Otherwise healthy, non-treatment seeking METH users were recruited through local newspaper, radio and Internet advertisements. All participants underwent an initial telephone screening and provided information on their medical, psychiatric and drug use histories. Potential participants that successfully completed the telephone screen were invited to an in-person screening that included questions regarding demographics and drug use, and a urine toxicology test. Eligible participants were also required to provide self-reports of mood and recent drug use, and a urine toxicology test on the test day. All participants received a detailed verbal and written description of the study procedures before giving written informed consent, as approved by the University of California Los Angeles Institutional Review Board.
Exclusion criteria included 1) history of any self-reported Axis I psychiatric diagnosis (other than METH or nicotine dependence), 2) vision or hearing impairments, 3) use of any medication or medical condition that may significantly effect cardiovascular function, 4) illicit drug use (cocaine, heroin, hallucinogens, etc), other than METH, in the past 30 days. Any subject reporting recreational alcohol (≤ 1 drink per day) or marijuana (≤ 3 use per week) use, not meeting criteria for abuse/dependence, was allowed to participate, but instructed to abstain prior to testing (confirmed with self-report, urine toxicology test and alcohol breathalyzer during the in-person screen and on the test day).
2.2 Cue Presentation Procedures
Participants were permitted to smoke cigarettes ad libitum prior to the start of the study, but were required to abstain from smoking during the study (approximately 2 hours). Participants first completed questionnaires (30 min) before starting the cue sessions. This procedure standardized the time since the last cigarette (30 minutes), and allowed for modest cigarette craving (Schuh and Stitzer, 1995
), while avoiding the possibility of heavy cigarette craving caused by prolonged abstinence. The cue condition presentation order was counterbalanced between participants (Latin Square). The participants viewed each cue condition for 10 min, with a ten minute break between each cue condition, in a sensory-attenuated setting on a Sharp Aquos 32″ LCD HDTV. The VR and video cues were run from a Dell Dimension DXP061 desktop containing a NVIDIA GeForce 8800 GTX graphics card and 768 MB of graphics memory. The participants navigated the VR environments using a Logitech Dual Action controller. Movement within the VR environments was limited to forward/backward walking (using the D-pad) and 360-degree head directional movements (using the right analog stick). Following completion of the last cue condition, participants were debriefed to ensure that their participation would not alter future drug taking behavior. Participants remained under supervision until their self-reported craving reached baseline levels, at which point they were discharged from the study session.
2.3 Virtual Reality Cues
Photographs of the real apartment were taken (using a 6.3 MegaPixel Digital Canon EOS camera) from multiple angles under two conditions: “METH-house” () and “neutral-house” () to capture realistic light and textures in digital form. The photographs were then visually manipulated using Adobe Photoshop ® (version 7.0) to include additional METH paraphernalia and to enhance the overall realism. The finished images were applied to a 3-D mock up of the real apartment created in Second Life (www.secondlife.com
). Finally, virtual avatars and drug-use animations (e.g. smoking, injecting, snorting) were created using Second Life tools and Poser Version 6, respectively, and placed into the VR environments.
Screenshots of the methamphetamine virtual reality (METH-VR) cue environment
Screenshots of the neutral virtual reality (neutral-VR) cue environment
The METH-VR environment was developed on the basis of self-reports from METH abusers’ to represent a “METH-house” (i.e. a location where drug transactions and use occurs). This VR environment included animate (avatars administering METH), inanimate (drug paraphernalia), contextual (“METH-house” characteristics) and auditory (music reported by each subject to be associated with METH use) cues (). The neutral-VR environment was modeled after a modern apartment (devoid of any drug cues) and includes neutral auditory stimuli (Latin jazz) (). The participants were instructed to explore each VR environment freely, but were restricted from leaving by natural barriers, such as doors and walls.
2.4 Video & In Vivo Cues
The METH-video included professional actors/actresses administering METH via multiple routes (smoking, snorting, injecting) in a variety of settings with a set soundtrack. The participants were also provided with in vivo mock METH paraphernalia (e.g. glass pipe, mock syringe, medical tubing, and a small plastic bag containing a substance that appears to be METH) to examine during METH-video. The neutral-video contained footage of tropical fish swimming in a tank and included neutral music (classical guitar). The participants were also provided with in vivo neutral objects (e.g. feather, pinecone, pencil) to examine during the neutral-video. The participants were instructed to “imagine yourself in the situation while you are watching” at the start of each video.
2.5 Subjective Response Monitoring
All subjective responses were recorded on a visual analogue scale (VAS) from 0 to 100 (“none” to “very much”). The VAS form incorporated the nine following questions: four regarding urges to use METH (“How much do you crave/desire/want METH right now?”, and “If you had access to METH right now, how likely would you be to use it right away?”) two questions regarding mood (“How depressed/anxious do you feel right now?”) and three questions regarding physical state (“Do you feel any drug effect right now?”, “How high are you right now?”, and “How stimulated do you feel right now?”). Desire was specifically defined in subtext next to the question as “to want (a feeling)” and crave as “strong or intense need (an internal force)”.
2.6 Heart Rate Variability Recording
Electrocardiogram (ECG) activity was recorded over 10-min intervals using two active EL126 snap leads and EL204 electrodes placed on the left pectoral and sternum with a third grounded lead/electrode placed on the left lateral rib cage. ECG data was filtered through a PSYLAB Isolation BioAmplifier and measured using a PSYLAB Stand Alone Monitor (Contact Precision Instruments, Cambridge, MA). The ECG data was recorded at 500 Hz and stored in PSYLAB Measurement acquisition software on a Latitude D600 Dell laptop.
2.7 Subjective Response Analysis
Subjective reports provided prior to (time = 0), during (time = 5), after (time = 10) and following (time = 15) each cue condition served as the dependent measure of greatest interest. Change in craving for each cue condition, rather than raw craving score, was analyzed in order to measure acute cue-induced craving, to eliminate baseline variability between participants, and to account for carry-over effects between cue conditions. The craving change score was calculated by subtracting the baseline rating (time = 0) for each cue condition from the ratings at later time points (time = 5, 10, 15). A within-subjects general linear model (GLM) for repeated measures was used to assess the effect of cue condition and time on each subjective measure independently. In the case that sphericity could not be assumed (Mauchly’s Test of Sphericity), the statistics reported were adjusted via the Greenhouse-Geisser method. A one-way ANOVA, including post hoc analysis (Tukey), was used to compare cue conditions at each time point (time = 5, 10, 15). A Pearson bivariate correlation was also applied to assess the relationship between recent drug use and subjective responding. Statistical analysis was performed using SPSS 11 for Mac OS X.
2.8 Heart Rate Variability Analysis
The ECG data was transferred to QRS Tool where the inter-beat interval (IBI) was manually extracted from an 8-min segment of each 10-min recording (excluding first and last minute to reduce artifacts) (Allen et al., 2007
). Successive R-waves in each QRS complex were marked using individualized amplitude thresholds and the average heart beat period as guiding factors. The IBI series was then transferred to Kubios HRV 2.0 analysis software where time-domain and frequency-domain (parametric AR modeling) analyses were conducted (1996). The three frequency bands extracted for analysis included a very low frequency band (VLF, 0–0.04 Hz), a low frequency band (LF, 0.04–0.15 Hz), and a high frequency band (HF, 0.15–0.4 Hz). The measures of interest extracted from each frequency band included 1) the relative powers of VLF, LF, and HF bands, 2) the normalized LF and HF band powers and 3) the LF/HF power ratio. The time domain and frequency domain measures were analyzed separately using two multivariate GLMs for repeated measures to assess for an overall effect of cue condition on each set of HRV measures. A Pearson bivariate correlation was also applied to assess the relationship between recent drug use and heart rate variability. Statistical analysis was performed using SPSS 11 for Mac OS X.
2.9 High and Low Craving Participant Analysis
The participants were characterized as “high craving” and “low craving” participants using a median split on baseline “crave METH” scores. The two groups were assessed for differences in demographic and drug use characteristics, and heart rate variability measures. A one-way ANOVA was used to compare all demographic and drug use characteristics, except gender and ethnicity, which were assessed using a Chi-Square test. A multivariate GLM for repeated measures was used to assess an effect of craving group on time domain and frequency domain HRV measures separately. A one-way ANOVA was then used to assess group differences in each time domain and frequency domain HRV measure independently. Lastly, a Pearson bivariate correlation was applied to each craving group separately to assess the relationship between change in subjective responses and HRV measures during each cue condition.