The Feasibility, Tolerability, and Safety of Administering a Very High Alcohol Dose to Drinkers with Alcohol Use Disorder

Abstract

Introduction:

There remains a paucity of research quantifying alcohol’s effects in drinkers with alcohol use disorder (AUD), particularly responses to very high alcohol doses (≥0.8 g/kg). As drinkers with AUD frequently engage in very heavy drinking (8-10 drinks/occasion), doses of ≤0.8 g/kg may lack ecological validity. The present study examined the feasibility, tolerability, and safety of administering a very high alcohol dose (1.2 g/kg) to non-treatment seeking AUD participants.

Methods:

Sixty-one young-adult AUD drinkers enrolled in the Chicago Social Drinking Project and completed three laboratory sessions at which they consumed a beverage with 1.2 g/kg, 0.8 g/kg, and 0.0 g/kg alcohol. Physiological responses (vital signs, nausea and vomiting, breath alcohol concentrations (BrAC)) were monitored throughout the sessions. After each session, participants completed a next-day survey of substance use, engagement in risky behaviors, and related consequences.

Results:

Overall, the sample demonstrated good compliance with study procedures; 93% of participants adhered to pre-session alcohol abstinence requirements (indicated by BrAC<0.003 g/dL), with no participants exhibiting serious alcohol withdrawal symptoms at arrival to study visits. The 1.2 g/kg alcohol dose achieved an expected mean peak BrAC of 0.13 g/dL at 60-minutes after drinking, which was well-tolerated; the majority of the sample did not experience nausea (70%) or vomiting (93%), and dose effects on vital signs were not clinically significant. Finally, we demonstrated that the 1.2g/kg alcohol dose is safe and not associated with post-session consequences, including reduced sleep time, atypical substance use, accidents or injuries, and severe hangovers.

Conclusion:

Results support the feasibility, tolerability, and safety of administering a very high alcohol dose to young adult drinkers with AUD within the context of a well-validated laboratory alcohol challenge paradigm. Utilizing an alcohol dose more consistent with naturalistic drinking patterns may foster greater ecological validity of laboratory paradigms for persons with moderate to severe AUD.

Introduction

Over the past several decades, researchers have used laboratory-based human alcohol administration paradigms to examine alcohol response phenotypes (Fillmore and Weafer, 2012; King et al., 2016, 2014, 2011; Weafer et al., 2018), biobehavioral and genetic mechanisms of alcohol use disorder (AUD) risk (Gowin et al., 2017; Ramchandani et al., 2011; Ray and Hutchison, 2004), and the influence of contextual factors and expectancies on alcohol responses and self-administration behavior (Corbin et al., 2015; Doty and de Wit, 1995; Sher, 1985; Wardell et al., 2012). Generally, studies employing these paradigms consist of light, moderate and/or heavy social drinkers, largely excluding persons with AUD. Although some early studies over fifty years ago examined alcohol self-administration behavior and other responses to very high doses of alcohol in individuals with alcohol dependence recruited from rehabilitation centers and correctional facilities (Mello and Mendelson, 1971, 1965; Mendelson and Mello, 1966), this area of research was quickly suspended due to ethical and safety concerns of unrestricted alcohol self-administration in alcohol dependent persons.

In 1989, the National Advisory Council on Alcohol Abuse and Alcoholism’s (NACAAA) Recommended Guidelines on Ethyl Alcohol Administration in Human Experimentation (National Advisory Council on Alcohol Abuse and Alcoholism, 2005, 1989) deemed that special populations, including drinkers with AUD, are appropriate for laboratory alcohol challenge research pending careful consideration of the individual’s treatment-seeking status and medical and psychological wellbeing. Thereafter, laboratory-based alcohol challenge studies in persons with AUD resumed but with a primary focus on alcohol choice behavior, and often to examine mechanisms of approved or novel pharmacotherapies (O’Malley et al. 2002; Anton et al. 2004; Leggio et al. 2013; Farokhnia et al. 2018; also see Bujarski et al. 2018). Thus, in contrast to the extensive literature examining alcohol responses and consequences across a range of peak blood alcohol concentrations (0.02-0.12 g/dL; Howland et al., 2008; King et al., 2011; King et al, in press; Plawecki et al., 2018; Ray et al., 2009; Wit and McCracken, 1990; Zimmermann et al., 2013, 2009) in social and heavy drinkers, few laboratory studies have quantified alcohol’s effects in drinkers with severe AUD, particularly responses to very intoxicating oral alcohol doses exceeding 0.8 g/kg. This lack of knowledge hinders the alcohol research field as investigators may assume that findings obtained from laboratory examinations of social drinkers also apply to drinkers with AUD.

Generally, the alcohol dose administered in laboratory challenge paradigms is determined on the basis of tolerability (i.e. consideration of a subject’s drinking history, per NACAAA guidelines), time constraints (i.e. to account for alcohol elimination), study design (i.e. experimenter vs self-administration, single vs repeated dosing, etc.), and reliability in producing specific alcohol responses (Cyders et al., 2020; Keiding et al., 1983; National Advisory Council on Alcohol Abuse and Alcoholism, 2005; Norberg et al., 2003). Prior fixed-dose alcohol administration studies in adult drinkers with AUD generally have administered a maximum oral dose of 0.08 g/kg (approximately 4-5 standard drink equivalent, per National Institute on Alcohol Abuse and Alcoholism 2015), although higher doses have been achieved in intravenous self-administration paradigms (Bujarski et al., 2018; Zimmermann et al., 2013). The usual 0.8 g/kg high oral alcohol dose produces acute subjective, behavioral, and physiological effects, aligns with current definitions of heavy episodic or binge drinking (National Institute on Alcohol Abuse and Alcoholism, 2015), and is within safety limits for tolerability in persons without AUD (King et al., 2011; de Wit and McCracken, 1990). However, as drinkers with AUD, particularly those with more severe symptoms, frequently engage in extreme heavy drinking up to two times the standard heavy drinking threshold (Anton et al., 2006), examining their responses to alcohol at or below 0.8g/kg may have limited ecological validity. As such, there is need to develop alcohol challenge paradigms for AUD drinkers at relevant doses, but first such paradigms must be shown to be feasible and safe to determine if their benefit to scientific discovery outweighs potential risks to participants.

To this end, the present study used a within-subjects design to examine the feasibility, tolerability, and safety of administering a very high oral alcohol dose (1.2 g/kg) that is 50% higher than the usual high fixed dose employed in prior studies in heavy and AUD drinkers (Kahler et al., 2014; King et al., 2016, 2011, 2002; Wardell et al., 2016). Participants were enrolled in the third cohort of the Chicago Social Drinking Project (CSDP; King et al. 2002, 2011, 2014, 2016) and consumed 1.2 g/kg , 0.8 g/kg, or 0.0 g/kg alcohol in each of three sessions. We first measured the feasibility of examining AUD drinkers in multi-session alcohol laboratory paradigms by evaluating their study visit attendance rates as well as their session arrival breath alcohol concentrations (BrAC) and withdrawal symptoms. We then examined the feasibility of the very high alcohol dose to produce an expected mean peak BrAC of 0.13 g/dL (approximately 50% higher than that achieved with the 0.08 g/kg dose in prior studies by our group (King et al., 2016, 2014, 2011) and with a similar degree of variance as that observed with the usual high alcohol dose. Tolerability and safety of the very high dose were examined by comparing measures of in-session nausea and vital signs and after-session behaviors and consequences relative to the usual high dose and placebo sessions.

Methods

Design

The data for this study were culled from the larger CSDP and included AUD participants in the third cohort who enrolled in the three-session study between June 2016 and February 2018. The CSDP is approved by the University of Chicago Institutional Review Board (IRB) and all sessions were conducted at the Clinical Addictions Research Laboratory at the University of Chicago.

Participants (N=61) attended three laboratory sessions separated by at least 48 hours, during which they consumed a beverage with 1.2 g/kg alcohol (7-8 drink equivalent; referred to in this paper as the “very high dose”), 0.8 g/kg alcohol (4-5 drink equivalent; referred to as “usual high dose”), or a 0.0 g/kg alcohol placebo (includes a 1% alcohol taste mask but with negligible alcohol content; referred to as “placebo”). The latter two conditions were double-blinded and randomized, but the very high alcohol dose session was single-blinded with an earlier start time and a longer session duration (7-8 hours vs. 4-5 hours for other sessions). These parameters allowed BrAC to descend to 0.04 g/dL or below before the participant could be released with similar dismissal times across sessions. As the very high dose is novel in alcohol administration research, the University of Chicago IRB advised precautionary measures and submission of safety information in the early stages of the study after the first 10 participants were completed. To respond to this guidance, and as an additional safety measure, the very high dose was conducted as the second or third session to ensure participants (n=26) could first tolerate the usual high dose. As there were no major adverse events reported, the very high dose was then assigned to the first session for the remainder of the sample (n=35). Participants were blind to the contents of the beverage across all sessions (see “Beverage Administration”), and session order was included as a covariate in analyses, as appropriate.

Eligibility and Screening

Participants were recruited via online advertisements and word-of-mouth referrals. Inclusion criteria were: age 21 to 35 years, weight 110 to 220 pounds, in good general health, and not pregnant or lactating; no current major psychiatric concerns, able to refrain from smoking for 8 hours, not currently seeking treatment for alcohol-related problems, and meeting 2 or more AUD symptoms in the past year; and engaging in at least 11 heavy drinking episodes (defined as ≥ 5 drinks for men, ≥ 4 for women according to NIAAA and SAMHSA guidelines) per month and consuming 28 or more alcoholic drinks per week (≥21 if female). Drinking quantity and frequency cutoffs were selected to ensure drinking behaviors would not overlap with previous cohorts of non-AUD heavy drinkers (King et al., 2011; Roche et al., 2014).

Candidates meeting basic study inclusion criteria as determined via an initial phone screen were scheduled for a 2-hour in-person screening to verify eligibility. During the scheduling process, candidates were instructed to abstain from alcohol for at least 24 hours and recreational drugs (excluding marijuana) for 2 – 5 days prior to screening in order to provide negative breath alcohol and urine drug tests. The screening session included an ID verification of age, a brief physical history, breath test for alcohol, a urine toxicology screen (amphetamines, benzodiazepines, cocaine, methamphetamine, opiates, and tetrahydrocannabinol), a blood sample for liver enzyme tests (AST, ALT, GGT within 3 standard deviations of normal), and surveys and interviews, including past-month alcohol and cigarette Timeline Follow-Back interviews (Sobell and Sobell, 1992), the Alcohol Use Disorders Identification Test (Babor et al., 2001), the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar; Sullivan et al. 1989) and the Structured Clinical Interview for DSM-IV, non-patient version (First et al., 1995). Persons meeting criteria for past year major DSM-IV disorders (schizophrenia, bipolar disorder, obsessive-compulsive disorder, mood disorder, or substance dependence, other than alcohol, cannabis, or nicotine) were excluded.

There were 153 candidates who met basic study criteria from the phone screening, of which, 53% (81/153) attended an in-person screening visit. Most (98%) candidates arrived to the screening visit with a BrAC ≤0.003 g/dL (negative) and all with a CIWA-Ar ≤10, indicating not exhibiting serious alcohol withdrawal symptoms [median (IQR):0.0 (0.0-1.0); 74% had total CIWA score=0]. The majority of candidates screened (66/81; 82%) were deemed eligible; reasons for ineligibility included not meeting AUD criteria or the minimal drinking threshold (n=8), meeting criteria for benzodiazepine or opioid dependence (n=2) or past year major psychiatric disorder (n=4), or not within the age range (n=1). Of eligible candidates, 61 (92%) attended the first session and thus comprised the study sample, and all but one of them completed all 3 study sessions. The five enrollment failures did not attend their study session and were either unable or willing to re-schedule the session; these individuals did not differ from the main study sample on major demographic or drinking characteristics.

Laboratory Sessions

All sessions were conducted in the afternoon or early evening and commenced between 11:00am and 4:00pm. Participants were instructed to abstain from alcohol and medications for at least 48 hours prior to the session, as well as caffeine, cigarettes, and food for 3 hours prior. Upon arrival, the participant completed a breathalyzer test (Alco-Sensor IV, Intoximeter, St. Louis, MO) to verify compliance with recent alcohol abstinence and the CIWA-Ar to assess alcohol withdrawal symptoms. Urine samples were collected before one session, chosen randomly, for toxicology in all participants and before each session for women to screen for pregnancy. After compliance measures, the participant consumed a snack at 20% daily kilocalorie needs per body weight (55% carbohydrates, 10% protein, and 35% fat) (Schofield, 1985) to reduce the possibility of alcohol-induced nausea. This was followed by completion of baseline blood pressure and heart rate readings and self-reported ratings of nausea for 10 minutes.

Beverage Administration:

The procedure for beverage administration was identical for each session. To reduce alcohol expectancy effects, the Alternative Substance Paradigm (Conrad et al., 2012) was used whereby participants were told that the beverage might contain a stimulant, a sedative, alcohol, or a placebo, or two substances in combination. At experimental time 0 (~45 minutes after arrival; approximately 12pm for the very high alcohol dose sessions and between 1:30-3pm for the usual high alcohol and placebo dose sessions), the participant began the 15-minute beverage consumption period. The participant received beverages in lidded, clear plastic cups in three equal portions and consumed each portion over three consecutive 5-minute intervals with the research assistant present to engage in light conversation and ensure that the beverages were consumed. Beverages consisted of 190-proof ethanol (1% volume for placebo as a taste mask, 16% volume for alcohol beverage) mixed with water, a flavored drink mix, and a sucralose-based sugar substitute (King et al., 2011). Doses for women were adjusted to 85% of those for men to adjust for sex differences in total body water (Frezza et al., 1990; Sutker et al., 1983; Watson et al., 1980). Pilot work revealed that for the very high dose, increasing the percent alcohol by volume while keeping the same beverage volume as the other two sessions resulted in a beverage that was unpalatable. Therefore, the average volume for each of the three beverage portions was 234 mL for the very high dose session and 157mL for the other dose sessions.

The research assistant administered dependent measures and breathalyzer tests at 30, 60, 120, and 180 minutes following beverage consumption. To reduce research assistant expectancy, breathalyzer readings were programed to read .000 mg/dL with actual BrAC values downloaded later. Between time points, the participant could view movies or read magazines from a standardized list provided by the study. Before discharging the participant, the experimenter confirmed BrAC level was ≤0.04 g/dL and completed a behavioral checklist for overt signs of intoxication on alertness, orientation, coordination, and gait. The research assistant instructed the participant to avoid operating machinery or driving a vehicle for the next 12 hours, and provided instructions on completing a short online survey that would be emailed at 11:00 a.m. the following day. A ride-share service transported the participant home after each session. At the end of the third session, the participant was debriefed and compensated $225 (with an additional bonus up to $100 for keeping to scheduled dates, arriving on time to each session, complying with alcohol abstinence procedures, and completing next-day surveys).

Measures

The main dependent measures captured the feasibility, tolerability, and safety of the study procedures. Feasibility included attendance at scheduled sessions, arrival with negative BrAC without significant alcohol withdrawal symptoms (per the CIWA-Ar), achieving an expected mean ± SD peak BrAC of 0.13 ± 0.02 g/dL within 60-minutes of beverage consumption, and compliance rates in completing next-day surveys. Tolerability of the very high dose was assessed by the incidence of vomiting or nausea, mean nausea ratings (rated from 0 ‘not at all’ to 10 ‘extremely’), and vital signs, including systolic and diastolic blood pressure and heart rate (Dinamap, ProSeries 100-400; Milwaukee, WI). Safety of the very high dose was determined via the next-day online survey assessing (from the time of returning home after the session to 11:00 am the next morning) quality and estimated number of hours of sleep, use of alcohol or other substances, incidence of risky behaviors (driving a vehicle, operating machinery, accidents, or injuries), and the total score on the 9-item Acute Hangover Scale (Rohsenow et al., 2007). This survey was added to the study after the first 9 participants, and initially after the second and third sessions only (n=20). As completion rates were excellent (100%), the survey was expanded with use after all sessions (n=31) with completion rates of 98%, 93%, and 88% following the very high alcohol, usual high alcohol, and placebo dose sessions, respectively.

Statistical Analyses

For the feasibility outcomes, incidence rates of rescheduling sessions due to arrival with a negative BrAC or withdrawal symptoms present were computed as a percentage of the total number of sessions. For assessing BrAC means and variances at each time point, the test of equality of variance for paired data (McCulloch, 1987) compared the variability produced by the very high alcohol dose vs the usual high alcohol dose. Secondary correlational analyses examined associations between peak BrAC and AUD symptoms or alcohol use behaviors (e.g., number of drinking days, heavy drinking days, drinks per drinking day, and AUDIT scores). Tolerability measures (e.g., nausea ratings and vital signs) were analyzed with generalized estimating equation (GEE) models examining the effects of dose, time, and their interaction on each outcome, with BrAC included as a covariate. As most nausea ratings were 0, this item was dichotomized as the presence (1) or absence (0) of nausea at each time point and analyzed by GEE with a logit link function. For safety outcomes, GEE models compared responses from the next-day survey after the very high alcohol dose session with those from the other two sessions with session order included as a covariate and repeated in a separate GEE controlling for post-session alcohol consumption after each session. As post-session alcohol use was significantly associated with baseline alcohol use characteristics (i.e. number of drinking days, heavy drinking days, and drinks per drinking day), these were included as covariates in a separate GEE analysis of post-session alcohol use. For all analyses, post-estimation tests determined the source of significant main effects or interactions, when appropriate.

Results

Sample demographic and alcohol use characteristics are presented in Table 1. The average age of the sample was 26.8 ± 0.5 (SEM) years, 43% were female, and racial background was diverse (55% White, 27% Black, 18% Other). Mean liver enzyme levels were within the range of normal at study enrollment, and, except for a significant positive association between liver AST and drinks per drinking days (r = 0.29, p = 0.03), liver enzyme levels were not associated with AUD symptoms, AUDIT scores, or other alcohol use behaviors. Though 14 participants had levels slightly above the upper limits for AST (n=4), ALT (n=4) and GGT (n=14), none of these elevations were clinically significant or precluded participation. Alcohol drinking occurred on 75% of days in the month prior to enrollment with an average of 7.6 ±0.4 (SEM) drinks consumed per drinking day. Nearly two-thirds of days were heavy drinking days (64%), with half of those days involving very heavy drinking (≥10 drinks for men, 8 for women; Miranda et al. 2020). All participants met DSM-5 criteria for AUD with over half (59%) in the severe range (6 or more symptoms endorsed).

Table 1:

Participant characteristics

	AUD Drinkers (N=61)
Demographics & Health
Age (years)	26.9 (0.5)
Education (years)	14.1 (0.2)
Sex (% male)	57%
Race (% White)	54%
AST (units/L)a	23.6 (1.6)
ALT (units/L)a	22.9 (2.4)
GGT (units/L)a	43.2 (6.0)
CIWA-Ar <3 at screeningb	97%
Drinking Characteristics
DSM-5 AUD mean symptom count	6.1 (0.3)
Mild (2 - 3 symptoms)	21%
Moderate (4 - 5 symptoms)	20%
Severe (6+ symptoms)	59%
AUDITc	19.9 (0.9)
Age of first drink (years)	15.8 (0.4)
Past Month Drinking Patterns
Drinks per drinking day	7.7 (0.4)
Maximum number drinks	14.4 (0.8)
Heavy drinking daysd (% past 28 days)	64%
Very heavy drinking dayse (% past 28 days)	30%
Past Month Substance Use
Cigarettes (% yes)	74%
Cannabis (% yes)	56%
Other drugs (% yes)	10%

Note: Data are means (SEM) or %, except where indicated.

^aAspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) blood tests for liver functioning;

^bClinical Institute Withdrawal Assessment of Alcohol Scale, Revised, % of sample with scores <3, score range: 0-67;

^cAlcohol Use Disorders Identification Test, score range: 0-40;

^dDefined as 4+ drinks for women and 5+ drinks for men;

^eDefined as 8+ drinks for women and 10+ drinks for men

Feasibility

Despite the sample meeting criteria for AUD, 93% of the participants arrived to all three study sessions with a negative BrAC reading. Four sessions (4/181, 2%) were rescheduled due to a positive BrAC reading [ranging from 0.02-0.95 g/dL] at arrival; in all cases, participants were safely transported home, willing to reschedule, and returned to their next visit with a negative BrAC and no future incident. There was also a low incidence of alcohol withdrawal symptoms at arrival for study sessions as 90% of the sample had CIWA-Ar scores <3 at all three sessions. The incidence rate of any withdrawal symptoms present at arrival was 16% (29/181 of sessions), and for these sessions, the mean CIWA-Ar scores were in the very low range (1.9 ± 0.3 on a scale of 0-67). No sessions were rescheduled due to severe alcohol withdrawal (CIWA-Ar ≥10).

The very high alcohol dose produced a mean peak BrAC at 60 minutes of 0.132 g/dL ± 0.024 (SD), with 72% of participants achieving peak BrAC within 60 minutes of beverage consumption. Analyses revealed that the very high dose yielded higher BrAC levels (dose, p<.001) and larger variance in BrAC than the usual high dose at each post-drinking time point (dose, ps<0.05). The temporal profiles of the BrAC curve for both alcohol sessions showed similar patterns with sharply rising ascending limbs to peak BrAC and then slow declining limbs (Figure 1a), with the very high alcohol dose taking about 3-4 hours longer than the usual high alcohol dose to reach 0.04 g/dL. Peak BrAC for each participant during the very high and usual high alcohol dose sessions are depicted in Figure 1b. Secondary analyses revealed no significant relationship between peak BrAC and AUD symptoms or alcohol use behaviors.

Figure 1. Breath alcohol concentrations (BrAC) during the alcohol dose sessions.

a) BrAC at each time point during the very high (1.2 g/kg) and usual high (0.8 g/kg) alcohol dose sessions. Data are means ± SD. b) Distribution of peak BrAC for the usual high and very high alcohol dose sessions. Each circle represents one participant (n=60) and the red line indicates the mean for each session.

Tolerability

The very high dose of alcohol was generally well-tolerated. Seventy percent of participants denied any nausea with ratings of “0” at all post-beverage time points. For the 30% who reported any nausea, the mean rating across all post-beverage time points was low (1.9 ± 0.4 on the 10-point scale) and did not differ from that reported during either the high dose or placebo sessions (1.3 ± 0.4 and 1.4 ± 0.4, respectively; dose, Waldχ²=2.95, p=0.23). Emesis was uncommon as 93% of participants completed the very high dose session without vomiting (vs. 100% in the other sessions). Four participants experienced emesis, and in all cases, it occurred within 30 minutes of completion of the beverages. None of these participants wanted to discontinue the session and there were no further incidents in the sessions. Notably, three of these four participants had a mean peak BrAC of 0.103 ± 0.015 (SD) g/dL, lower than the overall sample mean BrAC, but within 2 standard deviations, and still exceeding the legal definition of intoxication (≥0.08 g/dL). Removing these participants produced negligible effects on the sample’s mean BrAC (from 0.134 to 0.132 g/dL). They all had severe AUD, and during the month prior to enrollment, reported alcohol use on 93% of days with an average of 10.8 ± 2.2 drinks per occasion. Two of them reported that they did not eat food the day of their session, but all participants received a calorie-controlled snack at baseline. The fourth participant with emesis reported unpleasant feelings of sluggishness and fatigue that limited data collection for his very high dose session. Thus, out of an abundance of caution, as this was his first session, he was not tested further and was removed from subsequent analyses. Secondary analyses revealed no association (p≥0.26) between the incidences of nausea and vomiting and beverage volume.

Cardiovascular responses to each dose are shown in Figure 2. The very high alcohol dose initially increased systolic and diastolic blood pressure readings, which peaked at 30 minutes post beverage consumption, but this effect was transient and not statistically significant relative to the usual high alcohol and placebo doses. The declining limb of the very high alcohol dose produced decreases in diastolic (but not systolic) blood pressure relative to the placebo dose, and this decrease was comparable to that induced by the declining limb of the usual high alcohol dose (diastolic: time*dose, Waldχ²=73.94, p<0.001). The very high alcohol dose increased heart rate by an average of six beats per minute (bpm), from 70.7 ± 1.6 at baseline to 76.1±1.7 bpm at 30-minutes post beverage consumption, and this increase was sustained for the duration of the session. These heart rate increases were similar to those produced by the usual high dose, with both alcohol doses resulting in higher heart rates than those observed during placebo (time*dose, Waldχ²=20.51, p=0.009).

Figure 2: Vital signs.

Data are means ± SEM. Depicted are a) systolic and b) diastolic blood pressure and c) heart rate readings at each time point for the three dosing sessions. The grey bar indicates when beverage consumption occurred for all sessions. *p<0.04 for very high dose and usual dose versus placebo; ^p<0.05 for usual high dose versus placebo.

Safety

The next-day survey was feasible with a 91% completion rate, and outcomes are presented in Table 2. Participants reported getting an average of 8.4 ± 0.4 hours of sleep after their very high alcohol session, similar to that reported after the other two sessions (see Table 2). Nearly one-third of participants (30%) reported their sleep was of poor quality after the very high dose session, similar to that reported after the usual high dose (21%) and both significantly higher than after the placebo session (8%; dose, p=0.03). However, after including post-session alcohol use into the model, the effect of dose on sleep quality was no longer significant.

Table 2:

Post-session behaviors

	Placebo session, n=36	Usual high alcohol session, n=38	Very high alcohol session, n=50
Sleep time, hours (mean, SEM)	7.4 (0.4)	7.9 (0.5)	8.4 (0.4)
Poor sleep quality	8%	21%	30%
Any alcohol drinking	69%	61%	60%
Heavy alcohol drinking1	39%	37%	36%
Drug use	25%	34%	30%
Drove a car	14%	13%	16%
Passenger with a driver who had been drinking	3%	3%	6%
Operated machinery	0%	3%	2%
Accident or injury	0%	0%	2%

Note. Data are % of respondents reporting engagement in the specified behavior.

¹Heavy alcohol drinking post-session defined as ≥5 drinks for men, ≥4 for women.

The very high dose session did not result in greater frequency (Table 2) or quantity (Figure 3) of drinking after the session than the other two dose sessions, even after controlling for baseline alcohol use patterns. Use of recreational drugs after the very high dose session was comparable with the other two sessions (p>0.05). The majority of participants did not engage in risky behaviors after sessions (98%, 84%, and 94% did not operate machinery, drive a vehicle, or ride in a vehicle with a driver who had been drinking, respectively; Table 2). Engagement in risky behaviors following the very high alcohol dose session did not differ to those following the other two sessions (Table 2; ps>0.05). There was one report of a minor injury after the very high alcohol dose session, and this was described by the participant as a “swollen finger” with no additional details provided.

Figure 3: Post-session alcohol use and hangover severity.

Data are means ± SEM. a) Quantity of alcohol consumed after returning home from study sessions for participants who indicated alcohol use after the placebo (n=25), usual high alcohol dose (0.8 g/kg; n=23), and very high alcohol dose (1.2 g/kg; n=30) sessions. b) Total scores on the Alcohol Hangover Scale reported the day after each of the three dosing sessions. *p=0.03

Across all next-day surveys, the mean acute hangover score was low (0.96 ± 0.08 on a scale 0-7), indicating low hangover severity, with participants reporting the highest ratings for “thirsty” and “tired.” Following the very high alcohol dose session, the mean acute hangover score was similar to that following the usual high alcohol dose and significantly greater than the placebo dose (Figure 3; very high dose vs placebo, p=0.03). Results remained after controlling for additional drinking after the sessions.

Discussion

To our knowledge, this was the first oral alcohol challenge study employing a fixed dose of 1.2 g/kg, 50% higher than the usual 0.8 g/kg intoxicating dose. The collective results indicated that this very high dose administration was feasible, safe, and well-tolerated in AUD drinkers. Young adults with AUD, the majority of whom had severe symptomatology were successfully recruited and retained in this multi-session laboratory alcohol challenge study with few arrival violations of alcohol abstinence or significant withdrawal symptoms precluding examination. The very high alcohol dose produced BrAC levels with a similar temporal profile as observed with the 0.8 g/kg usual high alcohol, and in close approximation to the expected mean peak BrAC of 0.13 ± 0.02 g/dL (50% higher than the 0.09 g/dL from the usual high dose) one hour after drinking initiated. While self-administration studies with slower ingestion parameters also may eventually produce BrAC at this level or higher, the present study uniquely demonstrated that a very high, bolus oral dose is well-tolerated and, for the majority of the AUD sample, produced neither major adverse effects in the session nor serious consequences after the session.

The very high 1.2 g/kg oral dose was administered over a short fifteen minute interval to maintain consistency with the time course often used with the usual high dose (Cyders et al., 2020; Kahler et al., 2014; King et al., 2016, 2011, 2002) and to produce an alcohol challenge to AUD drinkers who average consuming 7-8 drinks per drinking occasion and frequently engage in very heavy drinking. General safety and tolerability was evident in this sample of young adults with stable patterns of very heavy alcohol use within the past year. While most of the sample tolerated the very high dose without any adverse effects, emesis did occur in four participants. We speculate that the increased beverage volume (50% higher than for the very high dose or placebo) could have contributed to the incidence of vomiting, particularly as intravenous alcohol clamped at BrAC =0.10 g/dL has been shown to not produce nausea and vomiting (Plawecki et al., 2018). In the present study, vomiting occurred so infrequently (7% of sample) so whether or not it was related to beverage volume or some other factor is unknown. Collectively, the results indicate that oral administration of a 0.12 g/kg bolus dose of alcohol can be safely implemented in laboratory studies of excessive drinkers, including those with severe AUD. Future research should investigate whether administration of this very high oral dose yielding a mean peak BrAC of 0.13g/dL is also safe without significant adverse events in non-AUD heavy drinkers.

In terms of alcohol pharmacokinetics, oral dose administration invariably produces a wider range of BrAC than intravenous infusion due to individual differences in gastric emptying, liver blood flow, systemic circulation, and other metabolic factors (Cyders et al., 2020; Norberg et al., 2003; Zimmermann et al., 2013). Potential confounds that would have introduced more variability in BrAC from oral dosing were controlled – such as accounting for sex and total body water content in dosing, standardizing beverage contents, pre-beverage snack composition, and the rate of drinking, and the within-subjects design to minimize the influence of interindividual differences in genetic factors affecting alcohol metabolism. Nevertheless, the greater BrAC variance observed with the very high versus usual high alcohol dose is not surprising given evidence that larger (vs. moderate) oral alcohol doses (≥0.9 g/kg) are associated with more variability in absorption rates, decreased first pass metabolism, and higher rates of elimination (Keiding et al., 1983; Norberg et al., 2003; Rangno et al., 1981). Other sample-specific factors, such as variability in drinking patterns and AUD severity were shown not to affect the variance in peak BrACs for each dose.

Importantly, the present study also addresses another issue that is largely absent in the alcohol challenge field – participant behaviors and experiences shortly after a laboratory alcohol session. Participant responses to our next-day survey revealed that despite instructions not to consume alcohol for 12 hours after the session, in AUD drinkers, additional post-session alcohol consumption was not uncommon. There were no differences in the incidence of post-session drinking across the two alcohol dose or placebo sessions, confirming that the very high dose did not increase the likelihood of later drinking. The relatively standard dismissal time across sessions may have been a factor in the stability of post-session behaviors. Self-reported alcohol and drug use were typical of participants’ usual patterns and the very high alcohol dose did not induce greater drinking or risky behavior than either the usual high dose or placebo.

While participants endorsed higher ratings of hangover severity after the very high alcohol sessions relative to placebo, overall ratings were low and thus not clinically significant. More broadly, and consistent with prior research, our findings demonstrate that direct alcohol administration in the laboratory to AUD participants, including those with severe symptomatology, does not have immediate adverse consequences on their overall well-being (Bacio et al., 2014; Drobes and Anton, 2000; Pratt and Davidson, 2005; Sinha et al., 1999). Nevertheless, despite providing a car service home to ensure safety and instructions to not drink alcohol, drive a car, or operate machinery, some participants still engaged in such behaviors after their sessions, albeit without serious adverse incident. We cannot rule out that more frequent heavy drinking or recreational drug use occurred than was reported, or that simply knowing there was a next-day survey may have curbed behavior. However, we recommend that studies examining alcohol responses in AUD drinkers employ assessments of post-session behaviors so that more data can be acquired on this important topic, with considerations for paradigm modifications, as needed.

Several limitations in the study are worth noting. First, our sample consisted of young adult AUD drinkers across a range of severity of the disorder, and thus we cannot infer feasibility, tolerability, and safety of our protocol in middle-aged or older adults or those with significant pathology related to chronic extended alcohol misuse. Second, while we demonstrated that the very high alcohol dose was not associated with an increased incidence of next-day adverse consequences, intermediate- or longer term outcomes may also be important to examine, although prior research examining lower alcohol dose response paradigms have reported minimal or no long-term changes in AUD participants’ drinking behavior or motivation for treatment (Bacio et al., 2014; Drobes and Anton, 2000; Pratt and Davidson, 2005). Third, rapid consumption of alcohol within a 15-minute period may not completely mimic excessive drinkers’ alcohol consumption pacing in the natural environment (Fridberg et al., 2019). However, it does have advantages in producing an alcohol challenge that minimizes interindividual variability in BrAC curves and is consistent with prior work by our group and others across a range of drinkers (Corbin et al., 2008; King et al., 2016, 2011; Roche et al., 2014). Last, while the NACAAA guidelines do not preclude treatment-seeking alcoholics from alcohol administration studies, we focused on non-treatment seekers in this proof-of-concept study. With careful consideration of the risk/benefit ratio associated with participation, inclusion of treatment-seeking alcoholics in alcohol administration research contributes importantly to understanding various mechanisms of AUD risk and pharmacotherapy efficacy (Dolinsky and Babor, 1997; Enoch et al., 2009; Ray et al., 2017; Spagnolo et al., 2014). As such, future research should consider evaluating this population in laboratory alcohol challenge paradigms. On a related point, the NACAAA guidelines encourage provision of post-session motivational counseling for drinking; however, given this work is part of the larger CSDP with long-term follow-up of the natural course of drinking behavior and AUD symptoms, that was not provided as part of the current study, but was available if requested.

The current study is the first demonstration that oral administration of a very high alcohol dose (1.2 g/kg) producing a mean peak BrAC of 0.13g/dL is feasible, tolerable, and safe in non-treatment seeking young adult drinkers with AUD, the majority of whom had severe AUD. Overall, our sample showed good compliance with our multi-session study procedures, including pre-session instructions to abstain from alcohol use prior to their scheduled sessions and willingness to complete a next-day survey, both of which may be attributed, at least in part, to the careful instructions, relationship-building with study staff, and financial bonuses employed. Further, the study did not present any increased immediate risk to the well-being of participants and provides empirical support for the safety and tolerability of oral administration of very high alcohol doses (0.8-0.12 g/kg) to drinkers for whom this dose is within the range of their customary drinking levels (National Advisory Council on Alcohol Abuse and Alcoholism, 2005, 1989). Findings encourage enrollment of young adult drinkers with AUD in laboratory alcohol challenge research and examination of acute responses to alcohol at doses that more closely approximate their excessive drinking patterns.