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An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults

Scott H. Kollins

a Department of Psychiatry and Behavioral Science, Duke University School of Medicine, Durham, NC

Erin N. Schoenfelder

b Department of Psychiatry; Seattle Children’s Hospital, Seattle, WA

Joseph S. English

a Department of Psychiatry and Behavioral Science, Duke University School of Medicine, Durham, NC

Alex Holdaway

a Department of Psychiatry and Behavioral Science, Duke University School of Medicine, Durham, NC

Elizabeth Van Voorhees

c Durham VA Medical Center, Durham, NC

Benjamin R. O’Brien

a Department of Psychiatry and Behavioral Science, Duke University School of Medicine, Durham, NC

Rachel Dew

a Department of Psychiatry and Behavioral Science, Duke University School of Medicine, Durham, NC

Allan K. Chrisman

a Department of Psychiatry and Behavioral Science, Duke University School of Medicine, Durham, NC

Abstract

Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10 mg oral doses of delta-9-tetrahydocannibinol (THC); and 0 mg, 10 mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10 mg THC + 0 mg, 10 mg, and 40 mg MPH = 89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of “Feel Drug,” “Good Effects,” and “Take Drug Again.” THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures.

1. Introduction

Methylphenidate (MPH) is considered a front-line treatment for the clinical management of attention deficit hyperactivity disorder (ADHD) (Pliszka et al., 2006). Although hundreds of studies have documented the efficacy of MPH for treating ADHD (Faraone, Biederman, & Roe, 2002; Faraone & Buitelaar, 2010; Faraone, Spencer, Aleardi, Pagano, & Biederman, 2004), significant increases in prescription rates of MPH over the last 15 years have led to controversy about abuse, misuse, and diversion of the drug (Robison, Sclar, Skaer, & Galin, 1999; Safer, Zito, & Fine, 1996; Sembower, Ertischek, Buchholtz, Dasgupta, & Schnoll, 2013; Visser, Blumberg, Danielson, Bitsko, & Kogan, 2013; Visser et al., 2014; Zito et al., 2000; Zosel, Bartelson, Bailey, Lowenstein, & Dart, 2013).

Prevalence of prescribed stimulant misuse is highest among individuals between 12 and 25 years of age, ranging from 0.9% to 10.0% across studies. A number of studies report that stimulant diversion is a common problem, even among children as young as 6th grade (Johnston, O’Malley, Bachman, & Schulenberg, 2006; Kroutil et al., 2006; McCabe, Boyd, & Young, 2007; McCabe, Knight, Teter, & Wechsler, 2005; McCabe, Teter, & Boyd, 2004; McCabe, Teter, & Boyd, 2006; McCabe & West, 2013; Poulin, 2001).

Illicit users of prescription stimulants, including MPH, have higher rates of other drug and alcohol use, including cannabis (Barrett, Darredeau, Bordy, & Pihl, 2005; Low & Gendaszek, 2002; McCabe, Cranford, & Boyd, 2006; McCabe, Cranford, Morales, & Young, 2006; McCabe &West, 2013; McCabe et al., 2004, 2005, 2007; Poulin, 2001; Teter, McCabe, Cranford, Boyd, & Guthrie, 2005; Wilens, Gignac, Swezey, Monuteaux, & Biederman, 2006; Williams, Goodale, Shay-Fiddler, Gloster, & Chang, 2004). Most studies, however, have not differentiated between concurrent use (use of more than one drug within some specified time period; e.g., past 12 months) and simultaneous use (co-ingestion of more than one drug at the same time) (Martin, Clifford, & Clapper, 1992; Massello & Carpenter, 1999; Schensul, Convey, & Burkholder, 2005). Those studies that have assessed simultaneous substance use among illicit prescription stimulant users, suggest that it is very common for these drugs to be used in combination with marijuana; one study found that 52% of undergraduate illicit MPH users reported simultaneous use with marijuana (Barrett, Darredeau, & Pihl, 2006).

Both MPH and oral formulations of delta-9-tetrahydrocannabinol (THC) – the primary psychoactive component of smoked marijuana – result in robust cardiovascular (Hart, Haney, Vosburg, Comer, & Foltin, 2005; Kollins & Rush, 1999; Rush, Essman, Simpson, & Baker, 2001; Rush, Kollins, & Pazzaglia, 1998), subjective (Hart et al., 2002, 2005; Rush et al., 1998, 2001), and performance effects (Coghill et al., 2013; Curran, Brignell, Fletcher, Middleton, & Henry, 2002; Hammerness, Fried, Petty, Meller, & Biederman, 2013; Lane, Cherek, Tcheremissine, Lieving, & Pietras, 2005; Linssen, Sambeth, Vuurman, & Riedel, 2014; McDonald, Schleifer, Richards, & de Wit, 2003; Nandam et al., 2011; Ramaekers et al., 2006). Although several studies have examined the interactive effects of smoked marijuana administered in combination with other stimulant-like drugs (e.g., cocaine, nicotine) (Foltin & Fischman, 1990; Penetar et al., 2005), no studies to date have explicitly examined the effects of MPH and THC co-administration.

The effects of simultaneous MPH and marijuana use may differ from the effects of either drug alone. Both MPH and marijuana, for instance, increase heart rate and blood pressure when administered acutely, even with oral formulations of delta-9-tetrahydrocannabinol (THC) (Hart et al., 2005; Kollins & Rush, 1999; Rush et al., 1998, 2001). With respect to subjective drug effects, both MPH and oral THC acutely increase ratings of “good effects,” “like drug,” and “like to take again” (Hart et al., 2002, 2005; Rush et al., 1998, 2001). In addition to physiological and subjective effects, MPH-THC co-administration may result in unique behavioral effects compared with the acute effects of each drug. THC administered alone either orally or in smoked form has been shown to disrupt a range of neurocognitive endpoints, including decision making (Lane et al., 2005), inhibitory control (McDonald et al., 2003; Ramaekers et al., 2006), and memory (Curran et al., 2002); though these effects have not been categorically replicated (Vadhan et al., 2007). By contrast, MPH has been shown to improve a range of neurocognitive endpoints, including inhibitory control and memory in individuals with and without ADHD (Coghill et al., 2013; Hammerness et al., 2013; Linssen et al., 2014; Nandam et al., 2011). It is not known whether the simultaneous use of THC and MPH results in additive effects on cardiovascular function and/or subjective effects; or whether MPH would serve to mitigate the performance impairing effects of marijuana.

Given the reported rates of simultaneous use of MPH and marijuana (Barrett et al., 2005, 2006), characterizing the effects of these specific drugs in combination is important to more fully evaluate the potential risks of co-administration. The primary objective of the present study therefore was to assess the effects of orally administered THC (dronabinol) alone (0 mg vs. 10 mg) and in combination with two doses of immediate release methylphenidate (0 mg, 10 mg, 40 mg) in a blinded fashion on measures of cardiovascular function (heart rate, blood pressure), subjective drug effects, and cognitive function (inhibitory control, attention, and working memory).

Given the exploratory nature of this study, we elected to use orally administered THC since it was more practical to administer in the context of a human laboratory study. Orally administered THC has been shown to have similar subjective and cardiovascular effects as smoked marijuana; and produces dose-dependent increases in plasma THC levels (Chait & Zacny, 1992; Hart et al., 2002; Wachtel, ElSohly, Ross, Ambre, & de Wit, 2002) and we therefore reasoned that an oral THC would be a safe and practical approach for an initial investigation of the combined effects of MPH and THC.

2. Methods

2.1. Subjects

Sixteen subjects (10 males, 6 females) with a history of recreational marijuana use participated in the study after providing informed consent approved by the local Institutional Review Board. All subjects underwent a physical examination by a licensed physician, and medical and developmental histories were obtained. Current and previous drug use, including alcohol and cigarettes, were also measured at screening. To participate in the study, subjects were required to be between the ages of 18–45 years (mean age = 24.6 years), inclusive; have a body mass index >18 but 100 beats/minute or a systolic blood pressure >150 mm/Hg; reported a history of any significant medical problems (e.g., seizures, cardiac abnormalities, etc.); were currently prescribed any psychoactive medications; had an estimated IQ of 100 bpm) following the combination of 40 mg MPH and 10 mg THC. The study physician monitored the participant and performed an ECG. The participant remained in the lab for several extra hours to ensure safety. Since this event occurred on his last study visit, he did not have to be return for any additional study visits.

3.1.1. Heart Rate

Table 1 shows peak effects results for heart rate, systolic and diastolic blood pressure, and rate-pressure product. Both MPH and THC resulted in significant main effects on heart rate. In the absence of MPH (i.e., MPH placebo condition), there was no difference between the placebo and 10 mg THC conditions (84.3 vs. 89.1 bpm, respectively). In the absence of THC, 40 mg MPH resulted in significantly greater heart rate compared to both the 10 mg MPH and 0 mg MPH conditions. The combination of 10 mg THC and both the 10 mg and 40 mg MPH doses resulted in significantly higher heart rate than either of these MPH conditions in combination with 0 mg THC. Finally, when administered in combination with 10 mg THC, 40 mg MPH resulted in significantly higher heart rate than 0 mg MPH.

Table 1

Mean peak effects (SD) for vital signs across dose levels of MPH and THC.

Peak Effects MPH Dose THC F MPH F THC ×
MPH F
0 mg 10 mg 40 mg
0 mg THC 10 mg THC 0 mg THC 10 mg THC 0 mg THC 10 mg THC
Heart Rate 84.3 (10.6) 89.1 (8.3) 83.6 (11.8) 95.9 (10.1) 95.3 (15.4) 102.0 (18.1) 26.73 ** 14.39 ** 1.32
Systolic BP 136.1 (13.2) 139.1 (16.9) 137.3 (9.8) 136.1 (15.8) 142.3 (15.3) 145.1 (17.1) 0.41 4.79 * 0.91
Diastolic BP 83 (5.9) 85.9 (11.8) 83.5 (8.0) 83.1 (5.6) 87.5 (11.2) 88.1 (9.7) 0.4 4.49 * 0.5
Rate pressure product 11441.8 (1584.1) 12352.0 (1610.5) 11425.5 (1478.6) 13031.1 (1847.0) 13461.1 (2025.5) 14845.8 (3429.0) 10.7 ** 16.45 ** 0.19

Right columns indicate F-values for 2 factor repeated measures ANOVA.

Table 2

Mean peak effects(SD)for subjective effects measures across dose levels of MPH and THC.

ARS peak effects MPH Dose THC F MPH F THC × MPHF
0 mg 10 mg 40 mg
0 mg THC 10 mg THC 0 mg THC 10 mg THC 0 mg THC 10 mg THC
Stimulant subscale 26.3 (3.7) 27.1 (4.6) 27.4 (5.0) 27.4 (5.9) 32.0 (7.3) 32.2 (5.8) 0.00 7.61 ** 0.01
Sedative subscale 27.3 (8.4) 30.5 (7.6) 23.8 (6.7) 30.9 (10.8) 24.6 (5.2) 29.8 (8.7) 11.35 ** 0.47 2.58
ARCI peak effects
PCAG 6.0 (3.6) 8.3 (3.8) 4.6 (2.6) 8.1 (3.9) 5.3 (2.9) 8.7 (3.8) 36.74 ** 0.71 1.47
BG 5.1 (2.1) 5.9 (2.3) 6.3 (2.7) 6.1 (3.1) 7.4 (2.8) 6.6 (2.2) 0.00 5.12 * 2.70
LSD 4.9 (2.0) 5.8 (2.3) 4.2 (2.3) 5.8 (3.0) 5.1 (2.7) 6.8 (2.4) 22.18 ** 2.47 1.00
MBG 7.0 (4.5) 9.9 (5.6) 9.3 (6.4) 10.6 (6.9) 11.5 (6.2) 12.3 (4.9) 3.69 7.64 ** 0.74
A 3.3 (2.5) 4.5 (2.9) 4.3 (3.0) 4.6 (2.8) 5.5 (2.7) 5.6 (2.4) 2.07 6.51 ** 0.72
DEQ peak effects
Feel drug effect 35.9 (32.3) 78.5 (17.3) 47.9 (32.1) 75.8 (21.3) 75.3 (24.5) 82.7 (16.5) 35.44 ** 10.71 ** 5.87 **
Good effect 34.9 (28.6) 68.9 (14.0) 55.6 (28.6) 68.3 (24.3) 67.9 (21.9) 78.8 (16.5) 26.35 ** 9.59 ** 4.62 *
Bad effect 19.6 (22.9) 41.9 (22.2) 22.3 (24.1) 28.3 (25.7) 36.1 (29.3) 47.6 (29.9) 9.10 ** 7.64 ** 2.68
Like drug 55.6 (13.6) 67.7 (15.2) 58.1 (22.1) 66.8 (20.5) 68.4 (17.9) 73.1 (15.9) 8.94 ** 6.50 ** 0.87
Friendly 72.8 (17.3) 70.7 (16.3) 68.8 (15.4) 75.1 (18.5) 76.5 (17.0) 74.9 (16.6) 0.04 1.40 1.61
Confused 18.6 (22.8) 34.7 (27.8) 16.9 (22.6) 32.6 (27.1) 29.3 (31.0) 41.7 (31.6) 13.15 ** 6.21 ** 0.05
Concentrate 77.8 (17.9) 74.8 (14.9) 76.1 (18.1) 73.9 (17.7) 81.4 (17.5) 77.4 (15.2) 3.99 2.01 0.04
Excited 51.6 (23.1) 52.1 (21.6) 51.6 (26.2) 52.3 (25.7) 63.8 (22.2) 67.2 (22.2) 0.33 7.15 ** 0.09
Alert 71.5 (19.2) 71.7 (14.6) 79.2 (15.8) 71.9 (19.3) 81.9 (14.1) 77.7 (13.8) 5.04 * 2.53 0.77
Relaxed 76.4 (16.7) 75.5 (13.0) 73.6 (16.1) 81.8 (15.3) 76.1 (17.3) 79.4 (16.5) 1.15 0.38 1.35
Take drug 57.6 (23.3) 65.2 (19.4) 54.8 (25.0) 67.2 (21.0) 71.9 (18.4) 71.3 (19.0) 3.92 4.72 * 4.57 *

Right columns indicate F-values for 2 factor repeated measures ANOVA.

Table 3

CPT and n-Back performance measures [mean (SD)] across dose levels of MPH and THC.

CPT MPH dose THC F MPH F THC ×
MPH F
0 mg 10 mg 40 mg
0 mg THC 10 mg THC 0 mg THC 10 mg THC 0 mg THC 10 mg THC
Omission errors (#) 3.2 (4.8) 5.3 (8.9) 1.4 (1.5) 1.9 (4.4) 1.3 (2.6) 3.9 (6.7) 2.11 2.61 0.6
Commission errors (#) 10.0 (9.2) 14.0 (7.4) 10.5 (7.3) 11.0 (7.9) 10.3 (10.1) 12.5 (9.9) 5.37 * 0.52 0.58
Reaction time (ms) 349.3 (109.1) 335.6 (99.7) 338.7 (99.2) 330.2 (99.0) 354.0 (49.1) 332.5 (108.7) 0.61 0.32 0.07
Reaction time SE (ms) 6.2 (3.2) 8.6 (7.9) 5.8 (2.8) 4.9 (2.1) 4.5 (1.8) 5.8 (4.2) 1.03 7.18 ** 1.34
n-Back % correct
0-back 0.99 (0.03) 0.98 (0.04) 0.98 (0.05) 1.0 (0.02) 0.99 (0.03) 1.0 (0.0) 0.03 1.46 2.03
1-back 0.99 (0.02) 0.96 (0.11) 0.94 (0.13) 0.98 (0.04) 0.98 (0.04) 0.96 (0.11) 0.08 0.11 1.9
2-back 0.88 (0.19) 0.87 (0.19) 0.82 (0.22) 0.85 (0.23) 0.86 (0.22) 0.95 (0.10) 0.04 1.64 0.92
3-back 0.80 (0.25) 0.73 (0.27) 0.72 (0.26) 0.79 (0.27) 0.76 (0.25) 0.77 (0.26) 1.42 0.07 3.33
n-Back reaction time (ms)
0-back 446.0 (57.6) 442.9 (61.8) 488.8 (84.4) 464.6 (65.1) 427.4 (65.7) 421.2 (36.4) 0.73 7.50 ** 0.47
1-back 457.7 (82.4) 493.3 (96.2) 465.5 (89.0) 460.8 (75.9) 424.5 (65.5) 451.6 (93.4) 3.51 2.46 0.86
2-back 552.9 (155.8) 577.6 (120.3) 575.2 (150.5) 552.8 (153.2) 477.5 (90.4) 499.7 (116.3) 0.23 4.40 * 0.85
3-back 611.0 (115.1) 674.1 (180.5) 596.4 (125.1) 631.6 (178.7) 526.5 (103.1) 600.4 (127.4) 5.98 * 2.62 0.33

Right columns indicate F-values for 2 factor repeated measures ANOVA.

An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy