[8] 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.

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.

[14] Some subjects had negative reactions to LSD (as noted above), but others found the experience "pleasant",[10] or even "dearly loved" it as long as the dosage was not too high (less than 2 micrograms per kilogram of body weight).

They found that intravenous methadone had similar subjective effects as morphine and heroin, and induced physical dependence with chronic use.

Isbell et al. (1950) did a controlled experiment (no other drugs involved, and proper nutrition) on the effects of chronic barbiturate administration.

[8] 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.

Upon abrupt withdrawal of barbiturates, initial symptoms included tremor, anxiety, weakness, and vomiting, followed by convulsion, delirium, and hallucinations.

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.

[42] 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.

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.