Psychopharmacology (2003) 165:188–193 DOI 10.1007/s00213-002-1271-3 ORIGINAL INVESTIGATION Wolfgang Tschacher · Robert Haemmig · Nina Jacobshagen Time series modeling of heroin and morphine drug action Received: 27 May 2002 / Accepted: 9 September 2002 / Published online: 29 October 2002  Springer-Verlag 2002 Abstract Rationale: Clinical observations and recent findings suggested different acceptance of morphine and heroin by intravenous drug users in opiate maintenance programs. We postulated that this is caused by differences in the perceived effects of these drugs, especially how desired and adverse effects of both drugs interacted. Objectives: We measured the desired and adverse effects of high doses of injected morphine and heroin in patients to determine the causal interactions between both types of effects and test the hypothesis of a differential mechanism of action. Methods: Thirty-three patients (five females, 28 males; mean duration of previous street heroin use 10.7 years, mean age 30.1 years) were randomly allocated double-blind to the substance groups. The average daily dose per participant in the heroin condition (n=17) was 491 mg, in the morphine condition (n=16) 597 mg. The observation period lasted 3 weeks; an average of 70 injections was received. After each injection of either substance, various aspects of drug effects were recorded systematically. Ratings were summarized into the factors “euphoria” and “adverse effects”. Time series models were computed for each participant on the basis of the factor scores, using vector autoregression (VAR). Results: A highly significant difference between the substances was found in the interaction between “eupho- ria” and “adverse effects”. Adverse effects of heroin preceded higher euphoria, whereas adverse effects of morphine preceded subsequent lower euphoria. Addition- ally, the finding of a higher level of adverse effects in morphine was replicated. Conclusions: Results point to different mechanisms of action of the two opioids when the perceived drug effects are evaluated in a field setting. This may explain the better acceptance of heroin in opiate-assisted treatment of intravenous drug patients. The method used can be a valuable tool for the comparison of substance groups other than opioids. Keywords Heroin · Morphine · Maintenance drug treatment · Perceived mechanism of action · Time series analysis Introduction The use of opiates as psychotropic agents is a societal concern in many countries. Because of the severe medical, social, and psychological hazards entailed by opiate use, a large number of treatment approaches have been developed that are well covered by psychiatric and psychological publications. Relatively little, however, is known of the behavioral and experiential effects of these drugs, especially when opiates such as heroin or morphine are taken habitually and in high dosages. Our review of the literature (based on PsycINFO and MEDLINE searches of heroin-related journal papers) showed that among several hundreds of articles on human users, virtually none addressed the perceived mechanisms of action of these drugs. Studies of drug-induced mood changes, such as that of Lasagna et al. (1955) and of the research group at the Alcohol and Drug Abuse Center at McLean Hospital in Belmont, Mass., USA (McNamee et al. 1976; Mirin et al. 1976), are rare exceptions. Interestingly, both groups reported that dysphoria has to be considered as a rather common effect of heroin, which stands in contrast to the general belief that heroin is a highly euphoriagenic substance. This absence of published research is, of course, due to ethical and legal considerations that rule out consumption of heroin even under experimental conditions. Addition- ally, non-confounded data on the effects of consumption by illicit users are almost inaccessible for scientific description. Therefore, the project reported here took the opportunity to investigate (self-) observed drug effects W. Tschacher ( ) ) · R. Haemmig Psychiatric Services, University of Bern, Laupenstrasse 49, 3010 Bern, Switzerland e-mail: tschacher@spk.unibe.ch Tel.: +41-31-3876164 Fax: +41-31-3829020 N. Jacobshagen Institute of Psychology, University of Bern, Muesmattstrasse 45, 3009 Bern, Switzerland