The American Journal on Addictions, 24: 435–442, 2015 Copyright © American Academy of Addiction Psychiatry ISSN: 1055-0496 print / 1521-0391 online DOI: 10.1111/ajad.12226
Associations Between Sensation Seeking and d-Amphetamine Reinforcement Mollie E. Miller, PhD,1,2 Gary J. Badger, MS,3 Sarah H. Heil, PhD,1,2,4 Stephen T. Higgins, PhD,1,2,4 Stacey C. Sigmon, PhD1,2,4 1
Vermont Center on Behavior and Health, University of Vermont, Burlington, Vermont Department of Psychology, University of Vermont, Burlington, Vermont 3 Department of Biostatistics, University of Vermont, Burlington, Vermont 4 Department of Psychiatry, University of Vermont, Burlington, Vermont 2
Background and Objectives: While many individuals experiment with stimulants, only a subset transition to abuse or dependence. One characteristic widely associated with stimulant abuse vulnerability in general is sensation seeking (SS), though less clear is how individuals’ baseline SS may predict their response to acute stimulant administration. Methods: In this secondary analysis, we examined associations between SS and d-AMPH choice and subjective response among healthy male (n ¼ 16) and female (n ¼ 21) adults participating in an outpatient laboratory study wherein they received repeated opportunities to sample and choose between d-AMPH (5, 10, and 20 mg/ 70 kg) and placebo. Results: Among males, elevated baseline SS was associated with increased d-AMPH choice and positive subjective effects at 5 and 10 mg/70 kg doses. Among females, there were no significant associations between SS and d-AMPH choice or subjective effects. Discussion and Conclusions: Elevated SS in males may be associated with increased sensitivity to d-AMPH reinforcement and positive subjective effects. Data from this study suggest that SS may not predict sensitivity to stimulants in females, though future studies with larger sample sizes are necessary to answer this definitively. Scientific Significance: Sensation seeking may reflect an important characteristic underlying sensitivity to stimulant reinforcement. Efforts to better understand these individual differences would inform efforts to identify and intervene with those at risk for developing abuse or dependence. (Am J Addict 2015;24:435–442)
BACKGROUND AND OBJECTIVES Stimulant abuse is a serious public health problem in the U.S. In addition to the 1.6 million current cocaine users, Received September 12, 2014; revised March 23, 2015; accepted March 23, 2015. Address correspondence to Miller, Brown University Center for Alcohol and Addiction Studies, Box G-S121-4, Providence, RI 02912. E-mail: [email protected]
there were 133,000 new methamphetamine initiates in 2012 alone.1 Abuse is also increasing for the stimulant medications used to treat attention deficit hyperactivity disorder (ADHD).2 Between 2005 and 2010, the number of annual emergency department visits involving these medications more than doubled from 13,379 to 31,244.3 While the abuse potential of stimulants is well established, many individuals experiment with these drugs without transitioning to abuse or dependence.4 Of those who report lifetime cocaine use, for example, only about 15% will go on to develop dependence.5 Individuals also vary in subjective and behavioral response to stimulants, which may translate to differences in susceptibility to abuse.6,7 An improved understanding of these individual differences would inform efforts to identify and intervene with those at risk for developing abuse or dependence.
SENSATION SEEKING AND STIMULANT ABUSE One characteristic associated with drug use and other risk behaviors is sensation seeking (SS). Sensation seeking is regarded as a stable personality trait and defined as the “seeking of varied, novel, complex, and intense sensations and experiences, and the willingness to take physical, social, legal and financial risks for the sake of such experiences.”8 SS is based on the premise that individuals vary widely in their optimal level of arousal, and these differences influence behavior.9 High sensation seekers are those who are more likely to engage in stimulating behaviors and therefore are hypothesized to have a greater likelihood of engaging in highrisk behaviors.8 The association between SS and psychomotor stimulant abuse is particularly established.9 In national surveys, elevated SS scores have been associated with higher prevalence rates of cocaine,10 ecstasy,11 methamphetamine,12 and prescription 435
stimulant abuse.12,13 In addition, seven laboratory studies have examined the association between SS and sensitivity to the subjective and reinforcing effects of psychomotor stimulants7,14–19 All used d-amphetamine (d-AMPH) as the exemplar stimulant, and SS was measured using either the Sensation Seeking Scale V (SSS20) or the ZuckermanKuhlman Personality Questionnaire (ZKPQ21). All seven studies examined the association between participants’ SS scores and their subjective response to dAMPH. In four, participants with higher SS scores showed increased sensitivity to d-AMPH effects compared to those with lower scores16–19 while three found no influence of SS on d-AMPH subjective effects.7,14,15 Among those demonstrating increased d-AMPH sensitivity among participants with higher SS scores; however, three reported increased sensitivity to d-AMPH’s positive effects,16,17,18 while one showed increased sensitivity to d-AMPH’s negative effects.19 Three of the seven studies also examined the role of SS in dAMPH reinforcement.7,15,19 Two employed a discrete-trial choice procedure, wherein participants were dichotomized into Choosers and Nonchoosers based on their choice for dAMPH over placebo, and there were no significant differences in Total SS scores between groups in either study.7,15 The third study used a progressive ratio procedure, wherein participants were dichotomized into High and Low SS groups and had the opportunity to work to receive 0, 8, or 16 mg of d-AMPH.19 High SS participants’ demonstrated increased break points for both d-AMPH doses compared to Low SS participants, suggesting that elevated SS was associated with increased sensitivity to d-AMPH reinforcement.19 While these studies generally suggested an association between SS and sensitivity to d-AMPH’s subjective and reinforcing effects, there was variability across studies. Methodological details may have contributed to this. First, prior studies may have been constrained by the failure to consider potential gender differences. Gender differences in SS have been consistently reported, and the developer of the SSS has published gender-specific norms for use in data interpretation.8,20,22 In addition, limited use of the SSS subscales may have precluded a full characterization of the SS-stimulant association. The questionnaire includes a total SS score as well as four subscales, with each contributing unique variance.8 However, only one prior study examined the four subscales and found a significant association between participants’ d-AMPH response and their scores on the Experience Seeking, Disinhibition, and Boredom Susceptibility scales.16 The current study is a secondary analysis of data obtained from an outpatient laboratory study aimed at prospectively evaluating whether d-AMPH reinforcement varies as a function of individuals’ dopamine receptor (DRD2) allele status.23 In that parent study, healthy adults completed doubleblind laboratory sessions wherein they received repeated opportunities to sample and choose between d-AMPH (5, 10, and 20 mg/70 kg) and placebo.23 Participants completed a Drug Effects Questionnaire (DEQ) prior to capsule ingestion 436
and again at 1, 2, 4, and 8 h postdrug administration. Percent of d-AMPH choices and self-report DEQ ratings served as measures of d-AMPH reinforcing and subjective effects, respectively. While the primary aim of the present study was to determine the influence of the DRD2 A1 allele on sensitivity to d-AMPH reinforcement, all participants completed the SSS20 at study intake providing an opportunity to assess associations between SS and sensitivity to d-AMPH reinforcing and subjective effects. We hypothesized that elevated SS would be associated with increased d-AMPH choice as well as positive subjective effects.
METHOD Participants Participants were 37 healthy adults, ages 18–50, with a history of limited recreational stimulant use, but did not meet DSM-IV criteria for current or lifetime abuse or dependence and were not seeking substance abuse treatment. All had to submit a drug-negative sample prior to participation. Participants were fluent in English and capable of understanding the protocol. Females had to be non-pregnant and non-lactating, and were required use appropriate birth control for the study duration. Exclusion criteria included medical contraindication to psychomotor stimulants, history of or current significant medical or psychiatric condition (including ADHD), diastolic blood pressure >90 mmHg or systolic pressure of >140 mmHg, body weight 20% above or below ideal body weight and use of medications that could interfere with the study. The study was approved by the local institutional review board and each participant provided written informed consent prior to participating. Intake Assessment Participants completed an intake assessment that included the Sensation-Seeking Scale Form V (SSS-V; 20, described below). A drug history questionnaire, modified Time-Line Followback (TLFB) interview24 and the DSM-IV psychoactive substance and alcoholism sections25 assessed lifetime and recent drug use. Participants also completed a medical history, which included questions about lifetime and current medical and psychiatric illnesses. Finally, urine and breath alcohol samples were collected and tested for recent drug and alcohol use. Measures of Sensation Seeking and d-AMPH Response The SSS-V contained 40 forced-choice questions yielding four subscales of 10 items each,20 as well as a total score. The Experience Seeking subscale assessed the desire to experience novel sensations and experiences through social nonconformity. The Disinhibition subscale assessed the desire to seek sensations through social activities such as parties, drinking, and sex. The Thrill and Adventure Seeking subscale measured the desire to engage in sports or risky physical activities. The
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Boredom Susceptibility subscale assessed intolerance to monotony. Total scores ranged from 0 to 40 and subscales ranged from 0 to 10; on both, increased scores represented increased levels of sensation seeking. The Drug Effects Questionnaire (DEQ) included five items that assess direct drug effects (ie, Drug Effect, Stimulant Effect, Good Effects, Bad Effects, Liking) shown to be related to abuse potential. All items, with the exception of Liking, were scored using a Likert scale that ranged from 0 (not at all) to 4 (extremely). Subjects rated their Liking of the drug from 4 (dislike very much) to þ4 (like very much), in order to permit a neutral or no drug liking rating. Procedures The double-blind, discrete-trial choice procedure consisted of 36 sessions (3–5 sessions per week) conducted over approximately 7 weeks. Three d-AMPH doses were evaluated, with each dose involving 12 sessions. Each of these 12-session series involved 4 sequences of 3 sessions per sequence (Sample–Sample–Choice). All visits were held between 8:00 am and 1:00 pm and session times were held consistent within participants across the 36 sessions. At each session, participants provided a urine sample (tested on-site using enzyme immunoassay MGC240 for cocaine, amphetamine, benzodiazepines, cannabinoids, methadone, and opiates; Microgenics, Fremont, CA) and breath alcohol (ALCOSENSOR III; Intoximeters, Inc., St. Louis, MO) sample to verify abstinence. They also completed a TLFB assessing alcohol, tobacco, caffeine, medication, and other drug use. If the TLFB, breath alcohol or urine toxicology tests showed evidence of recent drug use, the session was rescheduled pending submission of a negative sample. Participants then completed a baseline DEQ and ingested two color-coded capsules. After leaving the laboratory, participants completed the DEQ at 1, 2, 4, and 8 h postdrug. Each 3-session sequence began with two “sample” days, wherein participants received different color-coded capsules each day. One pair always contained placebo and the other dAMPH. On the subsequent “choice” day, participants reviewed their self-report data from the sample days and then chose to ingest one of the two capsule pairs. Participants were informed that the content of the capsules in the choice session was identical to that of the preceding sample sessions. This 3-day sequence (Sample–Sample–Choice) was repeated for a total of four experimentally independent assessments (12 total sessions) at each d-AMPH dose (5, 10, and 20 mg/70 kg). In summary, 36 total sessions were conducted, with 12 (4 Sample–Sample–Choice sequences) sessions at each dAMPH dose. The order of exposure to d-AMPH and placebo was counterbalanced within and across trials and subjects, and order of exposure to the different d-AMPH doses was counterbalanced across subjects. Study Medication d-AMPH capsules (5, 10, or 20 mg/70 kg; size 0, opaque hard gelatin) were prepared by the University of Vermont Miller et al.
investigational pharmacy using powdered lactose and damphetamine sulfate. Placebo capsules were weight matched (þ/ 5%) and prepared using powdered lactose. Color of dAMPH and placebo capsules varied across sessions, with 28 possible color combinations. Statistical Analyses t Tests compared male and female participants on mean SS scores, and for comparison within gender to published norms. The association between SS and d-AMPH reinforcing and subjective effects were analyzed within gender.8,22 Logistic regression analyses based on generalized estimating equations were used to examine the association between each SS scale and d-AMPH choice (SAS, PROC GENMOD). First, the association between SS and choice was evaluated across all three d-AMPH doses, with dose as additional predictors in the model. Subsequently, SS was used to predict choice at the individual dose levels. Goodness of fit was assessed based on Pan’s QIC. We investigated dose specific relationships despite the lack of evidence of a statistical interaction because the sample size was determined based on the parent trial, which was not sufficiently powered to examine interactions. Additionally, previous literature suggests that individual differences in responses to d-AMPH may be dose dependent.30 Predicted probabilities were computed based on the derived logistic regression equations. For the derived odds ratios to represent a meaningful change in SS score, a 5-point change was used for the Total SS scale (range: 0–40), and 2-point change was used for each of the subscales (range: 0–10). With regard to d-AMPH’s subjective effects, mixed model repeated measures ANCOVAs were used to examine the effects of each SS scale on the five DEQ items. The dependent variable was the area under the curve representing the cumulative drug effect over 8 h. Subjective effects data from the sampling sessions were used for these analyses; data from the choice sessions were not included because those self-report ratings could be confounded by the fact that participants were rating the capsule which they had chosen to ingest on that day.7 All regression models included participants’ subjective effects during placebo as a covariate. Similar to the logistic regression methodology, separate models were performed for each SS scale as a predictor. Initial models were run across dose with dose as an additional explanatory variable, followed by models evaluating the dose-specific association. Total Model R2 were computed as a measure of fit. Analyses were performed using SAS statistical software V9.3, with statistical significance based on a ¼.05 (SAS Institute, Cary, NC).
RESULTS Participant Characteristics The 37 participants were 22.9 2.9 years old, 43% male and had completed 15.1 1.3 years of education (Table 1). Participants’ mean SS scores are presented in Table 1. Compared to norms, the mean total score of our male participants was August 2015
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TABLE 1. Baseline demographic, drug use, and sensation seeking characteristics
Demographics Age Education (years) Drug use characteristics Current smoker (%) Current alcohol use (%) Lifetime THC use (%) Lifetime benzodiazepines use (%) Lifetime opioid use (%) Lifetime hallucinogen use (%) Lifetime stimulant use (%) Cocaine (%) Adderall (%) Methylphenidate (%) Ecstasy (%) Stimulants > 10 times Sensation seeking characteristics Total sensation seeking (0–40) Experience seeking (0–10) Disinhibition (0–10) Thrill and adventure seeking (0–10) Boredom susceptibility (0–10)
Total sample (n ¼ 37)
Males (n ¼ 16)
Females (n ¼ 21)
p
22.9 (2.9) 15.1 (1.3)
22.2 (2.2) 15.1 (1.0)
23.4 (3.3) 15.2 (1.6)
.20 .78
13.5 100 100 21.6 32.4 67.6 100 56.8 86.5 24.3 45.9 24.3 24.1 7.5 5.6 7.9 3.10
18.8 100 100 12.5 43.8 68.8 100 50.0 93.8 25.0 62.5 43.8 (5.1) (1.4) (2.3) (1.8) (1.9)
24.5 7.2 5.9 8.4 3.10
9.5 100 100 28.6 23.8 66.7 100 61.9 81.0 23.8 33.3 9.5
(5.2) (1.6) (2.5) (1.5) (2.0)
23.8 7.7 5.5 7.6 3.1
(4.9) (1.3) (2.3) (2.0) (2.0)
.42 1.00 1.00 .24 .21 .90 1.00 .47 .26 .93 .08 .03 .68 .28 .54 .19 .92
Means (þs.d.) unless otherwise specified.
estimated to be at the 60th percentile, with significantly higher mean scores on the Experience Seeking subscale compared to published male norms (p < .001).26 Similarly, our females’ mean total score was estimated to be at the 80th percentile of normative data, with significantly higher mean scores on the total, Experience Seeking and Thrill and Adventure Seeking scales compared to female norms (p’s < .01).26 Sensation Seeking and d-AMPH Choice Males chose 5, 10 and 20 mg/70 kg d-AMPH over placebo on 56% (SD ¼ 32%), 52% (SD ¼ 34%), and 61% (SD ¼ 36%) of occasions, respectively (Wald chi-square [2, n ¼ 16] ¼ 1.55, p ¼ .46). Among males, there was a significant positive association between Total (p ¼ .03), Experience Seeking (p ¼ .03), Disinhibition (p ¼.01) and Thrill and Adventure Seeking (p ¼ .04) and d-AMPH choice. Each 5-point increase in Total SS was associated with a 1.57 odds of choosing dAMPH, while each 2-point increase in Experience Seeking, Disinhibition, and Thrill and Adventure Seeking was associated with a 1.87, 1.52, and 1.91 odds of choosing dAMPH, respectively. When these effects were examined within dose, the association between SS and d-AMPH choice was strongest at the 10 mg dose. Each 5-point increase in Total SS was associated with an odds ratio of 2.20 for choosing dAMPH (Fig. 1, top left panel), while each 2-point increase in Experience Seeking (Fig. 1, bottom left panel), Disinhibition (Fig. 1, top right panel), and Thrill and Adventure Seeking 438
(Fig. 1, bottom right panel) subscales was associated with odds ratios of 2.39, 1.81, and 2.85 for d-AMPH choice, respectively. Females chose 5, 10, and 20 mg/70 kg d-AMPH over placebo on 62% (SD ¼ 27%), 67% (SD ¼ 23%), and 70% (SD ¼ 30%) of occasions, respectively (Wald chi-square [2, n ¼ 21] ¼ 1.70, p ¼ .43). In contrast to males, analyses performed across and within dose showed no significant associations between any SS scale and d-AMPH choice among females. Sensation Seeking and d-AMPH Subjective Effects Males showed a significant dose effect on all five DEQ items (F ¼ 11.43-60.27, p’s < .05). There was a significant positive association between Total (p ¼ .02) and Disinhibition (p ¼ .01) scores and d-AMPH Liking, as well as a positive trend between Thrill and Adventure Seeking and d-AMPH Liking (p ¼ .08). Each 5-point increase in Total SS was associated with a b of 1.17, while each 2-point increase in Disinhibition and Thrill and Adventure Seeking was associated with b’s of 1.00 and 1.39, respectively. Within dose analyses showed that the strongest associations between dAMPH Liking and the Total (b ¼ 1.35, p ¼ .07, Model R2 ¼ 53.2%; Fig. 2, top panel), Disinhibition (b ¼ 1.19, p ¼ .04, Model R2¼ 56.4%; Fig. 2, bottom left panel) and Thrill and Adventure Seeking (b ¼ 2.10, p ¼ .06, Model R2¼ 54.5%; Fig. 2, bottom right panel) scales occurred at the 5 mg dose. In addition, there was a significant negative
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FIGURE 1. Estimated and observed d-AMPH choice in males as a function of SS score. Estimated probabilities are based on logistic regression models. Data are presented from the Total (top left), Experience Seeking (bottom left), Disinhibition (top right), and Thrill and Adventure Seeking (bottom right) scales. Circles represent observed and squares represent predicted choice for d-AMPH over placebo at the 10 mg/70 kg dose, respectively.
association between the Experience Seeking subscale and ratings of Bad Effects (b ¼ 1.87, p ¼ .01). Within dose analyses revealed that the negative association between Experience Seeking and Bad Effects was significant at the 10 mg (b ¼ 2.25, p ¼ .01, Model R2 ¼ 45.0%) and 20 mg (b ¼ 2.91, p ¼ .04, Model R2 ¼ 70.1%) doses (Fig. 3). Females showed a significant dose effect on all DEQ items except Bad Effects (F ¼ 52.17–60.45, p’s < .05). There were no significant associations between any of the SS scales and dAMPH subjective effects in females.
DISCUSSION Stimulant abuse represents a serious public health problem, with over 3.4 million Americans reporting past-month illicit stimulant use.1 Efforts to identify the characteristics associated with susceptibility for stimulant abuse may help inform the development of more effective prevention and treatment efforts. In the present study, we examined whether sensation Miller et al.
seeking, a characteristic commonly associated with drug use and other risk behaviors, was associated with increased sensitivity to d-AMPH reinforcement. Among males, there was a significant association between SS and d-AMPH choice. Participants with increased Total, Disinhibition, Thrill and Adventure Seeking, and Experience Seeking scores had significantly greater odds of choosing dAMPH over placebo, particularly at the 10 mg/70 kg dose. These results are consistent Stoops et al.19 who controlled for gender and found that high-SS participants had increased break points for d-AMPH compared to low-SS participants. Our findings differ from the two prior discrete-trial choice studies that found no associations between SS and d-AMPH choice,7,15 perhaps due to a lack of controlling for gender differences. Given the mixed findings to date, more research to characterize the association between sensation seeking and dAMPH choice is still needed, as well as the extent to which the association is dose dependent. Sensation seeking was also significantly associated with d-AMPH subjective effects in males. With regard to positive August 2015
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FIGURE 2. Estimated and observed AUC d-AMPH Liking in males as a function of SS score. Estimates are shown from multiple regression models. Data are presented from the Total (top), Thrill and Adventure Seeking (bottom left) and Disinhibition (bottom right) and scales. Circles represent observed and squares represent predicted subjective effects at the 5 mg/70 kg dose, respectively.
d-AMPH subjective effects, males with higher total, Disinhibition and Thrill and Adventure Seeking scores reported greater d-AMPH Liking, particularly at the 5 mg/70 kg dose. These results are consistent with studies showing increased sensitivity to d-AMPH-associated positive effects among participants with higher SS scores,16–18 and the larger literature showing concordance between d-AMPH-related positive effects and increased choice.27,28 In terms of negative dAMPH effects, males with higher Experience Seeking scores reported lower ratings of Bad Effects, particularly at 10 and 20 mg/70 kg doses. This is also consistent with a prior study in which higher sensation seekers showed reduced sensitivity to dAMPH-associated unpleasant effects.17 Overall, these findings provide additional support for increased vulnerability for stimulant abuse among males with elevated SS. In contrast to males, we found no significant association between SS and d-AMPH choice or subjective response in female participants. One possible reason may be related to the inclusion criteria of the parent study, wherein eligible participants were required to have used stimulants. Thus, our sample of female participants may differ from the general female population in that their mean Total SS score was at the 80th percentile of normative data.26 Alternatively, the SSS-V may simply be a less sensitive predictor of d-AMPH response 440
in females. Indeed, a prior study examining impulsivity characteristics and sensitivity to nicotine reinforcement showed several significant relationships between SS and response to nicotine that were evident in males but not females.29 Ultimately, whether SS characteristics in females may be associated with response to psychomotor stimulants remains an empirical question. Several strengths of the present study should be noted. First, this study included a range of d-AMPH doses with multiple exposures at each dose level. Associations between SS and d-AMPH response were strongest at the 5 and 10 mg dAMPH doses, which supports previous findings suggesting that individual differences may be most pronounced at lower doses.30 Second, instead of ignoring gender or using it as a covariate, we directly examined the effects of SS on d-AMPH response within each gender and found a strong association between SS and d-AMPH in males that was not evident in females. Finally, this is the first study to our knowledge to use the SS Total score as well as each of the four subscales, thus providing the most thorough analysis to date of the association between SS and d-AMPH response. Several potential limitations should also be noted. First, our sample size was restricted by the number of participants who completed the parent study. That said, we observed several
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sensitivity to d-AMPH’s positive effects and greater dAMPH preference in males but not females. This suggests that SS may reflect an important characteristic underlying an individual’s sensitivity to stimulant reinforcement and risk for abuse, particularly among males. Measures of SS may be useful to inform efforts to identify and intervene with those at risk for developing abuse or dependence. This study was supported by research (R03 DA027480; University of Vermont, Burlington, VT; Stacey C. Sigmon, PhD) and training (T32 DA007242; University of Vermont, Burlington, VT; Stephen T. Higgins, PhD) grants from the National Institute on Drug Abuse. We thank John Brooklyn, MD, Kelsey Hughes, Allison Necheles and Kathryn Saulsgiver for their assistance conducting this study. We also thank Leigh Ann Holterman for her statistical support. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.
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FIGURE 3. Estimated and observed AUC d-AMPH Bad Effects in males as a function of SS score. Estimates are shown from multiple regression models. Data are presented from the 10mg/70 kg dose (top) and 20 mg/70 kg dose (bottom). Circles represent observed and squares and triangles represent predicted subjective effects at the 10 and 20 mg/70 kg doses, respectively.
statistically significant and potentially important associations between SS and d-AMPH response despite the limited sample. Also worth noting is that our sample size (n ¼ 37) was generally similar to those in prior studies on this topic (range ¼ 17–36). Second, as we used a convenience sample of participants from a previously completed study, our participant selection was constrained by its eligibility criteria. Those criteria may have skewed SS scores in our study sample and may have limited our ability to observe an association between SS and d-AMPH in females. Finally, significantly more males reported using stimulants on >10 occasions than females, which may at least partially account for the difference in outcomes between men and women.
SCIENTIFIC SIGNIFICANCE The present study found that among healthy volunteers, increased sensation seeking was associated with greater Miller et al.
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Associations Between Sensation Seeking and d-Amphetamine Reinforcement Mollie E. Miller, PhD,1,2 Gary J. Badger, MS,3 Sarah H. Heil, PhD,1,2,4 Stephen T. Higgins, PhD,1,2,4 Stacey C. Sigmon, PhD1,2,4 1
Vermont Center on Behavior and Health, University of Vermont, Burlington, Vermont Department of Psychology, University of Vermont, Burlington, Vermont 3 Department of Biostatistics, University of Vermont, Burlington, Vermont 4 Department of Psychiatry, University of Vermont, Burlington, Vermont 2
Background and Objectives: While many individuals experiment with stimulants, only a subset transition to abuse or dependence. One characteristic widely associated with stimulant abuse vulnerability in general is sensation seeking (SS), though less clear is how individuals’ baseline SS may predict their response to acute stimulant administration. Methods: In this secondary analysis, we examined associations between SS and d-AMPH choice and subjective response among healthy male (n ¼ 16) and female (n ¼ 21) adults participating in an outpatient laboratory study wherein they received repeated opportunities to sample and choose between d-AMPH (5, 10, and 20 mg/ 70 kg) and placebo. Results: Among males, elevated baseline SS was associated with increased d-AMPH choice and positive subjective effects at 5 and 10 mg/70 kg doses. Among females, there were no significant associations between SS and d-AMPH choice or subjective effects. Discussion and Conclusions: Elevated SS in males may be associated with increased sensitivity to d-AMPH reinforcement and positive subjective effects. Data from this study suggest that SS may not predict sensitivity to stimulants in females, though future studies with larger sample sizes are necessary to answer this definitively. Scientific Significance: Sensation seeking may reflect an important characteristic underlying sensitivity to stimulant reinforcement. Efforts to better understand these individual differences would inform efforts to identify and intervene with those at risk for developing abuse or dependence. (Am J Addict 2015;24:435–442)
BACKGROUND AND OBJECTIVES Stimulant abuse is a serious public health problem in the U.S. In addition to the 1.6 million current cocaine users, Received September 12, 2014; revised March 23, 2015; accepted March 23, 2015. Address correspondence to Miller, Brown University Center for Alcohol and Addiction Studies, Box G-S121-4, Providence, RI 02912. E-mail: [email protected]
there were 133,000 new methamphetamine initiates in 2012 alone.1 Abuse is also increasing for the stimulant medications used to treat attention deficit hyperactivity disorder (ADHD).2 Between 2005 and 2010, the number of annual emergency department visits involving these medications more than doubled from 13,379 to 31,244.3 While the abuse potential of stimulants is well established, many individuals experiment with these drugs without transitioning to abuse or dependence.4 Of those who report lifetime cocaine use, for example, only about 15% will go on to develop dependence.5 Individuals also vary in subjective and behavioral response to stimulants, which may translate to differences in susceptibility to abuse.6,7 An improved understanding of these individual differences would inform efforts to identify and intervene with those at risk for developing abuse or dependence.
SENSATION SEEKING AND STIMULANT ABUSE One characteristic associated with drug use and other risk behaviors is sensation seeking (SS). Sensation seeking is regarded as a stable personality trait and defined as the “seeking of varied, novel, complex, and intense sensations and experiences, and the willingness to take physical, social, legal and financial risks for the sake of such experiences.”8 SS is based on the premise that individuals vary widely in their optimal level of arousal, and these differences influence behavior.9 High sensation seekers are those who are more likely to engage in stimulating behaviors and therefore are hypothesized to have a greater likelihood of engaging in highrisk behaviors.8 The association between SS and psychomotor stimulant abuse is particularly established.9 In national surveys, elevated SS scores have been associated with higher prevalence rates of cocaine,10 ecstasy,11 methamphetamine,12 and prescription 435
stimulant abuse.12,13 In addition, seven laboratory studies have examined the association between SS and sensitivity to the subjective and reinforcing effects of psychomotor stimulants7,14–19 All used d-amphetamine (d-AMPH) as the exemplar stimulant, and SS was measured using either the Sensation Seeking Scale V (SSS20) or the ZuckermanKuhlman Personality Questionnaire (ZKPQ21). All seven studies examined the association between participants’ SS scores and their subjective response to dAMPH. In four, participants with higher SS scores showed increased sensitivity to d-AMPH effects compared to those with lower scores16–19 while three found no influence of SS on d-AMPH subjective effects.7,14,15 Among those demonstrating increased d-AMPH sensitivity among participants with higher SS scores; however, three reported increased sensitivity to d-AMPH’s positive effects,16,17,18 while one showed increased sensitivity to d-AMPH’s negative effects.19 Three of the seven studies also examined the role of SS in dAMPH reinforcement.7,15,19 Two employed a discrete-trial choice procedure, wherein participants were dichotomized into Choosers and Nonchoosers based on their choice for dAMPH over placebo, and there were no significant differences in Total SS scores between groups in either study.7,15 The third study used a progressive ratio procedure, wherein participants were dichotomized into High and Low SS groups and had the opportunity to work to receive 0, 8, or 16 mg of d-AMPH.19 High SS participants’ demonstrated increased break points for both d-AMPH doses compared to Low SS participants, suggesting that elevated SS was associated with increased sensitivity to d-AMPH reinforcement.19 While these studies generally suggested an association between SS and sensitivity to d-AMPH’s subjective and reinforcing effects, there was variability across studies. Methodological details may have contributed to this. First, prior studies may have been constrained by the failure to consider potential gender differences. Gender differences in SS have been consistently reported, and the developer of the SSS has published gender-specific norms for use in data interpretation.8,20,22 In addition, limited use of the SSS subscales may have precluded a full characterization of the SS-stimulant association. The questionnaire includes a total SS score as well as four subscales, with each contributing unique variance.8 However, only one prior study examined the four subscales and found a significant association between participants’ d-AMPH response and their scores on the Experience Seeking, Disinhibition, and Boredom Susceptibility scales.16 The current study is a secondary analysis of data obtained from an outpatient laboratory study aimed at prospectively evaluating whether d-AMPH reinforcement varies as a function of individuals’ dopamine receptor (DRD2) allele status.23 In that parent study, healthy adults completed doubleblind laboratory sessions wherein they received repeated opportunities to sample and choose between d-AMPH (5, 10, and 20 mg/70 kg) and placebo.23 Participants completed a Drug Effects Questionnaire (DEQ) prior to capsule ingestion 436
and again at 1, 2, 4, and 8 h postdrug administration. Percent of d-AMPH choices and self-report DEQ ratings served as measures of d-AMPH reinforcing and subjective effects, respectively. While the primary aim of the present study was to determine the influence of the DRD2 A1 allele on sensitivity to d-AMPH reinforcement, all participants completed the SSS20 at study intake providing an opportunity to assess associations between SS and sensitivity to d-AMPH reinforcing and subjective effects. We hypothesized that elevated SS would be associated with increased d-AMPH choice as well as positive subjective effects.
METHOD Participants Participants were 37 healthy adults, ages 18–50, with a history of limited recreational stimulant use, but did not meet DSM-IV criteria for current or lifetime abuse or dependence and were not seeking substance abuse treatment. All had to submit a drug-negative sample prior to participation. Participants were fluent in English and capable of understanding the protocol. Females had to be non-pregnant and non-lactating, and were required use appropriate birth control for the study duration. Exclusion criteria included medical contraindication to psychomotor stimulants, history of or current significant medical or psychiatric condition (including ADHD), diastolic blood pressure >90 mmHg or systolic pressure of >140 mmHg, body weight 20% above or below ideal body weight and use of medications that could interfere with the study. The study was approved by the local institutional review board and each participant provided written informed consent prior to participating. Intake Assessment Participants completed an intake assessment that included the Sensation-Seeking Scale Form V (SSS-V; 20, described below). A drug history questionnaire, modified Time-Line Followback (TLFB) interview24 and the DSM-IV psychoactive substance and alcoholism sections25 assessed lifetime and recent drug use. Participants also completed a medical history, which included questions about lifetime and current medical and psychiatric illnesses. Finally, urine and breath alcohol samples were collected and tested for recent drug and alcohol use. Measures of Sensation Seeking and d-AMPH Response The SSS-V contained 40 forced-choice questions yielding four subscales of 10 items each,20 as well as a total score. The Experience Seeking subscale assessed the desire to experience novel sensations and experiences through social nonconformity. The Disinhibition subscale assessed the desire to seek sensations through social activities such as parties, drinking, and sex. The Thrill and Adventure Seeking subscale measured the desire to engage in sports or risky physical activities. The
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Boredom Susceptibility subscale assessed intolerance to monotony. Total scores ranged from 0 to 40 and subscales ranged from 0 to 10; on both, increased scores represented increased levels of sensation seeking. The Drug Effects Questionnaire (DEQ) included five items that assess direct drug effects (ie, Drug Effect, Stimulant Effect, Good Effects, Bad Effects, Liking) shown to be related to abuse potential. All items, with the exception of Liking, were scored using a Likert scale that ranged from 0 (not at all) to 4 (extremely). Subjects rated their Liking of the drug from 4 (dislike very much) to þ4 (like very much), in order to permit a neutral or no drug liking rating. Procedures The double-blind, discrete-trial choice procedure consisted of 36 sessions (3–5 sessions per week) conducted over approximately 7 weeks. Three d-AMPH doses were evaluated, with each dose involving 12 sessions. Each of these 12-session series involved 4 sequences of 3 sessions per sequence (Sample–Sample–Choice). All visits were held between 8:00 am and 1:00 pm and session times were held consistent within participants across the 36 sessions. At each session, participants provided a urine sample (tested on-site using enzyme immunoassay MGC240 for cocaine, amphetamine, benzodiazepines, cannabinoids, methadone, and opiates; Microgenics, Fremont, CA) and breath alcohol (ALCOSENSOR III; Intoximeters, Inc., St. Louis, MO) sample to verify abstinence. They also completed a TLFB assessing alcohol, tobacco, caffeine, medication, and other drug use. If the TLFB, breath alcohol or urine toxicology tests showed evidence of recent drug use, the session was rescheduled pending submission of a negative sample. Participants then completed a baseline DEQ and ingested two color-coded capsules. After leaving the laboratory, participants completed the DEQ at 1, 2, 4, and 8 h postdrug. Each 3-session sequence began with two “sample” days, wherein participants received different color-coded capsules each day. One pair always contained placebo and the other dAMPH. On the subsequent “choice” day, participants reviewed their self-report data from the sample days and then chose to ingest one of the two capsule pairs. Participants were informed that the content of the capsules in the choice session was identical to that of the preceding sample sessions. This 3-day sequence (Sample–Sample–Choice) was repeated for a total of four experimentally independent assessments (12 total sessions) at each d-AMPH dose (5, 10, and 20 mg/70 kg). In summary, 36 total sessions were conducted, with 12 (4 Sample–Sample–Choice sequences) sessions at each dAMPH dose. The order of exposure to d-AMPH and placebo was counterbalanced within and across trials and subjects, and order of exposure to the different d-AMPH doses was counterbalanced across subjects. Study Medication d-AMPH capsules (5, 10, or 20 mg/70 kg; size 0, opaque hard gelatin) were prepared by the University of Vermont Miller et al.
investigational pharmacy using powdered lactose and damphetamine sulfate. Placebo capsules were weight matched (þ/ 5%) and prepared using powdered lactose. Color of dAMPH and placebo capsules varied across sessions, with 28 possible color combinations. Statistical Analyses t Tests compared male and female participants on mean SS scores, and for comparison within gender to published norms. The association between SS and d-AMPH reinforcing and subjective effects were analyzed within gender.8,22 Logistic regression analyses based on generalized estimating equations were used to examine the association between each SS scale and d-AMPH choice (SAS, PROC GENMOD). First, the association between SS and choice was evaluated across all three d-AMPH doses, with dose as additional predictors in the model. Subsequently, SS was used to predict choice at the individual dose levels. Goodness of fit was assessed based on Pan’s QIC. We investigated dose specific relationships despite the lack of evidence of a statistical interaction because the sample size was determined based on the parent trial, which was not sufficiently powered to examine interactions. Additionally, previous literature suggests that individual differences in responses to d-AMPH may be dose dependent.30 Predicted probabilities were computed based on the derived logistic regression equations. For the derived odds ratios to represent a meaningful change in SS score, a 5-point change was used for the Total SS scale (range: 0–40), and 2-point change was used for each of the subscales (range: 0–10). With regard to d-AMPH’s subjective effects, mixed model repeated measures ANCOVAs were used to examine the effects of each SS scale on the five DEQ items. The dependent variable was the area under the curve representing the cumulative drug effect over 8 h. Subjective effects data from the sampling sessions were used for these analyses; data from the choice sessions were not included because those self-report ratings could be confounded by the fact that participants were rating the capsule which they had chosen to ingest on that day.7 All regression models included participants’ subjective effects during placebo as a covariate. Similar to the logistic regression methodology, separate models were performed for each SS scale as a predictor. Initial models were run across dose with dose as an additional explanatory variable, followed by models evaluating the dose-specific association. Total Model R2 were computed as a measure of fit. Analyses were performed using SAS statistical software V9.3, with statistical significance based on a ¼.05 (SAS Institute, Cary, NC).
RESULTS Participant Characteristics The 37 participants were 22.9 2.9 years old, 43% male and had completed 15.1 1.3 years of education (Table 1). Participants’ mean SS scores are presented in Table 1. Compared to norms, the mean total score of our male participants was August 2015
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TABLE 1. Baseline demographic, drug use, and sensation seeking characteristics
Demographics Age Education (years) Drug use characteristics Current smoker (%) Current alcohol use (%) Lifetime THC use (%) Lifetime benzodiazepines use (%) Lifetime opioid use (%) Lifetime hallucinogen use (%) Lifetime stimulant use (%) Cocaine (%) Adderall (%) Methylphenidate (%) Ecstasy (%) Stimulants > 10 times Sensation seeking characteristics Total sensation seeking (0–40) Experience seeking (0–10) Disinhibition (0–10) Thrill and adventure seeking (0–10) Boredom susceptibility (0–10)
Total sample (n ¼ 37)
Males (n ¼ 16)
Females (n ¼ 21)
p
22.9 (2.9) 15.1 (1.3)
22.2 (2.2) 15.1 (1.0)
23.4 (3.3) 15.2 (1.6)
.20 .78
13.5 100 100 21.6 32.4 67.6 100 56.8 86.5 24.3 45.9 24.3 24.1 7.5 5.6 7.9 3.10
18.8 100 100 12.5 43.8 68.8 100 50.0 93.8 25.0 62.5 43.8 (5.1) (1.4) (2.3) (1.8) (1.9)
24.5 7.2 5.9 8.4 3.10
9.5 100 100 28.6 23.8 66.7 100 61.9 81.0 23.8 33.3 9.5
(5.2) (1.6) (2.5) (1.5) (2.0)
23.8 7.7 5.5 7.6 3.1
(4.9) (1.3) (2.3) (2.0) (2.0)
.42 1.00 1.00 .24 .21 .90 1.00 .47 .26 .93 .08 .03 .68 .28 .54 .19 .92
Means (þs.d.) unless otherwise specified.
estimated to be at the 60th percentile, with significantly higher mean scores on the Experience Seeking subscale compared to published male norms (p < .001).26 Similarly, our females’ mean total score was estimated to be at the 80th percentile of normative data, with significantly higher mean scores on the total, Experience Seeking and Thrill and Adventure Seeking scales compared to female norms (p’s < .01).26 Sensation Seeking and d-AMPH Choice Males chose 5, 10 and 20 mg/70 kg d-AMPH over placebo on 56% (SD ¼ 32%), 52% (SD ¼ 34%), and 61% (SD ¼ 36%) of occasions, respectively (Wald chi-square [2, n ¼ 16] ¼ 1.55, p ¼ .46). Among males, there was a significant positive association between Total (p ¼ .03), Experience Seeking (p ¼ .03), Disinhibition (p ¼.01) and Thrill and Adventure Seeking (p ¼ .04) and d-AMPH choice. Each 5-point increase in Total SS was associated with a 1.57 odds of choosing dAMPH, while each 2-point increase in Experience Seeking, Disinhibition, and Thrill and Adventure Seeking was associated with a 1.87, 1.52, and 1.91 odds of choosing dAMPH, respectively. When these effects were examined within dose, the association between SS and d-AMPH choice was strongest at the 10 mg dose. Each 5-point increase in Total SS was associated with an odds ratio of 2.20 for choosing dAMPH (Fig. 1, top left panel), while each 2-point increase in Experience Seeking (Fig. 1, bottom left panel), Disinhibition (Fig. 1, top right panel), and Thrill and Adventure Seeking 438
(Fig. 1, bottom right panel) subscales was associated with odds ratios of 2.39, 1.81, and 2.85 for d-AMPH choice, respectively. Females chose 5, 10, and 20 mg/70 kg d-AMPH over placebo on 62% (SD ¼ 27%), 67% (SD ¼ 23%), and 70% (SD ¼ 30%) of occasions, respectively (Wald chi-square [2, n ¼ 21] ¼ 1.70, p ¼ .43). In contrast to males, analyses performed across and within dose showed no significant associations between any SS scale and d-AMPH choice among females. Sensation Seeking and d-AMPH Subjective Effects Males showed a significant dose effect on all five DEQ items (F ¼ 11.43-60.27, p’s < .05). There was a significant positive association between Total (p ¼ .02) and Disinhibition (p ¼ .01) scores and d-AMPH Liking, as well as a positive trend between Thrill and Adventure Seeking and d-AMPH Liking (p ¼ .08). Each 5-point increase in Total SS was associated with a b of 1.17, while each 2-point increase in Disinhibition and Thrill and Adventure Seeking was associated with b’s of 1.00 and 1.39, respectively. Within dose analyses showed that the strongest associations between dAMPH Liking and the Total (b ¼ 1.35, p ¼ .07, Model R2 ¼ 53.2%; Fig. 2, top panel), Disinhibition (b ¼ 1.19, p ¼ .04, Model R2¼ 56.4%; Fig. 2, bottom left panel) and Thrill and Adventure Seeking (b ¼ 2.10, p ¼ .06, Model R2¼ 54.5%; Fig. 2, bottom right panel) scales occurred at the 5 mg dose. In addition, there was a significant negative
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FIGURE 1. Estimated and observed d-AMPH choice in males as a function of SS score. Estimated probabilities are based on logistic regression models. Data are presented from the Total (top left), Experience Seeking (bottom left), Disinhibition (top right), and Thrill and Adventure Seeking (bottom right) scales. Circles represent observed and squares represent predicted choice for d-AMPH over placebo at the 10 mg/70 kg dose, respectively.
association between the Experience Seeking subscale and ratings of Bad Effects (b ¼ 1.87, p ¼ .01). Within dose analyses revealed that the negative association between Experience Seeking and Bad Effects was significant at the 10 mg (b ¼ 2.25, p ¼ .01, Model R2 ¼ 45.0%) and 20 mg (b ¼ 2.91, p ¼ .04, Model R2 ¼ 70.1%) doses (Fig. 3). Females showed a significant dose effect on all DEQ items except Bad Effects (F ¼ 52.17–60.45, p’s < .05). There were no significant associations between any of the SS scales and dAMPH subjective effects in females.
DISCUSSION Stimulant abuse represents a serious public health problem, with over 3.4 million Americans reporting past-month illicit stimulant use.1 Efforts to identify the characteristics associated with susceptibility for stimulant abuse may help inform the development of more effective prevention and treatment efforts. In the present study, we examined whether sensation Miller et al.
seeking, a characteristic commonly associated with drug use and other risk behaviors, was associated with increased sensitivity to d-AMPH reinforcement. Among males, there was a significant association between SS and d-AMPH choice. Participants with increased Total, Disinhibition, Thrill and Adventure Seeking, and Experience Seeking scores had significantly greater odds of choosing dAMPH over placebo, particularly at the 10 mg/70 kg dose. These results are consistent Stoops et al.19 who controlled for gender and found that high-SS participants had increased break points for d-AMPH compared to low-SS participants. Our findings differ from the two prior discrete-trial choice studies that found no associations between SS and d-AMPH choice,7,15 perhaps due to a lack of controlling for gender differences. Given the mixed findings to date, more research to characterize the association between sensation seeking and dAMPH choice is still needed, as well as the extent to which the association is dose dependent. Sensation seeking was also significantly associated with d-AMPH subjective effects in males. With regard to positive August 2015
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FIGURE 2. Estimated and observed AUC d-AMPH Liking in males as a function of SS score. Estimates are shown from multiple regression models. Data are presented from the Total (top), Thrill and Adventure Seeking (bottom left) and Disinhibition (bottom right) and scales. Circles represent observed and squares represent predicted subjective effects at the 5 mg/70 kg dose, respectively.
d-AMPH subjective effects, males with higher total, Disinhibition and Thrill and Adventure Seeking scores reported greater d-AMPH Liking, particularly at the 5 mg/70 kg dose. These results are consistent with studies showing increased sensitivity to d-AMPH-associated positive effects among participants with higher SS scores,16–18 and the larger literature showing concordance between d-AMPH-related positive effects and increased choice.27,28 In terms of negative dAMPH effects, males with higher Experience Seeking scores reported lower ratings of Bad Effects, particularly at 10 and 20 mg/70 kg doses. This is also consistent with a prior study in which higher sensation seekers showed reduced sensitivity to dAMPH-associated unpleasant effects.17 Overall, these findings provide additional support for increased vulnerability for stimulant abuse among males with elevated SS. In contrast to males, we found no significant association between SS and d-AMPH choice or subjective response in female participants. One possible reason may be related to the inclusion criteria of the parent study, wherein eligible participants were required to have used stimulants. Thus, our sample of female participants may differ from the general female population in that their mean Total SS score was at the 80th percentile of normative data.26 Alternatively, the SSS-V may simply be a less sensitive predictor of d-AMPH response 440
in females. Indeed, a prior study examining impulsivity characteristics and sensitivity to nicotine reinforcement showed several significant relationships between SS and response to nicotine that were evident in males but not females.29 Ultimately, whether SS characteristics in females may be associated with response to psychomotor stimulants remains an empirical question. Several strengths of the present study should be noted. First, this study included a range of d-AMPH doses with multiple exposures at each dose level. Associations between SS and d-AMPH response were strongest at the 5 and 10 mg dAMPH doses, which supports previous findings suggesting that individual differences may be most pronounced at lower doses.30 Second, instead of ignoring gender or using it as a covariate, we directly examined the effects of SS on d-AMPH response within each gender and found a strong association between SS and d-AMPH in males that was not evident in females. Finally, this is the first study to our knowledge to use the SS Total score as well as each of the four subscales, thus providing the most thorough analysis to date of the association between SS and d-AMPH response. Several potential limitations should also be noted. First, our sample size was restricted by the number of participants who completed the parent study. That said, we observed several
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sensitivity to d-AMPH’s positive effects and greater dAMPH preference in males but not females. This suggests that SS may reflect an important characteristic underlying an individual’s sensitivity to stimulant reinforcement and risk for abuse, particularly among males. Measures of SS may be useful to inform efforts to identify and intervene with those at risk for developing abuse or dependence. This study was supported by research (R03 DA027480; University of Vermont, Burlington, VT; Stacey C. Sigmon, PhD) and training (T32 DA007242; University of Vermont, Burlington, VT; Stephen T. Higgins, PhD) grants from the National Institute on Drug Abuse. We thank John Brooklyn, MD, Kelsey Hughes, Allison Necheles and Kathryn Saulsgiver for their assistance conducting this study. We also thank Leigh Ann Holterman for her statistical support. Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.
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FIGURE 3. Estimated and observed AUC d-AMPH Bad Effects in males as a function of SS score. Estimates are shown from multiple regression models. Data are presented from the 10mg/70 kg dose (top) and 20 mg/70 kg dose (bottom). Circles represent observed and squares and triangles represent predicted subjective effects at the 10 and 20 mg/70 kg doses, respectively.
statistically significant and potentially important associations between SS and d-AMPH response despite the limited sample. Also worth noting is that our sample size (n ¼ 37) was generally similar to those in prior studies on this topic (range ¼ 17–36). Second, as we used a convenience sample of participants from a previously completed study, our participant selection was constrained by its eligibility criteria. Those criteria may have skewed SS scores in our study sample and may have limited our ability to observe an association between SS and d-AMPH in females. Finally, significantly more males reported using stimulants on >10 occasions than females, which may at least partially account for the difference in outcomes between men and women.
SCIENTIFIC SIGNIFICANCE The present study found that among healthy volunteers, increased sensation seeking was associated with greater Miller et al.
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