Elsevier

Drug and Alcohol Dependence

Volume 178, 1 September 2017, Pages 302-309
Drug and Alcohol Dependence

Full length article
Mixed-amphetamine salts expectancies among college students: Is stimulant induced cognitive enhancement a placebo effect?

https://doi.org/10.1016/j.drugalcdep.2017.05.024Get rights and content

Highlights

  • Non-medical use of prescription stimulants among college students is increasing.

  • Participants were given mixed amphetamine salts or placebo in four sessions.

  • Performed unable to identify whether they received stimulant or placebo.

  • Participants showed improvement on only 2 of 31 subtests during active medication.

  • Expectancies rather than non-medical use of stimulants enhance cognition.

Abstract

Introduction

Non-medical use of prescription stimulants for cognitive enhancement in college students is increasing, despite evidence showing little benefit in non-clinical populations. The balanced placebo design (BPD) was used to independently evaluate the pharmacologic versus expectancy effects of mixed amphetamine salts on cognitive performance among a non-clinical sample of college-aged students.

Method

Participants were screened and excluded for ADHD and other psychopathologies. A non-clinical sample (N = 32) completed four two-hour laboratory sessions and were administered a neurocognitive battery in each session. Medication Assignment (10 mg mixed-amphetamine salt (Adderall™) versus placebo) was crossed with Instructional Set (deception versus truth). A within-subjects design was used, such that all participants experienced each of the four conditions of the BPD during one of the four laboratory sessions.

Results

Participants performed no better than chance in identifying whether they received stimulant or placebo (Belief about Medication Assignment; 47% agreement; κ = −0.047, p = 0.590). Participants showed improvement on only two of 31 subtests during active medication. Expecting and receiving stimulants was associated with improved cognitive performance. However, expecting placebo was associated with worse cognitive performance, regardless of the type of medication given.

Discussion

This study demonstrated that although non-medical use of stimulants does not enhance cognition, expectancies prominently influence cognitive performance. Participants who believed they received active medication both subjectively rated themselves as performing better and objectively performed better on a minority of subtests, independent of medication state.

Introduction

Non-medical use of prescription stimulant medications among student populations is increasing (Swanson and Volkow, 2008, Forlini and Racine, 2009). Youth exaggerate the cognitive enhancing value of prescription stimulants and overestimate the frequency with which fellow students use these medications (White et al., 2006). College students estimate that up to 70% of their fellow students currently use stimulants to augment academic performance when only approximately 4.1% report last year use and 2.1% last month use (McCabe, 2008, McCabe et al., 2005, White et al., 2006). Low performing students report the highest use of cognitive enhancing medications (Caviola and Faber, 2015; Repantis et al., 2011); however, positive cognitive improvement studies have shown limited benefits.

Comprehensive reviews of controlled trials exploring cognitive enhancement in healthy subjects dosed with methylphenidate or amphetamine salts found an equivalent degree of null findings and limited improvement on select measures (Ilieva et al., 2015, Franke et al., 2014). Similarly, cognitive enhancement studies have shown limited benefits on simple attention tasks, but no consistent benefit for complex learning tasks (Ilieva et al., 2015, Linssen et al., 2014, Ilieva et al., 2013). Attention Deficit Hyperactivity Disorder (ADHD) was not carefully screened out in many of these studies and noted improvements may have been attributable to increased motivation and energy rather than enhanced episodic memory (Ilieva et al., 2015).

The use of stimulants among non-clinical students poses health risks (Franke et al., 2014, Linssen et al., 2014) and can even impair performance among high-performers (Finke et al., 2010, Mattay et al., 2000, Farah, 2015). Stimulant medications aggravate performance among individuals with adequate dopamine levels (Swanson et al., 2007, Pliszka, 2005, Wilens, 2006). Cognitive enhancement by non-medical stimulant use may be a myth based on powerful peer-to-peer testimonies of students who are struggling academically or who have undiagnosed ADHD (Munro et al., 2017, van Rooij et al., 2015, Nigg et al., 2004, Keshavarzi et al., 2014, Reh et al., 2014, Rommelse et al., 2007) responding to accepted treatments (Overmeyer et al., 2000, Swanson et al., 2007, Pliszka, 2005, Wilens, 2006).

The scientific community has not examined how stimulant-related expectancies influence cognitive enhancement in student populations (Franke et al., 2012). Studies of cognitive enhancement show a strong subjective belief in benefit of stimulant medication regardless of objective improvement on cognitive measures. A supra-therapeutic initial dose 20 mg of mixed-amphetamine salts showed no statistical benefit on 13 measures of cognitive ability on a SAT academic test, yet participants reported significant benefit (Ilieva et al., 2013). Looby and colleagues found enhancement of mood but no changes in cognitive performance in participants who were told they ingested a stimulant (Looby and Earleywine, 2011). Neuroimaging studies of placebo stimulant medication used in healthy individuals showed that the expectation of receiving a stimulant significantly modulated neurophysiological and neurochemical activity (Beauregard, 2007, Benedetti et al., 2005).

Overall, studies attributing cognitive enhancing properties to stimulants in non-clinical populations are limited (Advokat, 2010, Bagot and Kaminer, 2014, Ilieva et al., 2015, Smith and Farah, 2011). No previous studies have distinguished whether the partial cognitive benefits observed with stimulants arise from placebo expectation from the medication or true pharmacologically-induced performance enhancement. The balanced placebo design (BPD) has been utilized to separate the pharmacological effects versus expectations (Juliano and Brandon, 2002, Kelemen and Kaighobadi, 2007). The BPD consists of four conditions in which drug dose (active vs. placebo) is crossed with instructional set (deception vs. truth). This results in two conditions in which participants are told the truth (given placebo/told placebo and given active/told active) as well as two conditions where participants are deceived (given placebo/told active and given active/told placebo). Due to the strong enhancement perceptions held by youth, the BPD will be especially useful to separate physiological versus expectancy effects from mixed-amphetamine salts. The added deception condition that goes beyond a traditional placebo design (i.e., told placebo but, given active) allows for the examination of physiological effects in the absence of any positive expectancies, and possibly in the presence of negative expectations. Therefore, the utilization of BPD with mixed-amphetamine salts will provide a novel examination with more complete separation between physiology versus expectation.

In the present study, the BPD was used to independently evaluate the pharmacological effects of mixed-amphetamine salts versus stimulant-related expectancies on cognitive performance among a non-clinical sample of college-aged students with vigorous efforts to exclude subclinical ADHD. We hypothesized that positive expectation of benefit and/or presence of stimulant would improve performance on attention measures, but that higher level cognitive functions will be unaffected by the presence of stimulant or stimulant-related expectancies. Additionally, we explored whether expectancies moderated instructional set for the cognitive enhancing properties of stimulants.

Section snippets

Participants

Thirty-nine participants were recruited from the University of Alabama at Birmingham campus. The inclusion criteria included: age 19–30-years-old, willingness to reduce caffeine intake to less than 100 mg on testing days in heavy caffeine users, adequate birth control, and at least average IQ. Exclusion criteria included: pregnancy; breast feeding; history of psychiatric conditions including ADHD or first degree relatives with ADHD; substance use disorders, prescription stimulant use or illicit

Demographics and stimulant expectancies

The sample was 59.4% women with ages ranging from 19 to 30 years (M = 21.08, SD = 2.59). Participants self-identified as Non-Hispanic/White (46.9%), African American (40.6%), Hispanic (3.1%), Asian/Pacific Islander (3.1%), or Other (6.3%). With regard to educational attainment, 93.8% of participants reported having some college experience, 3.1% reported enrolling in some graduate courses, and 3.1% reported having a Ph.D. or Masters’ degree. Participants had an estimated IQ of 113.4 (SD = 4.9; range

Discussion

Our results of cognitive testing in a carefully screened population under conditions of receiving active stimulants or placebo confirm our hypothesis that active stimulant states do not enhance high level cognitive abilities or learning over placebo in healthy controls. Our results showed improvement on only two of thirty-one subtests based on active medication. Such findings may represent a Type I error. However, belief about receiving active medication (regardless of medication assignment)

Role of funding source

Nothing declared.

Contributors

Karen L. Cropsey, Psy.D., Peter S. Hendricks, Ph.D., Samantha Schiavon, M.A., Morgan Froelich, Iga Lentowicz, M.D., and Rachel Fargason, M.D. have all assumed an active role in the manuscript. All authors approved of the final manuscript before submission.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgements

None.

References (48)

  • N.N. Rommelse et al.

    Time reproduction in children with ADHD and their nonaffected siblings

    J. Am. Acad. Child Adolesc. Psychiatry

    (2007)
  • H.L. Rowley et al.

    Lisdexamfetamine and immediate release d-amfetamine − differences in pharmacokinetic/pharmacodynamic relationships revealed by striatal microdialysis in freely-moving rats with simultaneous determination of plasma drug concentrations and locomotor activity

    Neuropharmacology

    (2012)
  • B.C. Wittmann et al.

    Reward-related FMRI activation of dopaminergic midbrain is associated with enhanced hippocampus-dependent long-term memory formation

    Neuron

    (2005)
  • C. Advokat

    What are the cognitive effects of stimulant medications? Emphasis on adults with attention-deficit/hyperactivity disorder (ADHD)

    Neurosci. Biobehav. Rev.

    (2010)
  • K.S. Bagot et al.

    Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review

    Addiction

    (2014)
  • F. Benedetti et al.

    Neurobiological mechanisms of the placebo effect

    J. Neurosci.

    (2005)
  • S.J. Farah

    The unknowns of cognitive enhancement

    Science

    (2015)
  • K. Finke et al.

    Effects of modafinil and methylphenidate on visual attention capacity: a TVA-based study

    Psychopharmacology (Berl.)

    (2010)
  • C. Forlini et al.

    Disagreements with implications: diverging discourses on the ethics of non-medical use of methylphenidate for performance enhancement

    BMC Med. Ethics

    (2009)
  • A.G. Franke et al.

    What users think about the differences between caffeine and illicit/prescription stimulants for cognitive enhancement

    PLoS One

    (2012)
  • A.G. Franke et al.

    Substances used and prevalence rates of pharmacological cognitive enhancement among healthy subjects

    Eur. Arch. Psychiatry Clin. Neurosci.

    (2014)
  • D.J. Heal et al.

    Amphetamine, past and present-A pharmacological and clinical perspective

    J. Psychopharmacol.

    (2013)
  • I.P. Ilieva et al.

    Prescription stimulants' effects on healthy inhibitory control, working memory, and episodic memory: a meta-analysis

    J. Cogn. Neurosci.

    (2015)
  • L.M. Juliano et al.

    Effects of nicotine dose, instructional set, and outcome expectancies on the subjective effects of smoking in the presence of a stressor

    J. Abnorm. Psychol.

    (2002)
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