The rewarding effects of alcohol after bariatric surgery: Do they change and are they associated with pharmacokinetic changes?

Abstract

Background:

Research shows that surgery patients who have undergone Roux-en-Y gastric bypass (RYGB) are at increased risk for an alcohol use disorder (AUD). However, the mechanisms through which this increased risk is incurred are poorly understood. A host of variables have been proposed as potentially causal in developing AUDs, but empirical examination of many of these variables in human samples is lacking.

Objectives:

Our objective was to examine the extent to which alcohol pharmacokinetics (PK), the rewarding effects of alcohol, and the relationship between these variables change from before to after weight loss surgery.

Setting:

Large healthcare facility in the Midwest United States

Methods:

Thirty-four participants completed assessments prior to, and one year after, RYGB. They completed laboratory sessions and provided data on the PK of alcohol and the extent to which alcohol was reinforcing to them at each timepoint.

Results:

Findings show that the PK effects of alcohol (p<.01) and how rewarding alcohol was reported to be (p<.01) changed after from before, to one year after weight loss surgery. Further, statistically significant increases in the association between these variables were witnessed from before to one year after surgery (p<.01).

Conclusions:

These results implicate changes (from before surgery to one year after) in the reinforcing and PK effects of alcohol as possible mechanisms for increased risk of alcohol use disorder following Roux-en-Y gastric bypass surgery.

Introduction

The use of alcohol before and after bariatric surgery has been examined in a number of studies in the past two decades. Most of these studies have found increases in alcohol intake, alcohol use disorders (AUD), and treatment for problematic alcohol intake following surgery, particularly Roux-en-Y Gastric Bypass (RYGB). The studies that have not found increased rates of alcohol consumption have had much more modest sample sizes¹, while the three largest studies have all found significant increases in these areas^2–4. Our group² demonstrated that RYGB patients had significantly more AUDs than patients who received laparoscopic adjustable gastric banding surgery, which is a purely restrictive procedure. Even more compelling are the data that show when following these patients for longer periods of time after surgery (5–7 years), they experience significant additional increases in alcohol consumption and problems over time⁵. Specifically, seven years after surgery, approximately one in five patients report significant symptoms of alcohol problems. Our group⁶ and others⁷ have reviewed this topic and concluded that in total, the current body of literature convincingly demonstrates that patients who undergo RYGB are at increased risk for AUD and increased alcohol consumption in the years following surgery.

In spite of the strong evidence that patients who undergo RYGB are at an increased risk for alcohol problems after surgery, the mechanisms by which this increased risk is incurred are not well understood. While some research has been completed in animal models⁸, there is a paucity of empirical examination of the potential mechanisms in bariatric surgery patients. In the current study we examine reward and PK in a sample of patients who underwent RYGB. Understanding how these variables change from before to after surgery would be informative and shed light on two potentially relevant mechanisms of AUD in this group of patients.

Study aims

Although pre-clinical work has examined this topic, research with bariatric surgery patients examining the impact of alcohol reinforcement and precipitants of reinforcement on alcohol intake is lacking. The current study had three primary aims that will address these shortcomings: 1) examine the changes in rewarding effects of alcohol that bariatric surgery patients experience from pre-to post-surgery; 2) examine the changes in PK parameters from before to after surgery; and 3) study the associations between PK and reward changes before and after RYGB surgery.

Method

Participants

Participants were recruited from a population of patients undergoing RYGB at a large healthcare facility in the Upper Midwest between 2015 and 2020. All participants provided written informed consent prior to participation in the research. The protocol was approved by two institutional review boards.

Participants were included in the study if they were between 21–65 years of age, able to tolerate the alcohol dose administered, cognitively able to complete study activities, and medically stable. Participants were preliminarily screened via telephone for exclusion based on cognitive impairment, medical comorbidities that would make participation difficult or unsafe, or current treatment for alcohol or substance use. Additionally, participants were screened in person at pre-surgery and one year follow-up and excluded for psychosis, bipolar disorder, AUD-severe, and current suicidality assessed via the Structured Clinical Interview for DSM-IV (SCID-I/P⁹). Clinical interviews were conducted by a Master’s level assessor.

Overall Procedure

Study personnel administered a preliminary screening questionnaire over the phone, following which prospective participants were scheduled for three appointments: a screening assessment visit, a reinforcement/cognitive impairment laboratory visit, and a driving simulator laboratory visit (not reported in this manuscript). These visits were conducted at pre-surgery and 1 year following bariatric surgery. All measures included in this study have historically demonstrated strong psychometric properties.

Screening.

The in-person screening assessment took place at the Sanford Center for Bio-behavioral Research (SCBR). After written informed consent was obtained, participants completed the screening process to determine inclusion/exclusion criteria. Results of all screening measures were examined by the principal investigators prior to the first scheduled laboratory visit.

Interview Measures.

The SCID-I/P⁹ provided a thorough assessment of psychopathology in order to screen for exclusionary criteria.

Self-report Measures.

Participants were given the links to the computer administered self-report measures via e-mail and provided instructions on how to complete them remotely. All self-report measures were completed via secure on-line survey format except for the Beck Depression Inventory (BDI¹⁰), which was administered in paper form (at the screening visit) and assessed current suicidality and symptoms of depression. The Alcohol Use Disorders Identification Test (AUDIT¹¹), a measure developed by the World Health Organization assessed alcohol use and alcohol-related consequences. A number of other self-report measures were adminstered to assess a variety of variables that are unrelated to the current manuscript.

Reinforcement Lab.

The reinforcement/cognitive impairment lab visits were conducted at the SCBR. Participants were required to fast (food and drink) for four hours prior to the beginning of each study visit. Upon arrival, participants’ fasting status and any medication/health changes were assessed. Participants were given a breath alcohol content test (BrAC; measured with the Alco-sensor FST intoximeter) and blood pressure was taken. Participants were required to have a BrAC of 0% and blood pressure lower than 150/100 mm Hg in order to proceed with the study visit.

Participants received a standardized dose of ethanol (0.30 grams/kg of body weight) in the form of 80 proof vodka mixed 50/50 with orange juice. This combination was used to minimize the fluid volume administered, considering post-surgical patients have a small gastric pouch following RYGB. A smaller fluid volume reduced the time required for post-surgical patients to ingest the drink and therefore provided a more accurate PK assessment. The drink was administered over a 5 minute time period.

Table 1 shows the timeline of study activities. BrAC measurements were used to ensure participants reached safe levels to leave the lab once study activities were completed. Participants were asked to remain in the lab until BrAC was ≤ 0.02 mg/ml.

Table 1.

Timeline of Reinforcement Lab Activities

Reinforcement Laboratory
		Intensive Assessment Period
Time for Dose (min)	−5	1	2	3	4	5	6	7	8	9	10	15	20	25	30	41	55	60	81	90	100	140	180
Desire for Drug Scale	x					x				x		x	x		x			x			x	x	x
Blood sample	x	x	x	x	x	x	x	x	x	x	x	x	x		x			x			x	x	x
BP / pulse	x													x			x			x
Breathalyzer	x										x		x			x		x	x		x	x	x

Reinforcement Lab Measures.

The Desire for Drug Scale¹² assessed subjective ratings of the effect of a priming dose of alcohol (stimulation, sedation, intoxication, performance impairment), as well as one’s desire to consume alcohol and was the primary measure of reinforcement.

Pharmacokinetic (PK) assessment of ethanol

Blood samples were collected from an indwelling intravenous catheter into 4 mL vacutainer tubes containing sodium fluoride/potassium oxalate (10 mg/8 mg). Samples were collected more intensively over the initial ten minute time period post alcohol dose completion and at regular intervals thereafter (see Table. 1). Blood alcohol concentration (BAC; measured in g/dL) was determined by means of gas chromatography using flame ionization detection (FID) with a head space sampler.

PK Statistical Analysis

PK of ethanol concentration was analyzed using model-independent (noncompartmental) methods with the use of Phoenix WinNonlin® Version 6.1 (Pharsight, Mountain View, CA). Blood samples were collected according to the schedule in Table 1 to determine the area under the ethanol concentration time curve, (AUC), which approximates the total amount of ethanol present in systemic circulation and is a measure of the extent of bioavailability. AUC was calculated by the linear trapizoidal method. Key variables calculated from the BAC data included the maximum concentration (Cmax) and the time to maximum concentration (Tmax).

Statistical Analyses

Reward was calculated as the average of three questions on the Desire for Drug Scale (Cronbach’s alpha = .714): (1) “How much do you like the effects you are experiencing right now?” (2) “How stimulated do you feel right now?” (3) “How much desire do you have for alcohol right now?” Maximum reported reward (reward Cmax) and peak BAC (alcohol Cmax) were compared between pre-surgery and post-surgery using paired t-tests, while time to maximum reward (reward Tmax) and time to peak BAC (alcohol Tmax) were compared between pre-surgery and post-surgery using a Wilcoxon nonparametric tests due to positive skew. The association between reward and BAC was evaluated with a mixed-effects linear model using reward at each assessment point to predict concurrent BAC. Data were included from both the pre-surgery and post-surgery labs. Models included a random intercept, and fixed effects for reward, laboratory (pre vs. post), and a reward-by-laboratory interaction testing whether the association between reward and BAC differed from pre-surgery to post-surgery. All hypotheses were evaluated using a two-tailed significance level of .05. All analyses were performed using SPSS Version 25.0 (IBM Corp., 2017).

Results

Participants (N = 34) included 26 (76.5%) women and 8 (23.5%) men with an average age of 36.9 years (SD = 8.9, range = 21–57). Participants were predominantly Caucasian (n = 33; 97.1%) and not Hispanic/Latino (n = 32; 94.1%).

Hypothesis 1 was that compared to before surgery, participants would experience greater reward from alcohol following bariatric surgery. The maximum reported reward (reward Cmax) was statistically significantly (t[33] = −3.44; p = .002; d = .52) higher at post-surgery (M = 57.14; SD = 23.15) compared to pre-surgery (M = 46.37; SD = 17.81). In addition, the time to maximum reward (reward Tmax) was statistically significantly (Wilcoxon z = −3.07; p = .002; d = .36) shorter at post-surgery (M = 15.29 minutes; SD = 37.37) compared to pre-surgery (M = 27.35 minutes; SD = 29.34).

The second hypothesis was that peak alcohol concentration (alcohol Cmax) would be higher and time to peak alcohol concentration (alcohol Tmax) would be lower at post-surgery. Peak alcohol concentration was statistically significantly (t[33] = −6.270; p < .001; d = 1.54) higher at post-surgery (M = .1010 mg/ml; SD = .0275) compared to pre-surgery (M = .0646 mg/ml; SD = .0185). In addition, time to peak alcohol concentration (alcohol Tmax) was statistically significantly shorter at post-surgery (M = 6.80 minutes; SD = 2.89) compared to pre-surgery (M = 42.60 minutes; SD = 24.46; Wilcoxin z = −5.09; p < .001; d = 2.06).

Finally, the third hypothesis was that there would be a significant positive association between reward and BAC, and this association would be stronger for the post-surgery laboratory. As predicted, there was a statistically significant positive association between reward and BAC (est. = .709; SE = .060; p < .001). In addition, this association was found to be statistically significantly stronger for the post-surgery laboratory (est. = −.347; SE = .093; p < .001).

Discussion

There has been a paucity of clinical research investigating mechanisms that may be responsible for the increased risk for AUDs associated with bariatric surgery. Gaining a better understanding of how and why bariatric surgery patients are at greater risk for AUDs is crucial, not only because of the serious problems AUDs convey, but also because bariatric surgery patients are approximately three times more likely to die of a drug- or alcohol-related cause than the general public¹³. Increases in the rewarding effects of alcohol have been postulated as a mechanism linking bariatric surgery with increased alcohol use problems, but little empirical data in humans have examined the extent to which these changes may be associated with risk for AUD. In the current study, we replicated past findings indicating that post-bariatric surgery patients achieve higher maximum BAC, and reach their peak BAC more quickly after surgery, compared to before¹⁴. Considerable evidence has demonstrated that the faster a substance enters the central nervous system, the more rewarding, and therefore addictive, that substance will be¹⁵. The parallels of these findings in bariatric surgery patients are clear: after surgery, RYGB patients become more intoxicated considerably more rapidly than before surgery, which may ultimately play a role in putting them at greater risk for addiction to alcohol. Further, this finding has obvious implications for patients who undergo bariatric surgery and may help to explain why some individuals have been cited for driving while intoxicated after consuming what they believed to be a relatively small and safe amount of alcohol. This may be especially the case for those individuals who are less adept at identifying just how impaired they are from alcohol after bariatric surgery¹⁶.

A novel, and we believe important, finding in the current study is that after surgery patients experience alcohol-related reward differently than they do before surgery. Following bariatric surgery, patients reported greater levels of reinforcement (compared to before surgery) and they achieved this greater reinforcement sooner after receiving the dose of alcohol than they did before surgery. To our knowledge this is the first study in humans to show that after surgery, patients experience alcohol to be more reinforcing than before surgery. We speculate that the increased level, and rapidity of achieving this level of reinforcement, may play a role in the development of AUDs in post-bariatric surgery patients. This relationship has been shown in the general population: when the experience of consuming alcohol is made even more rewarding, people consume greater level of alcohol¹⁷.

Empirical study of obese and pre-bariatric surgery patients has suggested that these clinical groups may be marked by decreased dopamine 2 (D2) receptor availability in reward regions of the brain¹⁸. As a result, some patients with obesity may suffer from what some have called a “reward deficiency” phenomenon¹⁹. The theorized result of this reduced dopamine receptor availability is that these individuals tend to engage in behaviors that are more appetitive in nature in an effort to compensate for their under-stimulated reward system. While the reward deficiency is not specific to any one appetitive substance or behavior, for obese individuals the behavior that accomplishes this is commonly eating, particularly high glucose, high carbohydrate food options²⁰. However, evidence suggests that the deficiency in dopamine receptor availability may be “reset” after bariatric surgery, particularly after RYGB²¹. Neuroimaging data have shown mixed results regarding the change in striatum D1 and D2 density following RYGB²², with some data showing an increase in D1 and D2 receptor availability following RYGB, and other data showing D2 upregulation only after a prolonged (i.e., 2 years) period of time²³. This has led some researchers to speculate that the protracted period of time following surgery when D2 receptor availability may remain low presents an opportunity for the development of substance use disorders²⁴.

Additionally, we demonstrated that overall there is a significant positive correlation between level of intoxication (assessed via BAC) and reinforcement (assessed via self-report). Importantly, this association is significantly stronger after surgery compared to before. This means that following surgery, the reinforcing effects of alcohol are more tightly aligned with the patients’ BAC. Although these data do not demonstrate causality, these findings provide clues as to why some patients may struggle with alcohol problems after surgery. As an individual imbibes alcohol after surgery, he/she becomes more intoxicated than he/she previously experienced from a similar (weight-normalized) amount of alcohol. Patients who engage in similar drinking behavior before and after surgery (e.g., two glasses of wine over one hour) are likely to have even more exaggerated BAC responses following surgery, as alcohol dose functionally increases in relationship to weight loss²⁵. Importantly, the higher BACs experienced after surgery are associated with even higher levels of reinforcement, making the experience of drinking after surgery provide greater reward than it did before surgery.

While the current study provides support for the notion that PK changes after bariatric surgery may increase the likelihood of problematic drinking after surgery, we do not believe PK is the only variable that may serve this function. Social/environmental changes may serve to place post-surgical patients at risk. For example, while some patients avoid restaurants and bars before surgery, some frequent these establishments after surgery²⁶ and being in social settings where alcohol is commonly consumed may serve as a risk factor for problems with alcohol. Social/environmental changes from before to after surgery are poorly understood and the extent to which they may impact likelihood of problems with alcohol is mostly anecdotal and speculative at this point. Additionally, changes to the neurobiology of the reward system²¹ may serve to make patients more likely to develop problems of addiction after bariatric surgery. Importantly, not only do the main effects of other potential mechanisms need to be further examined, interactions between them may be equally, or possibly even more, important.

The current study has some limitations. First, the sample size is relatively modest. In spite of this, we found significant effects in the hypothesized directions. Second, the current findings were limited to the laboratory. The dose of alcohol was weight-based and certainly may not reflect the real-world drinking practices of post-bariatric surgery patients. Similarly, the assessment of reinforcement may have been impacted by the artificiality of a laboratory assessment. It is possible that the reinforcing value of alcohol may depend upon drink type, dose, and/or the social/environmental context in which the patient is drinking. Naturalistic, real-time assessments of drinking behavior and the reinforcing effects of alcohol could provide an advancement of our understanding of alcohol consumption and problematic drinking behavior in post-surgery patients. Also, all data were collected using RYGB patients. Therefore the results cannot be generalized to those undergoing other bariatric procedures, such as laparoscopic sleeve gastrectomy. Finally, one year after surgery is before most patients demonstrate problems with alcohol^2,5. Importantly however, the current study demonstrates that two potentially mechanistic variables in the development of AUD (i.e., pharmacokinetics and reinforcement) change with appropriate temporal precedence and in a manner consistent with the model proposed by Ivezaj and colleagues⁶.

Conclusion

Taken together, the current study demonstrates that after the same weight-based dose of alcohol, post-bariatric surgery patients become more intoxicated in less time, they report higher levels of reinforcement from alcohol, they experience these higher reinforcing effects more quickly, and their level of intoxication and how reinforcing they find the alcohol to be are more closely associated. In total, these findings support the notion that PK changes after bariatric surgery may play a role in the increased reinforcing value of alcohol following RYGB and ultimately the development of AUD.

Highlights.

• While a number of causal variables have been postulated to predict increased risk for alcohol use disorders in weight loss surgery patients, data are lacking in this area.

• We examined the impact of the changing pharmacokinetic effects of alcohol as well as how reinforcing alcohol is to weight loss surgery patients.

• We found that both the pharmacokinetic effects of alcohol as well as how reinforcing alcohol was to patients changed from before to after surgery and that these variables are more closely associated with each other after weight loss surgery.