To Infuse or Ingest in Human Laboratory Alcohol Research

Abstract

Human alcohol laboratory studies use two routes of alcohol administration: ingestion and infusion. The goal of this paper was to compare and contrast these alcohol administration methods. The work summarized in this report was the basis of a 2019 Research Society on Alcoholism Roundtable, "To Ingest or Infuse: A Comparison of Oral and Intravenous Alcohol Administration Methods for Human Alcohol Laboratory Designs." We review the methodological approaches of each and highlight strengths and weaknesses pertaining to different research questions. We summarize methodological considerations to aid researchers in choosing the most appropriate method for their inquiry, considering exposure variability, alcohol expectancy effects, safety, bandwidth, technical skills, documentation of alcohol exposure, experimental variety, ecological validity, and cost. Ingestion of alcohol remains a common and often a preferable, methodological practice in alcohol research. Nonetheless, the main problem with ingestion is that even the most careful calculation of dose and control of dosing procedures yields substantial and uncontrollable variability in the participants' brain exposures to alcohol. Infusion methodologies provide precise exposure control but are technically complex and may be limited in ecological validity. We suggest that alcohol ingestion research may not be the same thing as alcohol exposure research; investigators should be aware of the advantages and disadvantages that the choice between ingestion and infusion of alcohol invokes.

Keywords: Alcohol Experiments; Human Laboratory Research; Intravenous Alcohol Infusion; Oral Alcohol Ingestion.

Figure 1A-1D.. Comparison of Experienced BrAC trajectories across ingestion and infusion paradigms. 1A top left. 1B top right. 1C bottom left. 1D bottom right.

A. Individual BrAC trajectories in ingestion. Alcohol ingestion yields variable trajectories of BrAC even under carefully controlled circumstances. Here, individual BrAC trajectories after ingestion are plotted for 44 participants. The doses were calibrated according to total body water, based on the participant’s age, height, weight, and gender, to produce a peak BrAC of 80 mg/dl, then administered to minimize further variability in BrAC due to time of day, food, consumed, technician and testing environment. B. Mean and range of BrAC over time in ingestion. Lower smooth line: The average BrAC as a function of time after ingestion of 1.0 gm alcohol per liter total body water, calculated from data in Figure 1A. BrAC was measured approximately every ~10 min, then interpolated precisely to every 3 min over the 4-hour experiment. Upper jagged line: The range of BrAC between the maximum and minimum BrACs noted in the sample across time are plotted; expressing the uncertainty in brain exposure to alcohol across time after ingestion, even when control of dosing was the only goal. 1C. Peak BrAC and latency in ingestion. The relationship between an individual’s peak BrAC and the latency to that peak BrAC (min) in the response to careful oral dosing, calculated from Figure 1A. Peak BrAC ranges from 47 to 124; mean = 80 mg/dl. Latency to peak ranged from 18 to 129; mean = 51 min. In general, the longer it took to reach peak BrAC, the lower the peak concentration, reflecting the interplay between variable absorption and first-pass metabolism in alcohol pharmacokinetics. D. BrAC trajectory in infusion clamping. A trajectory of brain exposure to alcohol can be prescribed and achieved by real-time computation of an individual’s required infusion rate profile using CAIS-based PBPK modeling. The example shown here is from a BrAC clamping experiment conducted in 50 young adults with the goal of raising BrAC to 60 mg/dl in10 minutes, then maintaining it for 3 hours. The result minimizes the variability in BrAC trajectories across participants. Nearly any prescribed, physiologic trajectory, including the biphasic oral alcohol exposure curve, can be achieved.

Figure 2:

Portion of the CAIS technician’s video monitor screen displays the BrAC trajectory (top) and the infusion rate profile employed (bottom) for the entire experimental session. This example is from a hazardous drinker’s self-administered BrAC trajectory in a progressive work paradigm using infused water as an alternative reward. Triangles along the bottom of the upper screen indicate where rewards were administered. BrAC measurements obtained occasionally during the experiment are shown in dots along the upper trajectory of the modeled BrAC, validating the trajectory of modeled BrAC, and used by CAIS to adjust a parameter of the PBPK model in order to overcome any modeling errors. The bottom portion notes the infusion rate for alcohol (upper lines) and water (smaller triangles along the bottom) rewards. The increment in BrAC is a ‘slopelet’; a steady increase in BrAC for a specified interval, followed by a steady decline until the next increment commences. The slopelet used in this experiment raised the BrAC by 12 mg/dl in 3 min (4.0 mg/dl/min) before descending at −0.75 mg/dl/min and is one such example. Parameters of the slopelet are specified by the investigator in the setup file linked to the particular experiment. Other incremental shapes and exposure parameters are possible.