Untreated Addiction Imposes an Ethical Bar to Recruiting Addicts for Non-Therapeutic Studies of Addictive Drugs

Nutt D.J. , “Addiction: Brain Mechanisms and their Treatment Implications,” Lancet, 347 (1996): 31–36, at 32

(“Because addiction is an imprecise and potentially pejorative term, the WHO [World Health Organization] recommended in 1969 that it should be replaced by the term drug dependence.”). Since the term “addiction” is the more familiar term, I will use “addiction” interchangeably with “substance dependence,” as defined by the DSM-IV criteria, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (Washington, D.C.: American Psychiatric Association, 1994).

In 1990, deaths attributed to drug use were estimated as follows: 400,000 from tobacco; 100,000 from alcohol; and 20,000 from “illegal” drugs. It was estimated that 3 million people in the United States had serious problems related to illegal drugs. McGinnis J.M. Foege W.H. , “Actual Causes of Death in the United States,” in Areen J. , eds., Law, Science and Medicine, 2nd ed. (Westbury, New York: Foundation Press, 1996): 502–10. Overall lifetime prevalence of drug use disorders is 6.2 percent; overall lifetime prevalence of alcohol disorders is 13.5 percent.

Crum R.M. , “The Epidemiology of Addictive Disorders,” in Graham A.W. Schultz T.K. , eds., Principles of Addiction Medicine, 2nd ed. (Chevy Chase, Maryland: American Society of Addiction Medicine, 1998): 3–15. In 1995, illegal drug use was estimated to have cost approximately $110 billion and to have resulted in approximately 9,300 deaths. Drug-related emergency room visits were over half a million annually. The social costs of drug and alcohol abuse in 1995 were estimated at $277 billion.

National Drug Control Strategy (Washington, D.C.: Office of National Drug Control Policy, 1999): at 14–15. From 1990 to 1992, the National Comorbidity Survey of more than 8,000 Americans ages 15–54 demonstrated that 7.5 percent had developed dependence on illicit drugs. Injection drug use is the leading factor for new HIV infections in the United States.

Institute of Medicine, Pathways of Addiction: Opportunities in Drug Abuse Research (Washington, D.C.: National Academy Press, 1996): at 102, 161.

The neurochemical mechanisms responsible for addiction to “legal” and “illegal” drugs are similar. The same ethical considerations apply to alcohol and nicotine dependence as illegal drug dependence because it is the impact of compulsive use and denial on an addict's competency to consent that are in question. That alcohol and cigarettes are “legal drugs” is not germane to the discussion.

See, for example, Adler M.W. , College on Problems of Drug Dependence, “Special Report: Human Subject Issues in Drug Abuse Research,” Drug and Alcohol Dependence, 37 (1995): 167–75;.

Leshner A.I. , “What We Know: Drug Addiction Is a Brain Disease,” in Graham A.W. Schultz T.K. , eds., Principles of Addiction Medicine, 2nd ed. (Chevy Chase, Maryland: American Society of Addiction Medicine, 1998): xxix–xxxvi.

Nutt , supra note 1.

Gardner E.L. Lowinson J.H. , “Drug Craving and Positive/Negative Hedonic Brain Substrates Activated by Addicting Drugs,” The Neurosciences, 5 (1993): 359–68.

See Diagnostic and Statistical Manual of Mental Disorders, supra note 1.

See, for example, Gorelick D.A. Pickens R.W. Bonkovsky F.O. , “Clinical Research in Substance Abuse: Human Subjects Issues,” in Pincus H.A. Liberman J.A. Ferris S. , eds., Ethics in Psychiatric Research (Washington, D.C.: American Psychiatric Association, 1998): 177–218;.

Adler , supra note 4.

Ernst M. London E.D. , “Brain Imaging Studies of Drug Abuse: Therapeutic Implications,” Seminars in Neuroscience, 9 (1997): 120–30;.

Grant S. ., “Activation of Memory Circuits During Cue-Elicited Cocaine Craving,” Proceedings of the National Academy of Science, 93 (1996): 12040–45;.

London E.D. ., “Morphine-Induced Metabolic Changes in Human Brain. Studies with Positron Emission Tomography and [Fluorine 18]-Fluorodeoxy-glucose,” Archives of General Psychiatry, 47 (1990): 73–81;.

London E.D. ., “Cocaine-Induced Reduction of Glucose Utilization in Human Brain. Studies with Positron Emission Tomography and [Fluorine 18]-Fluorodeoxyglucose,” Archives of General Psychiatry, 47 (1990): 567–74;.

Volkow N.D. , “Long-Term Frontal Brain Metabolic Changes in Cocaine Abusers,” Synapse, 11 (1992) 184–90;.

Volkow N.D. ., “Cocaine Addiction: Hypotheses Derived from Imaging Studies with PET,” Journal of Addictive Diseases, 15 (1996): 55–71;.

Volkow N.D. ., “Brain Glucose Metabolism in Chronic Marijuana Users at Baseline and During Marijuana Intoxication,” Psychiatry Research and Neuroimaging, 67 (1996): 29–38.

Grant , supra note 8;.

London , “Cocaine-Induced Reduction of Glucose Utilization in Human Brain. Studies with Positron Emission Tomography and [Fluorine 18]-Fluorodeoxyglucose,” supra note 8.

London , “Morphine-Induced Metabolic Changes in Human Brain. Studies with Positron Emission Tomography and [Fluorine 18]-Fluorodeoxy-glucose,” supra note 8.

Volkow , “Brain Glucose Metabolism in Chronic Marijuana Users at Baseline and During Marijuana Intoxication,” supra note 8.

Kreek M.J. , “Methadone-Related Opioid Agonist Pharmacotherapy for Heroin Addiction. History, Recent Molecular and Neurochemical Research and Future in Mainstream Medicine,” Annals of the New York Academy of Science, 909 (2000): 186–216.

Ernst London , supra note 8.

Volkow , “Long-Term Frontal Brain Metabolic Changes in Cocaine Abusers,” supra note 8.

Cohen P.J. , “Immunization for Prevention and Treatment of Cocaine Abuse: Legal and Ethical Implications,” Drug and Alcohol Dependence, 48 (1997): 167–74.

Beauchamp T. Childress J.F. , Principles of Biomedical Ethics, 4th ed. (New York: Oxford University Press, 1994).

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects in Research, DHEW Pub. No. (OS) 78–0012 (Washington, D.C.: U.S. Gov't Printing Office, 1978).

See, for example, Appelbaum P.S. , “Drug-Free Research in Schizophrenia: An Overview of the Controversy,” IRB: A Review of Human Subjects Research, 18 (1996): 1–5;.

Bor J. , “Mental Patients at Risk in Research,” Baltimore Sun, June 7, 1998, at A1;.

Hilts P.J. , “Agency Faults a U.C.L.A. Study for Suffering of Mental Patients,” New York Times, March 10, 1994, at A1;.

Hilts P.J. , “House Panel Told of More Tests Done Without Consent,” New York Times, May 24, 1994, at A13;.

Hilts P.J. , “Psychiatric Researchers Under Fire,” New York Times, May 19, 1998, at F1;.

Marshall E. , “NIMH to Screen Studies for Science and Human Risk,” Science, 283 (1999): 464–65;.

Pear R. , “Study Finds Risks to Patients in Drug Trials,” New York Times, May 30, 1998, at A9;.

Weiss R. , “Research Volunteers Unwittingly at Risk,” Washington Post, August 1, 1998, at A1.

National Bioethics Advisory Commission, Research Involving Subjects with Mental Disorders That May Affect Decisionmaking Capacity (Rockville, Maryland: National Bioethics Advisory Commission, 1998) [hereinafter cited as NBAC Report]. The NBAC Report, facilitated by input from the bioethical, scientific, and public communities, was submitted to the President on January 8, 1999. On January 16, 2001,

U.S. Department of Health and Human Services (DHHS) Secretary Donna E. Shalala Sent the NBAC the Department's response: HHS Working Group on the NBAC Report, Analysis and Proposed Actions Regarding the NBAC Report: Research Involving Persons with Mental Disorders That May Affect Decisionmaking Capacity (Washington, D.C.: DHHS Working Group, 2001) [hereinafter cited as DHHS Working Group Report]. The DHHS Working Group consisted of “representatives from all the relevant agencies within the Department, [and] was convened to review and address the specific recommendations of the NBAC Report.” See Secretary Shalala's January 16, 2001 letter to the NBAC Chair, Harold Shapiro. The NBAC's charter expired October 2001, at which time there had been neither a final response to nor implementation of the report.

This charge is succinctly presented in the NBAC Report, supra note 17, at i:.

See NBAC Report, supra note 17, at 9.

Mental status is likely to fluctuate as a result of either internal stimuli (e.g., altered level of craving or occurrence of drug-associated memories) or external stimuli (e.g., verbal, visual, or auditory). The conduct of a proposed study may also affect mental status, e.g., does it involve the subject's drug of choice or is it “neutral” with respect to substance dependence?.

See NBAC Report, supra note 17, at 21.

Id. at 8 (emphasis added).

Id. (emphasis added).

McLellan A.T. ., “Psychosocial Services in Substance Abuse Treatment?: A Dose-Ranging Study of Psychosocial Services,” JAMA, 269 (1993): 1953–59.

See, for example, Kreek M.J. , “Rationale for Maintenance Pharmacotherapy of Opiate Dependence,” Research Publication — Association for Research in Nervous and Mental Diseases, 70 (1992): 205–30.

See NBAC Report, supra note 17, at 8.

Harrison K. ., “Medical Eligibility, Comprehension of the Consent Process, and Retention of Injection Drug Users Recruited for an HIV Vaccine Trial,” Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 10 (1995): 386–90.

Id. at 390.

See NBAC Report, supra note 17, at 23.

High D.M. ., “Guidelines for Addressing Ethical and Legal Issues in Alzheimer Disease Research: A Position Paper,” Alzheimer Disease and Associated Disorders, 8 no. 4 (Supp. 1994): 66–74.

quoted in the NBAC Report, supra note 17, at 23).

Elliott C. , “Caring About Risks: Are Severely Depressed Patients Competent to Consent to Research?,” Archives of General Psychiatry, 54 (1997): 113–16.

quoted in the NBAC Report, supra note 17, at 23).

See Diagnostic and Statistical Manual of Mental Disorders, supra note 1.

I emphasize that this potential decision-making impairment applies only to non-therapeutic protocols that involve individuals who have met the DSM-IV criteria (supra note 1) for substance dependence and where the study involves administering the addict's drug of choice

As already stressed, addicts (as long as they are not acutely intoxicated or in withdrawal) should not be presumed to lack competence to participate in other types of studies, including those in which substance abuse treatment is evaluated. This concept is consistent with the principle that an individual's capacity to consent to participate in research must be balanced against his or her right to participate in research. This concept was reiterated in the DHHS Working Group Report (supra note 17, at 4–5):.

Sugarman J. , “Toward Achieving Meaningful Informed Consent in AIDS Vaccine Trials with Injection-Drug Users,” AIDS and Public Policy Journal, 9 (1994): 167–72.

Leshner , supra note 4.

Pope T.M. , “Balancing Public Health Against Individual Liberty: The Ethics of Smoking Regulations,” University of Pittsburgh Law Review, 61 (2000): 419–98 (quotations appear at pages 461 and 466–68).

Elliott , supra note 31.

Denial is present even when craving is minimal or absent. Therefore, a fundamental biological and ethical issue — denial — must be confronted whether or not craving exists. The foundation of my thesis is that prospective subjects' failure to understand the nature of their disease or admit that they have the disease is prima facie evidence that they lack the information and decision-making competence necessary for making an informed consent to receive their drug of choice in non-therapeutic research. The presence of craving only exacerbates this situation.

I do not use the concept of coercion to imply that clinical investigators, those treating substance abuse, or any other individuals are compelling the addict (with money or any other type of inducement) to participate in clinical research. Rather, I am suggesting that coercion is internal, resulting from the state of addiction itself, such that the associated craving and denial are likely to interfere with the ability to make a rational decision.

Adler , supra note 4, at 170.

Id. at 170–71.

Id. at 171.

O'Brien C.P. McLellan T. , “Myths About the Treatment of Addiction,” in Graham A.W. Schultz T.K. , eds., Principles of Addiction Medicine, 2nd ed. (Chevy Chase, Maryland: American Society of Addiction Medicine, 1998): 309–14.

Marwick C. , “Physician Leadership on National Drug Policy Finds Addiction Treatment Works,” JAMA, 279 (1998) 1149–50.

Ernst London , supra note 8;.

Volkow , “Long-Term Frontal Brain Metabolic Changes in Cocaine Abusers,” supra note 8.

See, for example, Faillace L.A. ., “Giving Alcohol to Alcoholics: An Evaluation,” Quarterly Journal of Studies of Alcohol, 33 (1972): 85–90;.

Gorelick D.A. ., “Influence of Enforced Abstinence on Cocaine Use by Research Subjects,” Journal of Addictive Diseases, 18 (1999): 115;.

Kaufman M.J. ., “Illicit Cocaine Use Patterns in Intravenous-Naïve Cocaine Users Following Investigational Intravenous Cocaine Administration,” Drug and Alcohol Dependence, 58 (2000): 35–42;.

Kranzler H.R. Dolinsky Z. Kaplan R.F. , “Giving Ethanol to Alcoholics in a Research Setting: Its Effect on Compliance with Disulfiram Treatment,” British Journal of Addiction, 85 (1990): 119–123;.

Modell J.G. Glaser F.B. Mountz J.M. , “The Ethics and Safety of Alcohol Administration in the Experimental Setting to Individuals Who Have Chronic, Severe Alcohol Problems,” Alcohol and Alcoholism, 28 (1993): 189–197.

Kirulis K. Zacny J. , “Do Healthy Volunteers Increase Drug Usage After Participation in Research Involving Opioids and Nitrous Oxide?,” Anesthesiology, 89 (1998): A-1222.

Gorelick , supra note 46.

Kaufman , supra note 46.

Faillace , supra note 46.

Kranzler Dolinsky Kaplan , supra note 46.

Leshner Alan , personal communication with author, October 6, 2001, at Smithsonian Associate Lecture, “Storm Center: The Brain on Drugs.” I have also observed the difference between self-administration and physician-guided administration in evaluating the histories of patients monitored by the Physician Health Committee. That patients with a history of addiction can safely receive addicting drugs under medical supervision is generally accepted by treating physicians.

See note 46, supra.

National Institute on Drug Abuse, Intramural Research Program, Policies and Procedures, Recruitment of IRP Research Participants, I(A)(4)(a) (internal memorandum) (Baltimore, 2000) (“Participants who were enrolled in a treatment program or treatment study in the preceding 90 days or seeking … treatment are excluded from all non-therapeutic research studies.”).

National Advisory Council on Alcohol Abuse and Alcoholism, Recommended Council Guidelines on Ethyl Alcohol Administration in Human Experimentation (Rockville, Maryland: National Institute on Alcohol Abuse and Alcoholism, 1989).

Adler , supra note 4, at 172.

Capron A.M. , “Ethical and Human Rights Issues in Research on Mental Disorders That May Affect Decision-Making Capacity,” N. Engl. J. Med., 340 (1999): 1430–34.