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. Author manuscript; available in PMC: 2025 Mar 3.
Published in final edited form as: Psychopharmacology (Berl). 2023 Sep 23;241(1):109–118. doi: 10.1007/s00213-023-06467-8

Expectancy for Adderall influences subjective mood and drug effects regardless of concurrent caffeine ingestion: A randomized controlled trial

Alison Looby 1, Annalisa V Piccorelli 2, Lauren Zimmerman 1, Caitlin Falco 1, Nicholas R Livingston 1, Cody Akin 1, Samuel Benton 1, Laura M Juliano 3
PMCID: PMC11874872  NIHMSID: NIHMS2055275  PMID: 37740001

Abstract

Rationale

Nonmedical prescription stimulant use (NPS; use without a prescription or in ways other than prescribed) is common among college students. Despite the potential for negative consequences, students continue engaging in NPS for cognitive enhancement purposes, which may be maintained by expectancy and placebo effects.

Objectives

This study examined if a placebo administered under the guise of Adderall influenced subjective mood/drug effects and cognitive performance. Furthermore, this study examined if concurrent caffeine ingestion incrementally enhanced Adderall-related placebo effects.

Methods

Undergraduate students with features that put them at elevated risk for NPS (N = 121) completed measures of mood and drug effects and cognitive assessments on two separate laboratory visits in this parallel randomized controlled trial. Visit 1 was a baseline control visit, on which no drug was expected or received. On visit 2, subjects were randomized to: (1) expect/receive no drug (control); (2) expect Adderall/receive placebo; or (3) expect Adderall/receive 200 mg caffeine.

Results

There were several significant condition × visit interactions for subjective effects, including amphetamine effects, energy and efficiency effects, and feeling high. In most cases, participants who expected Adderall reported greater positive subjective effects on visit 2 compared to controls; however, there were generally not incremental enhancements for those ingesting caffeine compared to placebo. There were no significant effects for any cognitive tests.

Conclusions

Expectation for prescription stimulant effects influenced subjective outcomes in a sample of high-risk college students. These findings may inform expectancy challenge interventions to reduce NPS.

Trial registration

ClinicalTrials.gov Identifier: NCT03648684.

Keywords: Prescription stimulants, Caffeine, Expectancy, Cognition, College students, Placebo effects

Introduction

Medications for attention-deficit hyperactivity disorder (ADHD), including methylphenidate (Ritalin, Concerta) and dextroamphetamine-amphetamine combination (Adderall), are commonly used nonmedically by individuals without a prescription. Nonmedical prescription stimulant use (NPS; use without a prescription or in ways other than prescribed) is particularly prevalent among college students (Bavarian et al. 2013; Faraone et al. 2020; Wong et al. 2022), with an estimated lifetime rate of 17% among US students (Benson et al. 2015). Furthermore, rates of college student NPS have increased in recent years, despite simultaneous decreases or leveling out of misuse of other prescription medications (e.g., opioids; McCabe et al. 2014). Although college students tend to minimize the dangers of NPS (Desantis and Hane 2010), it is associated with myriad negative consequences (Arria et al. 2008, 2013; Faraone et al. 2020; McCabe and Teter 2007), and serious psychological and physical symptoms including depression, elevated body temperature, arrhythmia, cardiovascular failure, and seizures (National Institute on Drug Abuse 2020). Given these potential consequences, and that NPS is the second most common illicit drug use behavior by college students (Schulenberg et al. 2021), the need to further understand mechanisms driving use to inform intervention efforts is warranted (Arria and Dupont 2010; Butler et al. 2021; Faraone et al. 2020; Rabiner 2013).

College students most commonly cite academic and cognitive enhancement motives for NPS, including improving concentration and alertness (Benson et al. 2015; Weyandt et al. 2009). Though cognitive enhancement motives are reported by nearly all users (Kilwein et al. 2016; Thiel et al. 2019), there is not a conclusive demonstrated cognitive enhancement effect of prescription stimulants for individuals without ADHD (see Edinoff et al. 2022). Using a balanced placebo design, Cropsey et al. (2017) found that enhanced cognitive performance following prescription stimulant administration was entirely explained by expectation. Furthermore, a longitudinal study found that initiation of NPS does not convey significant GPA advantage or academic achievement over non-using peers (Arria et al. 2017). These findings highlight the unfavorable benefit-to-risk ratio likely experienced by many users, as the perceived cognitive benefits of use are likely not outweighing the potential for harm.

It is important to consider the role that expectancy and placebo effects play in the initiation and maintenance of NPS. College students tend to hold strong expectancies, or consequence-oriented beliefs, about the cognitive enhancement effects of prescription stimulants (Holt and Looby 2018; Looby et al. 2013), and several studies demonstrate placebo effects related to prescription stimulant use (Cropsey et al. 2017; Looby and Earleywine 2011; Volkow et al. 2006; Weyandt et al. 2018). Individuals tend to behave in accordance with their expectations (Winkler and Hermann 2019); thus, if students hold strong cognitive enhancement expectancies for NPS, their experience during use is likely to be such that they report enhanced alertness and concentration, further strengthening their expectancies and maintaining the likelihood of future use. Furthermore, there is good evidence that students who engage in NPS report academic and executive functioning difficulties, and consequently may be most likely to seek out prescription stimulants to overcome deficits in cognitive abilities (Looby et al. 2015; Looby and Sant’Ana 2018; Munro et al. 2017; Sattler et al. 2014; Wilens et al. 2017). Therefore, NPS appears to be largely driven by strong positive expectancies for the effects of stimulant medication, combined with perceived cognitive deficits for which they are motivated to compensate.

From this understanding, challenging positive cognitive enhancement expectancies may be helpful in deterring NPS. One study by Looby and colleagues (2013) attempted to challenge these expectancies by demonstrating the existence of placebo effects for mood and cognitive enhancement in students at-risk for NPS. Though positive expectancies were weakened following the intervention, NPS was not successfully prevented. It is possible that attempts to weaken cognitive enhancement expectancies for NPS may not be sufficient without simultaneously providing an alternative means of coping with cognitive or academic difficulties. Given that students who engage in NPS tend to report poor self-efficacy for academic abilities (Looby et al. 2015), they may be particularly prone to seeking external enhancement or support in the form of drug use. It is interesting to consider why students may preferentially choose prescription stimulants instead of other drugs that may confer similar perceived benefits without the large potential for associated harms, such as caffeine. Unlike NPS, caffeine use is relatively safe, legal, and has more consistently demonstrated efficacy in producing enhancement in certain areas of cognition, including subjective alertness, vigilance, and reaction time at low (40 mg) to moderate (300 mg) doses (Giles et al. 2012; McLellan et al. 2016). If NPS is at least in part driven by desire for external cognitive enhancement, promotion of caffeine as a safer, legal, and more effective means of enhancing cognition may be one avenue of decreasing NPS among college students. Yet, knowing that placebo effects exist for prescription stimulants, it is important to further understand the incremental benefit of caffeine use on mood and cognition.

To date, little comparative research has been conducted on caffeine and prescription stimulants among college students. A recent experimental study found that caffeine produced mood and drug enhancement effects in college students compared to placebo, and these effects were further strengthened when students expected to receive Adderall (Looby et al. 2022). However, lack of a control group that did not expect to receive any drug limited the ability to fully examine the impact of expectancy versus pharmacology. Thus, the current study utilized a mixed between (3 conditions)—and within (2 visits)—subject design to test whether subjective mood/drug effects and cognition are enhanced following the expectation to receive Adderall, and whether these effects are further enhanced following ingestion of 200 mg caffeine.

Method

Participants

Undergraduates attending a Rocky Mountain West university were recruited via targeted emails, flyers, and via a psychology department subject pool. An online screening survey assessed eligibility, including age between 18 and 25 years, current undergraduate enrollment, past-month caffeine use with no history of adverse effects, no lifetime history of using a prescription stimulant for any purpose (to enhance the credibility of the placebo), and reported willingness to ingest a prescription stimulant or caffeine in the laboratory. Participants also had to report at least two risk factors for NPS that are consistently supported in the literature (Faraone et al. 2020; Herman-Stahl et al. 2007; McCabe et al. 2005, 2006; Teter et al. 2005): (1) Greek-life involvement, (2) GPA below 3.5, (3) past-two-week binge drinking, (4) past-month cannabis use, and (5) white European descent or male sex. We recruited at-risk participants to best generalize our results to the population of NPS users and to assess whether they would initiate NPS in the future, which is part of a larger investigation. Participants were excluded if they self-reported a current psychiatric diagnosis or psychiatric medication use, daily nicotine use, history of adverse reactions to caffeine, history of cardiac problems, diabetes or regular hypoglycemia (due to fasting concerns), or current pregnancy or breastfeeding. Participants (N = 131; 50.4% male) enrolled in the study were predominantly White (90.0%) and non-Hispanic (89.9%), with a mean age of 20.05 years (SD = 1.53).

Measures

Substance Use Questionnaire

Participants reported frequency of past-month use of nicotine, alcohol, caffeine, and cannabis; and presence of lifetime and past-month use of cocaine, methamphetamine, hallucinogens, heroin, and other recreational opioids. This measure was investigator-generated, but has been used in prior research (Looby et al. 2022). Denial of lifetime prescription stimulant use for any purpose was also confirmed.

Addiction Research Center Inventory (ARCI)

The 49-item short form of the ARCI (Martin et al. 1971) assessed acute drug-related effects. Participants responded to each true/false item according to whether they presently experienced each effect. Four subscales from the ARCI were examined in the current study: euphoria (MBG scale; α = 0.85), intellectual energy and efficiency (BG scale; α = 0.70), amphetamine effects (AMPH scale; α = 0.79), and sedation (PCAG scale; α = 0.79). The ARCI subscales have been found sensitive to placebo-related stimulant effects among undergraduates (Looby and Earleywine 2011).

Visual Analogue Scales (VAS)

Separate VAS scales were used to assess seven current mood states: “good,” “bad,” “attentive,” “focused,” “high,” “stimulated,” and “motivated.” Each scale consisted of a 100 mm line, anchored at each end by not at all and extremely. Participants were instructed to complete each scale to represent how they were feeling at that moment. Similar VASs have been found sensitive to placebo-related stimulant effects among undergraduates (Looby and Earleywine 2011).

Cognitive assessments

The Selective Reminding Test (SRT; Hannay and Levin 1985; Larrabee et al. 2000) was used to assess learning and memory. Participants were read a list of 12 unrelated words across six trials. Participants immediately recalled as many words as they could from the entire list after each trial; however, each subsequent reading of the list included only words that were not recalled by the participant on the prior trial. Participants also recalled the words after a 30-min delay. Outcomes of interest included total words recalled across the six trials, short-term recall (i.e., the number of words recalled inconsistently, which have not entered long-term storage), consistent long-term retrieval (i.e., the number of words continuously recalled on all subsequent trials), and total words recalled following delay. The Symbol Search subtest from the Wechsler Adult Intelligence Scale-IV (Wechsler 2008) assessed processing speed. For each item, participants were shown two target symbols and asked to denote whether either one was identical to five alternative symbols. The number of correct responses minus number of errors in 120 s was the outcome for this measure. The Verbal Fluency subtest from the Delis-Kaplan Executive Function System (Delis et al. 2001) measures verbal behavioral productivity, whereby participants have 60 s to generate words beginning with a specific letter. Total generated words across three letters was the outcome measured. The Conners’ Continuous Performance Test 3 (Conners 2014) is a computer-administered test assessing inattention, sustained attention, and impulsivity. Participants were instructed to press a computer key quickly upon the appearance of a stimulus on the computer screen, and to inhibit responding in the presence of a specific target. Outcomes of interest included omission errors, commission errors, and change in response speed across the test duration (i.e., hit reaction time block change). The Paced Auditory Serial Addition Test (PASAT; Gronwall 1977) assessed working memory, divided attention, and information processing speed. This test was computer-administered using Inquisit 5. Participants listened to an auditory presentation of digits and consecutively added pairs of numbers such that each number was added to the one immediately prior. Participants selected the current sum from a circle of visually presented numbers (1–18). Participants completed four trials of 61 items; the interstimulus interval of auditory digit presentation on each trial was incrementally shortened (i.e., 2400 ms, 2000 ms, 1600 ms, 1200 ms). Total number of correct responses summed across the four trials was used as the outcome for this measure. Finally, the Stroop Test (Stroop 1935) assessed selective attention and ability to inhibit cognitive interference. This test was also computer-administered using Inquisit 5. Participants were shown words that were color names (e.g., “red”) that were printed in either congruent or incongruent font colors. Participants used the keyboard to indicate the font color the word was displayed in as quickly as possible across 85 trials. The outcome measure was an interference score, calculated as the mean response time to the incongruent words minus the mean response to the congruent words.

Manipulation check

Participants who were told to expect Adderall were asked at the end of the study to rate along a 10-point scale (0 = not at all; 9 = extremely) to what extent they believed they received Adderall.

Procedure

This study was approved by the University of Wyoming Institutional Review Board. We use the CONSORT reporting guidelines to present data from this trial (Schulz et al. 2010). Data collection occurred between Fall 2018 and Spring 2020; see Supplemental Table 1 for the CONSORT flow diagram. Eligible individuals were invited to participate in a study assessing the effects of stimulant medication on mood and cognition. They were informed that they would participate in two laboratory visits spaced 2 to 3 weeks apart. On each visit they would complete measures of mood and drug effects, plus a battery of cognitive tests, and they may be asked to ingest 10 mg Adderall on one visit. Within subjects, study visits were completed at the same time in the morning, following an overnight fast for at least 8 h. Upon arrival at the laboratory on each visit, participants self-reported their last use of food and beverage, alcohol, caffeine, nicotine, and illicit drugs to verify their abstention.

Participants were randomized via computerized random number generator to one of three conditions based on manipulation that was delivered during the second visit as follows: expect/receive no drug (control group; N = 40), expect Adderall/receive placebo (N = 40), or expect Adderall/receive caffeine (N = 41). Block randomization was used to evenly balance biological sex across conditions. The lead author was responsible for enrolling and randomizing participants. At the start of visit 1, participants provided informed consent and completed demographic and substance use questionnaires, as well as pre-test ARCI and VAS measures. All subjects were then informed they would not receive any drug on that visit. Following a 20-min delay to keep study protocol consistent with visit 2, participants completed the cognitive tests in a counterbalanced order. Afterwards, they completed post-test ARCI and VAS measures. Participants were reminded to return for their second visit and compensated with cash or research credit to be applied to a psychology course. On visit 2, participants again completed pre-test ARCI and VAS measures. Participants in the control group were informed that they would not receive any drug during that visit. Participants in the expect Adderral/receive placebo condition were told they would receive 10 mg Adderall, though they truly ingested a placebo pill. Participants in the expect Adderall/receive caffeine condition were told they would receive 10 mg Adderall, though they truly ingested a 200 mg caffeine pill. Pills were disguised in a capsule that mimicked the appearance of a mixed amphetamine salts capsule (i.e., generic Adderall); caffeine and placebo pills were identical in appearance, and both the participants and the researcher were blind to type of substance ingested by subjects expecting Adderall. Participants were not provided with additional details regarding the effects of Adderall in order to examine the effects of their pre-existing outcome expectations on mood and cognition. Following a 20-min delay to allow for caffeine absorption (Smith 2002), participants again completed cognitive tests, using alternate forms where available, followed by post-test ARCI and VAS measures. Participants in the expect Adderall conditions then completed the manipulation check to assess the credibility of the deception, followed by a debriefing of the true substance consumed. Participants were again compensated with either cash or psychology research credit.

Data analysis

Repeated measures analyses of covariance (ANCOVAs) examined the 3 (condition) × 2 (visit) interactions for post-test mood and drug effects while controlling for pre-test measures of that effect on both visits. Pre-test scores were entered as unique covariates given that they were not highly correlated across days (0.36 < rs < 0.69). Repeated measures analyses of variance (ANOVAs) were used to examine the condition × visit interaction on cognitive performance. Where significant interactive effects emerged, parameter estimates were examined for between-group differences. Significance was evaluated at p < 0.05. A post-hoc power analysis in G*Power indicates that our analyses were sufficiently powered (power = 0.99) to detect significance for medium-sized effects.

Results

Ten participants did not return for visit 2, limiting the analytic sample and number of participants randomized to N = 121. Non-completers did not significantly differ from completers on any demographic variable. There were no significant group differences on demographic variables (see Table 1).

Table 1.

Demographic information for the total sample and by group

Control (N = 40) Expect Adderall/ receive placebo (N = 40) Expect Adderall/ receive caffeine (N = 41) Total sample (N = 121)
M (SD) or % Fχ2 p
Age 20.10 (1.65) 20.18 (1.55) 20.05 (1.43) 20.11 (1.53) 0.07 .94
Male gender 52.5% 50.0% 46.3% 49.6% 0.31 .86
White race 90.0% 87.5% 90% 89.2% 0.17 .92
Years of education 13.40 (1.19) 13.50 (1.06) 13.43 (0.90) 13.44 (1.05) 0.10 .91
Cumulative GPA 3.27 (0.52) 3.27 (0.70) 3.24 (0.47) 3.26 (0.57) 0.04 .97
Greek involvement 17.5% 15.0% 22.5% 18.3% 0.78 .68
Caffeine use 331.10 (254.40) 303.31 (336.17) 249.85 (230.26) 294.00 (276.35) 0.90 .41
Binge drinking 52.5% 55.0% 70.7% 59.5% 3.30 .19
Cannabis use 32.5% 25.0% 36.6% 31.4% 1.30 .52
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Caffeine use refers to past-month use in ounces. Binge drinking refers to the percentage of participants who endorsed past-two-week binge drinking (i.e., 4 + /5 + drinks for women/men in a single drinking period). Cannabis use refers to the percentage of participants who endorsed past-month cannabis use

Credibility of the deception

The belief that subjects ingested Adderall was generally moderate. Mean believability scores were 6.38 (SD = 2.00) for subjects receiving a placebo, and 5.90 (SD = 2.70) for subjects receiving caffeine. There was not a significant difference between conditions [t (73.66) = 0.90, p = 0.37].

Subjective effects

There were significant condition × visit interactions on the four ARCI subscales assessed at post-test, while controlling for pre-test measures (see Table 2). For amphetamine effects, both expect Adderall/placebo (B = 1.64, p < 0.001, ƞ2p = 0.10) and expect Adderall/receive caffeine (B = 1.99, p < 0.001, ƞ2p = 0.15) subjects reported significantly increased effects across visits compared to the control group, who had decreases in effect across visits; however, there were no significant differences between the two expect Adderall groups. A similar pattern was found for other effects: compared to controls who decreased in effect across visits, expect Adderall/receive placebo subjects reported increased euphoria effects (B = 1.37, p = 0.02, ƞ2p = 0.05) and intellectual energy and efficiency effects (B = 1.33, p = 0.01, ƞ2p = 0.06) across visits, and expect Adderall/receive caffeine subjects reported increased euphoria effects (B = 2.23, p < 0.001, ƞ2p = 0.12) and intellectual energy and efficiency effects (B = 2.26, p < 0.001, ƞ2p = 0.15) across visits; yet there were no differences between the expect Adderral groups on either of these measures. Finally, expect Adderall/receive caffeine subjects demonstrated a greater decrease in sedation effects across visits compared to expect Adderall/receive placebo subjects (B = 1.45, p = 0.01, ƞ2p = 0.05), and a significant difference from control subjects who increased in sedation effects across visits (B = − 1.88, p = 0.001, ƞ2p = 0.09).

Table 2.

Group × visit interaction effects for subjective mood and drug effects

Control (N = 40) Expect Adderall/ receive placebo (N = 40) Expect Adderall/ receive caffeine (N = 41)
EMM (SE) F p ƞ2p
Euphoria (MBG) 6.48 .002 0.10
 Visit 1 3.02 (0.32) 3.06 (0.32) 2.82 (0.31)
 Visit 2 2.47 (0.41) 3.84 (0.41) 4.70 (0.39)
Sedation (PCAG) 3.96 .022 0.06
 Visit 1 4.29 (0.40) 5.40 (0.40) 4.40 (0.39)
 Visit 2 5.39 (0.41) 4.96 (0.40) 3.51 (0.40)
Intellectual energy (BG) 9.33 < .001 0.14
 Visit 1 5.05 (0.30) 4.30 (0.30) 4.86 (0.30)
 Visit 2 4.26 (0.36) 5.58 (0.36) 6.52 (0.36)
Amphetamine (AMPH) 9.52 < .001 0.14
 Visit 1 2.38 (0.23) 2.06 (0.23) 2.23 (0.22)
 Visit 2 1.70 (0.32) 3.34 (0.32) 3.69 (0.31)
Feeling good 1.30 .276 0.02
 Visit 1 59.61 (2.69) 56.72 (2.68) 58.43 (2.65)
 Visit 2 58.79 (2.70) 61.55 (2.70) 64.25 (2.67)
Feeling bad 0.81 .449 0.01
 Visit 1 26.15 (3.07) 26.41 (3.06) 23.38 (3.03)
 Visit 2 26.51 (2.99) 20.75 (2.98) 18.84 (2.96)
Feeling attentive 1.63 .201 0.03
 Visit 1 59.24 (3.14) 56.03 (3.12) 59.04 (3.13)
 Visit 2 55.44 (3.20) 59.28 (3.18) 63.77 (3.18)
Feeling focused 1.13 .327 0.02
 Visit 1 58.84 (3.01) 59.43 (2.99) 59.59 (2.99)
 Visit 2 55.36 (3.42) 59.72 (3.40) 63.63 (3.40)
Feeling high 7.86 < .001 0.12
 Visit 1 7.83 (1.58) 7.52 (1.62) 7.92 (1.57)
 Visit 2 7.56 (2.56) 22.33 (2.62) 20.03 (2.54)
Feeling stimulated 1.90 .154 0.03
 Visit 1 38.28 (4.14) 30.53 (4.14) 36.55 (4.07)
 Visit 2 36.55 (3.87) 36.29 (3.86) 48.26 (3.81)
Feeling motivated 3.22 .044 0.05
 Visit 1 57.67 (3.39) 53.00 (3.37) 57.13 (3.34)
 Visit 2 52.98 (3.07) 59.49 (3.05) 64.57 (3.03)
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Estimated marginal means (EMMs) indicate post-test responses by visit while controlling for pre-test scores. Visit 1 was a control visit where no drug was expected or received. On visit 2, participants completed pre-test measures prior to learning of their drug condition; post-test measures were completed approximately 80 min post-drug administration

There were significant condition × visit interactions on two VAS measures: feeling high and feeling motivated (see Table 2). Both expect Adderall/receive placebo (B = 14.77, p < 0.001, ƞ2p = 0.12) and expect Adderall/receive caffeine (B = 12.47, p < 0.001, ƞ2p = 0.09) subjects reported increases in feeling high across visits compared to controls, but did not differ from one another. Compared to control subjects who declined in motivation across visits, expect Adderall/receive caffeine Table 1 Demographic information for the total sample and by group subjects reported an increase in feeling motivated across visits (B = 11.59, p = 0.01, ƞ2p = 0.06), but expect Adderall/receive placebo subjects did not significantly differ from either group despite motivation levels increasing across visits (vs control: B = 6.51, p = 0.14, ƞ2p = 0.02; vs caffeine: (B = − 5.08, p = 0.24, ƞ2p = 0.01)).

Cognitive performance

There was a significant condition × visit interaction for only Symbol Search (see Table 3). Though expect Adderall/receive placebo subjects evidenced the greatest increase in performance across time, there were no significant group differences upon examination of the parameter estimates.

Table 3.

Group × visit interaction effects for cognitive performance

Control (N = 40) Expect Adderall/ receive placebo (N = 40) Expect Adderall/ receive caffeine (N = 41)
M (SE) F p ƞ2p
SRT: Immediate recall 0.08 .927 0.00
 Visit 1 55.23 (1.21) 53.15 (1.21) 55.03 (1.19)
 Visit 2 56.13 (1.13) 53.60 (1.13) 55.54 (1.12)
SRT: Short-term recall 2.80 .065 0.05
 Visit 1 8.23 (0.82) 7.33 (0.83) 6.88 (0.81)
 Visit 2 6.83 (0.76) 8.56 (0.77) 7.59 (0.75)
SRT: Long-term recall 0.31 .734 0.01
 Visit 1 41.60 (1.93) 38.87 (1.95) 40.66 (1.90)
 Visit 2 42.13 (1.84) 39.10 (1.86) 42.78 (1.81)
SRT: Delayed recall 0.75 .474 0.02
 Visit 1 8.56 (0.41) 7.97 (0.42) 8.43 (0.41)
 Visit 2 8.53 (0.42) 7.68 (0.43) 7.80 (0.43)
Symbol search 4.70 .011 0.07
 Visit 1 35.56 (1.03) 34.25 (1.03) 35.59 (1.02)
 Visit 2 40.83 (1.08) 42.20 (1.08) 40.02 (1.07)
Verbal fluency 0.01 .990 0.00
 Visit 1 35.65 (1.53) 36.43 (1.53) 38.02 (1.51)
 Visit 2 37.38 (1.52) 37.95 (1.52) 39.56 (1.51)
CPT: Omission errors 1.81 .169 0.03
 Visit 1 48.23 (0.91) 46.58 (0.91) 46.61 (0.90)
 Visit 2 48.70 (1.05) 47.53 (1.05) 45.73 (1.03)
CPT: Commission errors 1.40 .250 0.02
 Visit 1 53.10 (1.48) 54.10 (1.48) 51.73 (1.47)
 Visit 2 50.85 (1.61) 51.88 (1.61) 47.32 (1.59)
CPT: HRT block change 0.25 .778 0.00
 Visit 1 52.55 (1.08) 51.20 (1.08) 50.66 (1.06)
 Visit 2 51.10 (1.27) 49.28 (1.27) 50.29 (1.26)
PASAT 0.35 .708 0.01
 Visit 1 67.95 (4.13) 61.65 (4.02) 67.71 (3.97)
 Visit 2 94.18 (4.97) 89.20 (4.84) 97.10 (4.78)
Stroop: Interference 0.17 .844 0.00
 Visit 1 171.01 (25.55) 188.91 (25.23) 184.58 (24.92)
 Visit 2 141.53 (21.74) 180.28 (21.47) 159.31 (21.20)
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Visit 1 was a control visit where no drug was expected or received. On visit 2, participants completed cognitive assessments between approximately 20–80 min post-drug administration. SRT Selective Reminding Test, CPT Continuous Performance Test, HRT hit response time. CPT scores reflect t-scores

Discussion

Because college students report strong motivation to engage in NPS for cognitive enhancement despite little supportive evidence of its efficacy, it is imperative to understand how expectation for a prescription stimulant affects both subjective and objective outcomes. The present results add to the literature demonstrating the presence of prescription stimulant-related expectancy effects on subjective measures of mood and drug effects. However, there were no placebo-related enhancements in cognitive performance, highlighting the unique influence that expectancy appears to exert on subjective compared to objective outcomes (Looby and Earleywine 2011; Schwarz and Buchel 2015). This study also investigated whether expectation for prescription stimulant effects can be enhanced via pharmacological effects of ingested caffeine. Contrary to predictions, with few exceptions, the addition of caffeine to the Adderall expectancy manipulation did not enhance effects.

Several studies now clearly demonstrate the role that expectancy plays in the subjective experience of prescription stimulant use, as the presence of mood- and drug effect-related placebo effects are consistently demonstrated (e.g., Cropsey et al. 2017; Looby and Earleywine 2011; Looby et al. 2022). In the present study, placebo effects for Adderall continued to emerge on several indices, predominantly surrounding the experience of cognitive (e.g., intellectual energy and efficiency effects; amphetamine effects, such as sharper memory) and mood enhancement (e.g., feeling high; euphoria). Surprisingly, there were no significant effects for some of the other related measures, such as feeling stimulated, attentive, or focused. However, examination of Table 2 demonstrates that while control subjects generally decreased across visits on these measures, both groups expecting Adderall increased, though changes in these effects were somewhat small, particularly when considering the size of the standard deviations. Participants receiving caffeine reported stronger motivation and less sedation than those receiving placebo. Yet, no other group differences were found on any other subjective measure, suggesting that there does not seem to be a generalized additive effect of combining expectancy for Adderall with the pharmacological effects of a moderate dose of caffeine. These results differ from prior work finding stronger subjective enhancements among college students expecting Adderall who ingested caffeine compared to those ingesting a placebo substance (Looby et al. 2022). Participants in the prior work expected either caffeine or Adderall, without the possibility of expecting no drug as in the present study. This expectation for any stimulant drug in general may have enhanced believability of the manipulation and strengthened Adderall-related placebo effects, particularly when participants noticed physiological caffeine effects.

Similar to other research (Looby and Earleywine 2011; Looby et al. 2022), no group differences were found on any cognitive test, which assessed a broad range of cognitive functions including facets of memory, psychomotor speed, attention, response inhibition, and verbal fluency. Yet, it is important to note that other research has demonstrated prescription stimulant expectancy-related enhancements in particular areas of cognitive performance that showed no significant effects in the present study, including working memory (Looby et al. 2022), long-term memory, and attention (Cropsey et al. 2017). These studies varied in rigor of methodology and in subject selection, which may have contributed to differences in results. Nevertheless, it seems clear that prescription stimulant-related expectancy effects inconsistently convey objective cognitive enhancements, certainly in comparison to the more consistent subjective mood effects.

Contrary to predictions, caffeine did not enhance the effects of Adderall expectancy on cognitive outcomes. There is evidence that caffeine can improve cognitive performance especially when baseline performance is degraded by fatigue, sleep deprivation, or acute caffeine abstinence among regular users (James and Rogers 2005; Juliano et al. 2014), as well as among light or infrequent caffeine users (Lyvers et al. 2004). Caffeine-related enhancements may have been tempered among our participants who had varied caffeine use and who concurrently were expecting Adderall. Future research could assess caffeine use with greater precision to statistically control for baseline use. Furthermore, other measures of cognitive performance may be more sensitive to the effects of caffeine (e.g., vigilance, simple reaction time). It is also possible that the administration of caffeine could have resulted in greater credibility of the expectancy manipulation if subjects perceived caffeine’s mild stimulating effects as Adderall. However, manipulation check scores suggest that caffeine administration did not increase the believability of the manipulation. However, it should be noted that it is not known what subjects believed at the time they were engaging in the subjective and cognitive assessments.

The present study suggests that placebo effects related to mood and perceived drug effects are likely to be experienced by college students following expected Adderall ingestion. This may maintain NPS, as students perceive these enhancements following use, outside of pharmacological effects. This information may be used to challenge the expectations that students have for prescription stimulants in an effort to decrease NPS, perhaps via expectancy challenge interventions. This study did not provide strong support for the use of caffeine as an alternative to prescription stimulants, as 200 mg of caffeine did not incrementally enhance cognition above and beyond Adderall expectation, nor did it produce enhancement on any cognitive performance measure.

Several important limitations warrant consideration. We studied these effects in a homogenous sample of predominantly white college students from a single university. One eligibility criterion used for recruitment was a demographic risk factor related to male sex or white race, which likely restricted demographic diversity. Importantly, only one of these risk factors could be used for eligibility determination, and the individual needed to endorse a subsequent risk factor as well. Furthermore, our sample was balanced across biological sex, representative of the student population where this study took place, and is likely representative of NPS users, who are also largely white (Benson et al. 2015). Despite this, our results may not generalize to more diverse samples nor to non-college individuals. Although we recruited at-risk participants, they all were prescription stimulant-naïve, so we do not know if these effects would persist in those with a history of use. Additionally, our results must be understood in the context of expectation for 10 mg Adderall and the pharmacological effects of a 200 mg caffeine pill; different patterns of results may emerge at different doses and for different types of prescription stimulants. Furthermore, though peak plasma levels of caffeine in humans occur 15–45 min post-ingestion (Smith 2002), it is possible that caffeine absorption varied between subjects, resulting in differential caffeine effects across the cognitive battery. To account for this, we counterbalanced the order of test administration, though it is possible that caffeine effects may have been weaker due to the brief time allotted for absorption. Finally, we were unable to biologically verify overnight abstinence from psychoactive drugs, and we relied on self-report to rule-out psychiatric diagnoses.

Nevertheless, the current study adds to existing literature demonstrating the effect of prescription stimulant-related placebo effects on subjective measures of mood and perceived drug effects. Specifically, expecting to receive a prescription stimulant resulted in reported enhancements in intellectual energy/efficiency, amphetamine effects, and positive mood. Importantly, these findings provide a potential avenue for intervention and/or prevention via expectancy challenge interventions, as correcting expectations for positive prescription stimulant effects may lead to reductions in placebo effects and lower levels of NPS.

Supplementary Material

Supplemental Table 1

Funding

This work was supported by an Institutional Development Award (IDeA) by the National Institute of General Medical Sciences (2P20GM103432).

Footnotes

Conflict of interest The authors declare no competing interests.

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00213-023-06467-8.

Declarations

Disclaimer The content is the authors’ responsibility and does not necessarily represent the views of NIGMS.

Data Availability

The data that support the findings of this study are available from the corresponding author, AL, upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Table 1
NIHMS2055275-supplement-Supplemental_Table_1.pdf (241.1KB, pdf)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, AL, upon reasonable request.

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