PREAMBLE

Research involving the administration of alcohol to human research participants is a critical experimental approach to address fundamental questions on the pharmacokinetics and pharmacodynamic responses to alcohol and underlying biobehavioral mechanisms, as well as the etiology, treatment, and prevention of alcohol use disorder (AUD). Furthermore, in the context of early medication development, alcohol administration studies are important to investigate drug-alcohol interactions and rule out potentially concerning safety issues early on during the medication development process. However, ethical principles exist that must be adhered to during the conduct of such research, and other considerations particular to this research warrant attention. The following guidance replaces the National Institute on Alcohol Abuse and Alcoholism’s (NIAAA) 2001 guidance, “Administering Alcohol in Human Studies”.

Fundamental ethical principles for research involving human participants include the concepts of respect for persons, beneficence, and justice. These principles have been well summarized in a report issued by the National Commission for the Protection of Human Participants of Biomedical and Behavior Research, titled "Ethical Principles and Guidelines for the Protection of Human Subjects of Research" (The Belmont Report). The general principles of ethics in human investigation are also addressed in such documents as the Nuremberg Code of 1946, the Helsinki Declaration of 1964 (revised in 1975, 1983, 1989, 1996, and 2000), in guidelines from professional organizations such as the International Council for Harmonisation (ICH) specifically ICH E6 (R2). NIH policies pertaining to Human Subjects Research can be found here.

Important aspects of research practice are derived from these ethical principles. Respect for the person requires meaningful, informed, and voluntary consent. Beneficence requires that researchers shall refrain from doing harm and, wherever possible, they should promote the well-being of the research participants. The selection of research participants must apply principles of justice.

The following information conveys important considerations, requirements, and expectations for NIAAA-supported researchers who plan and conduct studies that may involve the administration of alcohol to research participants.

Note: The site-affiliated Institutional Review Board retains final approval rights and oversight responsibilities for all human subject research including alcohol administration studies. 

Protections for Alcohol-Naïve Individuals

In general, alcohol should not be administered to alcohol-naïve participants. The first exposure to alcohol is a necessary condition for any subsequent alcohol-related problems, and currently, researchers do not know which alcohol-naïve individuals may be at risk for subsequently developing alcohol-related problems. Therefore, the first exposure to alcohol has an unknown level of risk.

Inclusion of Populations at Risk for AUD

Individuals with certain familial and/or genetic backgrounds are at higher risk for the development of AUD, including individuals with a family history of alcohol misuse, or other alcohol-related problems. Other individuals at risk include those with a history of adverse responses to alcohol, and those with any other clinically determined risk related to alcohol exposure or the proposed method of alcohol administration. Thus, special consideration needs to be given to the risk/benefit assessment before exposing any such participant to alcohol, and even more so when dosing regimens and systemic exposure (i.e., blood alcohol levels) exceed those associated with the typical drinking practice of the participant.

Inclusion of Individuals with AUD

Research that requires individuals who have AUD to be exposed to alcohol warrants special attention. Essential issues to address include: 1) medical examination, evaluation, and screening to assure the absence of any medical and/or mental condition for which further alcohol exposure at the experimental dose or exposure contemplated would be contraindicated; 2) assessment of current treatment-seeking status, duration of abstinence within the treatment regimen, and the risks entailed through exposure to alcohol.

Considerations for Participants Seeking Treatment for AUD and Alcohol-Related Problems

Preferably, alcohol administration experiments should be conducted in individuals who are not seeking treatment; however, efforts to encourage non-seeking treatment individuals to enter treatment should be made after their participation in the study has been completed.

In some circumstances alcohol administration research may be appropriate in individuals who are seeking or receiving treatment for AUD. A strong scientific justification for why the research question cannot be answered reasonably or validly in a non-treatment-seeking study sample, and a strongly favorable risk/benefit assessment are both necessary. Treatment should be initiated or continued after conclusion of research participation for a sufficient period to facilitate recovery.

Duration of Abstinence

Some research entails eliciting a reaction (e.g., withdrawal, craving) in actively drinking individuals which requires the participant to maintain a period of abstinence. The risk in implementing required periods of abstinence maybe greater among participants with AUD or in recovery from AUD. If justified, short-term abstinence prior to alcohol administration may be instituted with appropriate safeguards (e.g., selection of participants who are at low-risk for clinically significant withdrawal symptoms). The duration of this abstinence should be consistent with that typically experienced by the participant. A medical professional should be readily available for participants that experience withdrawal from alcohol.

For participants in the early phase of treatment who may have achieved a short-term period of abstinence, the consent form should advise of the risk of re-introducing alcohol after a period of abstinence. Again, substantial efforts should be made to help reestablish abstinence following the study.

Participants who have achieved a sustained period of abstinence while living in the community should not be included as participants in research involving alcohol administration. Although the risk of provoking relapse through experimental administration of alcohol has not been studied in research, the attainment of long-term abstinence by these individuals is a recognized achievement that should not be subjected to any risk of a return to drinking by administration of alcohol.

Underage Populations

Individuals under the minimum legal drinking age of 21 should be excluded from participation in alcohol administration studies.

Pregnant Individuals

There is no known safe threshold for alcohol use during pregnancy; therefore, pregnant women should not be included in alcohol administration research studies. The possibility of pregnancy should, at minimum, be assessed by recent medical history (e.g., current pregnancy, current attempt to become pregnant, birth control use, any other relevant information) and pregnancy test immediately prior to each alcohol administration. Women who are pregnant or possibly pregnant, should be excluded from participation. Research has continued to define the range of prenatal alcohol-derived adverse birth outcomes and to uncover cognitive, behavioral, and physiological problems that may arise from prenatal alcohol exposure.

Older Adults

Some research may necessitate the inclusion of older adults (i.e., aged 65 or older). Health conditions that are common or more prevalent among these older adults should be considered when evaluating the potential adverse medical consequences of alcohol administration in research. Age-related changes in how the body processes alcohol present added problems since a given dose of alcohol may lead to greater intoxicating effects in older adults compared to younger adults. As with participants of all ages, special consideration should be taken to assess concomitant medications that may interact negatively with alcohol. This is especially relevant with older adults who may be prescribed multiple concomitant medications.

Alcohol Exposure Levels

Researchers need to consider a potential participant's typical drinking history when establishing exclusion criteria for a given experiment. In general, it is not recommended that alcohol be administered at a level that would result in estimated higher blood alcohol concentrations (BAC) than those estimated to be reached by the participant on at least some occasions in the past year, even still risk/benefit issues must be considered.

In all cases, the exact dosing parameters must be explained in clear and explicit language concerning the number of drink equivalents, their concentration, their total volume, route of administration (particularly if the alcohol is not administered orally), and the amount of time allotted for administration and included as part of the informed consent procedure. The participant should also be informed about the range of potential peak BACs that might be reached during the experimental session, based on factors such as the participant's age, height, weight, and sex. Participants should be informed that they do not have to ingest the entire dose provided to them and can stop the administration of alcohol at any time if they feel uncomfortable or experience any adverse effects.

Administration studies in which participants control the rate and quantity of alcohol administered, can present unique safety challenges. Although one might expect participants in these self-administration studies to drink within their customary levels, some experimental manipulations are known to have large effects on drinking and could be expected to unduly influence participants to drink more than they might otherwise. On the other hand, care should always be taken to ensure that participants do not feel coerced or pressured to consume more alcohol than they feel comfortable with, or that alcohol administration does not exceed levels that participants have previously experienced. For these reasons, the exposure to alcohol should not exceed the target peak BAC specified in the study protocol.

Medical/Clinical Oversight

The potential for adverse medical consequences of alcohol administration varies substantially in association with the age, drinking status, and physical and emotional health of the participants, and also with the route of administration, total dose, and time course of alcohol exposure. The concern may be compounded by the co-administration of another drug with alcohol. Assessments of risk should include considerations of such experimental parameters when characterizing potential adverse consequences in the proposed research. A study physician or clinician should be available to assess risk and provide medical oversight throughout the study.

Post-administration Considerations

For outpatient studies, participants should be informed that they cannot leave the site until their BAC returns to the pre-determined threshold for discharge (typically between 0.00% and 0.02%). Participants should also be informed of the potential for prolonged impairment following the experimental session, even after BACs have returned to safe thresholds, and to avoid operating complex machinery or performing functions that require concentration. They should also be informed about the likelihood of hangover symptoms that may occur several hours through the day after the experimental session. Investigators should ensure that participants understand any restrictions on transportation from the clinical site following the conclusion of their session.

Providing adequate accommodation for participants while at the clinical site is essential and requires the following:

• A comfortable waiting area with nearby easily accessible restroom facilities.
• Ability of study staff to unobtrusively monitor participants on a continuous or near-continuous basis.
• Ability to access emergency care without leaving the participant alone.
• Provision of adequate amount of food and hydration to help with recovery from the acute effects of alcohol.
• Participants also need to be assessed for any signs of impairment or other adverse effects that require medical attention, monitoring, and/or intervention.

Follow-Up Assessments

Follow-up assessments of delayed reactions to alcohol administration should strongly be considered, such as when participants have AUD or when the participant experiences an adverse reaction during the session. As such, appropriate follow-up, as deemed clinically appropriate, is very important to maximize human subject protection.

Participants that report high-risk drinking patterns or have a diagnosis of AUD should receive a post-study assessment, brief intervention and possible referral to treatment resources as appropriate (see NIAAA Healthcare Professional’s Core Resource on Alcohol for guidance).

For questions, please contact NIAAAClinicalTrialsInquiries@mail.nih.gov.