Author Topic: Performance and subjective effects of diazepam and amphet. in sensation seekers  (Read 123 times)

Offline Chip (OP)

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source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148198/

Ha, I'm always mixing benzos with (methylated/)amphetamines. I know most of you prefer to mix them with opiates but that could kill you, so it's best to be safe and become a tweaker instead  ::). I jest. I also mix benzos with alcohol and even gabapentinoidsWiki. Purely for scientific reasons but if getting trashed is a side effect then fuckit, so be it  ;).

Performance and subjective effects of diazepam and d-amphetamine in high and low sensation seekers

Abstract

Although sensation-seeking status is associated with age of initiation and amount of drug use among adolescents, and sensitivity to the behavioral and reinforcing effects of drugs among young adults, it is unclear whether sensation-seeking status among adolescents is predictive of sensitivity to the pharmacological effects of drugs (i.e. abuse potential) as adults.

This study examined the acute behavioral effects of oral diazepam and d-amphetamine in young adults, ages 18–21 years, who had consistently scored in the highest or lowest third of their grade-based cohort on a modified Sensation Seeking Scale that was completed annually between ages 10 and 14 years.

Healthy participants completed 16 7.5-h test days, with test days separated by a minimum of 48 h. Each day, assessments consisting of computer task performance, verbal report of drug effects, and cardiovascular measures were completed 0, 50, 110, 170, 230, and 290 min after drug administration. Placebo and three active doses of diazepam and d-amphetamine (2.5, 5.0 and 10.0 mg/70 kg) were tested under double-blind conditions according to a randomized-block design.

Typical stimulant and sedative effects were obtained with d-amphetamine and diazepam, respectively. Drug effects varied as a function of sensation-seeking status, with magnitude of effects on cardiovascular function, task performance, and report of positive drug effects being greater among high sensation seekers, and report of negative drug effects being greater among low sensation seekers. Adolescents who report high levels of sensation seeking on a consistent basis are more sensitive to pharmacological effects of stimulant and sedative drugs that are associated with abuse potential as young adults.

Introduction

Sensation seeking, defined as the preference for novel, complex, ambiguous, and/or emotionally intense sensations and experiences and willingness to take risks for such experiences (Zuckerman, 1994), is associated with impulsivity, reward sensitivity, and vulnerability to drug abuse (e.g. Depue and Collins, 1999; de Wit and Richards, 2004).

Adolescents and young adults characterized as high sensation or novelty seekers, using personality scales such as the Zuckerman or Cloninger inventories (Zuckerman and Link, 1968; Cloninger, 1987), are more likely to initiate drug use, begin using at an earlier age, and report greater frequency and amount of drug use compared with their low sensation seeking counterparts (Wills et al., 1994, 1995).

Regular drug users and substance abusers score higher on sensation-seeking dimensions than control subjects (Kosten et al., 1994; Gelernter et al., 1997; Mitchell, 1999).

High sensation seekers in drug treatment also relapse at a greater rate than low sensation seekers (Schubiner et al., 2002). These data suggest that high sensation seekers may be more vulnerable to drug abuse.

Individual differences in sensation-seeking status have been related to biological factors. Sensation seeking seems to be heritable, with twin studies suggesting that genetic factors account for as much as 58% of the variance in sensation-seeking status (Fulker et al., 1980).

Sensation-seeking levels are high in children of alcoholics, who are at increased genetic risk for drug abuse (Loukas et al., 2001). High and low sensation seekers exhibit differences in physiological responses to novel stimuli (Neary and Zuckerman, 1976; Netter et al., 1996), and differences in hormone and enzyme levels and neuro-transmitter system function have been reported as a function of sensation-seeking status (Schooler et al., 1978; Balada et al., 1992; Netter et al., 1996).

Although evidence is mixed, studies suggest that variation in dopamine receptor genes may also be linked to individual differences in sensation-seeking status (Ebstein et al., 1996; Ekelund et al., 1999; Suhara et al., 2001). Given a biological basis for sensation-seeking status, sensation-seeking status among adolescents should predict subsequent sensitivity to the pharmacological effects of drugs of abuse.

Several clinical studies suggest that adults reporting characteristics associated with high sensation-seeking status are more sensitive to the behavioral effects of drugs than are low sensation seekers (e.g. de Wit et al., 1987; Cheong and Nagoshi, 1998; Sax and Strakowski, 1998; Hutchison et al., 1999; Perkins et al., 2000, 2008; Alessi et al., 2003; Kelly et al., 2006; White et al., 2006; Stoops et al., 2007; Fillmore et al., 2009; cf. Carrol et al., 1982; Nagoshi et al., 1991; Chait, 1993; Corr and Kumari, 2000).

As such, high sensation seekers, who are more likely to engage in high-risk behaviors, including drug use, may also be at greater risk for repeated use, given enhanced sensitivity to pharmacological effects. However, given that sensation-seeking status was assessed among adults in those studies, it remains uncertain whether sensation-seeking status assessed during adolescence would predict the relative sensitivity to the pharmacological (i.e. reinforcing) effects of drugs in later life.

The purpose of this study was to evaluate the association between sensation-seeking status among adolescents and subsequent sensitivity to the pharmacological effects of drugs as young adults. Although there are heritable factors associated with sensation-seeking status, social psychological factors can also influence expression of the trait (Stacy et al., 1991).

As such, participants were recruited in a manner designed to maximize stable differences in sensation-seeking status over time, thereby increasing the likelihood that trait expression was associated with heritable factors. Three consecutive cohorts of adolescents, entering the sixth grade in Fayette County, Kentucky, completed a modified version of the Sensation Seeking Scale (Form V) for 4 consecutive years, as part of an evaluation of the efficacy of a drug prevention program (Clayton et al., 1996; Lynam et al., 1999).

Individuals scoring in the top or bottom third of their grade-based cohort on each assessment were contacted as young adults and invited to participate in a follow-up study examining drug abuse potential. It was assumed that individuals identified as high or low sensation seekers at a relatively early age (i.e. 6th grade) and who remained as such over a 4-year period would be highly likely to continue to express differences in sensation-seeking status over time, independent of social psychological influences.

A small subset of 17 young adults (11 high and six low sensation seekers) met these stringent eligibility criteria and completed a randomized, placebo-controlled, double-blind evaluation of the abuse potential of diazepam and d-amphetamine, to determine whether individual differences in sensitivity to drug effects were associated with their sensation-seeking status as adolescents.

Discussion

Diazepam and d-amphetamine, examined using a double-blind repeated-measures design in which each drug was tested in every subject, engendered characteristic sedative- like and stimulant-like effects, respectively. A range of therapeutic doses of diazepam (2.5–10 mg/70 kg) impaired performance on psychomotor and cognitive tasks, decreased blood pressure, and engendered a sedative-like profile of verbal reports of drug effect, including increases on the ARCI PCAG, POMS Fatigue, and VAS Sedated and Sleepy scales, in a dose-dependent manner. In contrast, a therapeutic dose range of d-amphetamine (2.5–10 mg/70 kg) enhanced psychomotor and cognitive task performance, increased blood pressure, and engendered a stimulant-like profile of verbal reports of drug effect, including increases on the ARCI Amphetamine and BG and POMS Elation, Arousal, Vigor, and Total Positive scales, also in a dose-dependent manner.

Young adult groups of high and low sensation seekers were established, based on the consistency with which subjects scored in the upper or lower third of their age-based cohorts on the sensation-seeking personality questionnaire annually over a 4-year period of adolescence (6th through 10th grade).

After controlling for sensation-seeking group differences in baseline performance, sex and alcohol use, differences in the magnitude of diazepam-induced sedative effects and d-amphetamine- induced stimulant effects were observed among the high and low sensation-seeking groups.

Diazepam engendered significantly greater sedative effects (i.e. performance impairment on the DSST and RA tasks, sedative-like effects on the POMS Fatigue and VAS Sleepy scales) among high sensation seekers. In contrast, diazepam decreased verbal-report measures related to abuse potential (i.e. VAS Like Drug, POMS Total Positive, and ARCI MBG scales) and stimulant effects (i.e. POMS Vigor and ARCI A scales), and increased ratings on verbal-report measures that have been categorized as negative (i.e. increases in POMS Depression and Confusion and VAS Stressed scales) in low sensation seekers. d-Amphetamine improved performance on the DSST and RA tasks, and increased verbal-report measures associated with drug abuse potential (ARCI BG and POMS Vigor scales) only among high sensation seekers.

Furthermore, the magnitudes of d-amphetamine effects on the ARCI MBG and Amphetamine scales and on VAS Like Drug were greater among high than low sensation seekers. In contrast, greater sensitivity to d-amphetamine effects among low sensation seekers was generally limited to measures associated with negative drug effects (e.g. POMS Anger, VAS Light-Headed and Thirsty scales).

These results are consistent with previous studies showing that young adults who report sensation-seeking-type personality characteristics are more sensitive to the effects of drugs associated with abuse liability than low sensation seekers (e.g. de Wit et al., 1987; Cheong and Nagoshi, 1998; Sax and Strakowski, 1998; Hutchison et al., 1999; Perkins et al., 2000, 2008; White et al., 2006; Kelly et al., 2006; Stoops et al., 2007; Fillmore et al., 2009), and suggest that low sensation seekers may be more sensitive to negative drug effects. Importantly, these results also extend previous studies by showing that the association between sensation-seeking status and vulnerability to drug abuse can be determined based on the sensation-seeking status of adolescents.

Individual differences in vulnerability to the abuse potential of benzodiazepines are influenced, in part, by sedative-use history (e.g. Woods et al., 1992). Individuals with a history of heavy alcohol use, for example, show greater sensitivity to the reinforcing effects of benzodiazepines.

In this study, alcohol use was greater among high sensation seekers. However, none of the subjects reported heavy or problematic alcohol use (none reported more than 14 drinks per week, and SMAST scores were low), and individual differences in alcohol use were controlled as a covariate in the statistical analyses. Diazepam decreased verbal reports associated with drug abuse potential (e.g. VAS Like Drug, POMS Total Positive, and ARCI MBG scales) among low sensation seekers, but had no effect on these measures among high sensation seekers. Furthermore, despite reporting greater alcohol use, high sensation seekers exhibited greater sensitivity to diazepam-induced sedation and performance impairment.

As such, it is not likely that group differences in diazepam effects can be explained by heavier alcohol use among high sensation seekers.

High and low sensation seeker groups also differed on factors other than alcohol use, including sex, ethnicity, extraversion, conduct disorder symptoms, levels of maturation, and on baseline (i.e. predrug) performance on several of the study measures. Some of these differences would be expected based on the strict selection criteria that were used to establish group status.

Only those individuals who were consistently in the upper or lower third of their grade-matched cohort on the Sensation Seeking Scale in 4 consecutive years met eligibility criteria as high and low sensation seekers. These individuals also remained high and low on their sensation-seeking status as young adults, suggesting that sensation-seeking status was stable over a 6–11-year interval (i.e. between the ages of 10 and 22 years). Extraversion and conduct disorder symptoms are positively correlated with sensation-seeking status (de Wit and Richards, 2004; Martin et al., 2004), so group differences on these factors is not surprising.

Previous research has shown that drug effects vary as a function of both sex and ethnicity. Sex and ethnicity distributions varied across groups, with 36 and 86% of the high and low sensation seeking groups being female, and 91 and 50% of the high and low sensation seeking groups being Caucasian. Baseline differences in ratings on several verbal-report scales were also apparent (e.g. ARCI MGB, BG, Amphetamine; POMS Vigor, Arousal, Anger).

Although it is not possible to rule out the potential influence of these factors on group differences in drug effect, other studies (e.g. Sax and Strakowski, 1998; Hutchison et al., 1999; Perkins et al., 2000, 2008; Kelly et al., 2006; White et al., 2006; Stoops et al., 2007; Fillmore et al., 2009) have shown group differences in sensitivity to drug effects similar to those reported in this study (i.e. high sensation seekers showing greater sensitivity to measures of drug abuse potential than low sensation seekers). In these studies, group differences in sensation-seeking status were not associated with sex or ethnic distribution, extraversion, conduct disorder symptoms, maturation, drug use, or baseline differences on outcome measures, suggesting that sensation-seeking group differences in sensitivity are independent of such factors.

It is also possible that pharmacokinetic variation among high and low sensation seekers could contribute to group differences in the behavioral effects of drugs observed in this study, particularly given the available evidence for biological/genetic influences on sensation-seeking status.

If blood levels of d-amphetamine and/or diazepam were greater among high sensation seekers, for example, it would be anticipated that behavioral effects would also be greater in this group.

In this study, the effects of both diazepam and d-amphetamine were greater among high sensation seekers than low sensation seekers on a number of variables.

However, the magnitude of drug effects was not consistent across measures. In addition, qualitative differences between groups in sensitivity to drug effects were not consistent, as some measures indicated greater sensitivity to drug effects among low sensation seekers. For example, diazepam decreased ratings of POMS Vigor and Total Positive, and d-amphetamine increased Anger ratings only among low sensation seekers. Given qualitative and quantitative differences in the magnitude of drug effects across measures, group differences in drug pharmacokinetics does not seem to be the most parsimonious explanation for differential drug effects among high and low sensation seekers.

However, future studies examining pharmacokineticsWiki among high and low sensation seekers will be required to rule out pharmacokinetic influences on group differences in sensitivity to drug effects.

A number of study limitations are apparent. The participation requirements of this study were substantial (16 days, each lasting 7.5 h), and in combination with the strict eligibility criteria that limited the number of eligible participants, resulted in a relatively small sample size. The proportion of the pool of eligible participants that completed the study (17 of 123) was low, limiting the generality of the results, as well as the statistical power to detect group × dose interactions. In addition, although multiple doses within the therapeutic range were examined (0, 2.5, 5, and 10 mg/70 kg), the peak dose tested in this study was limited.

Despite the limitations in sample size and statistical power, the results of this study provide clear evidence that the behavioral effects of both diazepam and d-amphetamine vary among young adults who scored consistently in the upper or lower third of their grade-matched cohorts on the Sensation Seeking scales over 4 years of adolescence. Sensation-seeking status is associated with individual differences in impulsivity and reward sensitivity (e.g. Depue and Collins, 1999; de Wit and Richards, 2004). d-Amphetamine enhanced performance (e.g. DSST and RA response rate) and increased verbal report measures associated with drug abuse potential (e.g. ARCI BG, POMS Vigor) only among high sensation seekers, whereas diazepam impaired task performance by high sensation seekers and decreased verbal report measures associated with drug abuse potential among low sensation seekers.

These results suggest that high sensation-seeking adolescents with elevated levels of impulsivity and reward sensitivity may be at increased vulnerability to abuse potential of drugs, and support a strategy of targeting high sensation seekers for drug abuse prevention efforts (Palmgreen et al., 1995; Stephenson et al., 2002).

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