The Human Behavioral Pharmacology Laboratory conducts research studies on the effects of psychoactive drugs in human volunteers. The research is supported by the National Institute on Drug Abuse and the National Institute on Alcoholism and Alcohol Abuse. The studies are designed to identify factors that affect the risk for drug abuse, and to characterize the behavioral effects of drugs in different individuals. The laboratory studies different types of drugs, including stimulants (such as caffeine and amphetamine), alcohol, delta-9-tetrahydrocannabinol (found in marijuana), and nicotine. We are investigating genetic variation in responses to several drugs, by assessing the subjective and behavioral effects of the drugs in relation to variations in the genes involved in their actions in the brain. We are also studying the effects of stress or environmental context on responses to drugs, to identify variables that could increase or decrease the likelihood of drug taking. Finally, in other studies we are investigating the effects of drugs on impulsive behaviors, memory and reactions to emotional stimuli. The research is conducted under highly controlled laboratory conditions, in which many extraneous factors that could influence drug responses are minimized (e.g., expectancies, other drug use, peer influences). The studies use standardized behavioral procedures, some of which are parallel to procedures used in preclinical, animal studies. The following summarizes some of our recent interesting findings.
In one recent study (Bedi et al, 2011), we examined craving responses to smoking-related stimuli (pictures of cigarettes and ashtrays) in cigarette smokers who abstained from smoking for 7, 14 or 35 days. The group who abstained for 35 days reported greater cue-induced craving than the groups who abstained for 7 or 14 days. Thus, cue-induced craving does not simply dissipate with time, but may “incubate”. The study was based on parallel, published studies conducted with rats. In those studies, cues that were paired with drug self-administration also elicited greater responses after the animals were left undisturbed in their home cages for weeks or months. This finding has direct clinical implications for drug abuse inpatient treatment settings where drug users are removed from their home environments and all their drug-related stimuli for extended periods of time: They may experience more, rather than less, craving when they return to their home settings.
Genetic variation in the effects of caffeine:
People differ in their subjective responses to caffeine: In some people caffeine produces feelings of stimulation and energy whereas other people experience unpleasant effects such as anxiety. We have studied these inter-individual variations in the effects of caffeine, in relation to the subjects’ DNA (Alsene et al, 2003; Childs et al. 2008; Yang et al, 2010). We found that people who have a certain form of the adenosine receptor gene (caffeine acts on adenosine receptors) experience more anxiety from the drug than people without this variant.
Place preference with drugs:
People often form strong positive associations with the places where they use drugs (e.g., bars, sports arenas, casinos). Studies with animal models indicate that learning processes mediate these associations, and show that rodents also form strong preferences for places where they have experienced drugs believed to be rewarding. We have developed a procedure to study place conditioning in humans (Childs et al, 2009; Childs and de Wit, in press). We find that participants come to like a place (i.e., a room) where they have received a stimulant drug more than a room where they received a placebo. Learned associations between drugs and environments may increase drug-taking behavior, or other risky behavior, in the drug-associated context. Thus, it is a potential target for developing treatment interventions for people who are trying to abstain from drug use.
Publications: 2010 - 2012
King, A.C., D. Cao, S.S. O’Malley, H.R. Kranzler, X. Cai, H. de Wit, A.K. Matthews, R.J. Stachoviak. (in press) Efficacy of naltrexone on smoking cessation quit rates and weight gain in men and women. Journal of Clinical Psychopharmacology.
Yip, S.W., J. Doherty, J. Wakeley, K. Saunders, C. Tzagarakis, H. de Wit, G.M. Goodwin, R.D. Rogers. (2012) Reduced subjective response to acute ethanol administration among young people with the bipolar phenotype. Neuropsychopharmacology. PMID:22491350.
de Wit, H. and T. J. Phillips (2012). Do initial responses to drugs predict future use or abuse? Neuroscience and Biobehavioral Reviews. PMID:22542906.
Hart, A. B., H. de Wit, et al. (2012). Genetic Factors Modulating the Response to Stimulant Drugs in Humans.Current Topics in Behavioral Neurosciences. PMID:22261702.
Wardle, M. C., M. J. Garner, et al. (2012). Amphetamine as a social drug: effects of d-amphetamine on social processing and behavior. Psychopharmacology (Berl). PMID:22526538.
Ballard, M. E., Bedi, G., & de Wit, H. (2012) Effects of delta-9-tetrahydrocannabinol on evaluation of emotional images. Journal of Psychopharmacology. PMID:22585232.
Rabinak, C., C. Sripada, C.M. Angstadt, H. de Wit, and K.L. Phan. (2012) Cannabinoid modulation of subgenual anterior cingulate cortex activation during experience of negative affect. Journal of Neural Transmission. PMID:22160489.
Ballard, M.E., Gallo, D.A., and de Wit, H. (2012) Psychoactive drugs and false memory: comparison of dextroamphetamine and delta-9-tetrahydrocannabinol on false recognition.Psychopharmacology PMID:21647577.
Wardle, M.C., Yang, A., and de Wit, H. (2012) Effect of d-amphetamine on post-error slowing in healthy volunteers.Psychopharmacology PMID: 21894485.
Wardle, M.C., and de Wit, H. (2012) Effects of amphetamine on reactivity to emotional stimuli.Psychopharmacology. PMID: 21947316.
Childs, E., Roche, D.J., King, A.C., and de Wit H. (2012) Varenicline potentiates alcohol-induced negative subjective responses and offsets impaired eye movements.Alcoholism: Clinical Experimental Research. PMID: 22339626
Wardle, M.C., M.T. Treadway, L.M. Mayo, D.H. Zald, and H. de Wit (2011) Amping up effort: Effects of d-amphetamine on human effort-based decision-making. Journal of Neuroscience. 31, 16597-602 PMID: 22090487
Wardle, M., M. Munafo, & de Wit, H. (2011) Effect of social stress during acute nicotine abstinence. Psychopharmacology. PMID: 21234550
Childs, E., S. O'Connor, H. de Wit (2011) Bidirectional interactions between acute psychosocial stress and acute IV alcohol. Alcoholism: Clinical and Experimental Research. PMID: 21762177.
Dlugos, A.M., A. Hamidovic, C.A. Hodgkinson, S. Pei-Hong, D. Goldman, A.A. Palmer, & de Wit, H. (2011) OPRM1 gene variants modulate amphetamine-induced euphoria in humans. Genes, Brain and Behavior, 10, 199-209 PMID: 2102937
King, A, H. de Wit, P. McNamara, & D.-C. Cao (2011). Stimulant and sedative alcohol responses and relationship to future drinking. Archives of General Psychiatry, 68, 389-399. PMID: 21464363
Ballard, M., & de Wit, H. (2011). Combined effects of acute, very-low-dose ethanol and delta(9)- tetrahydrocannabinol in healthy human volunteers. Pharmacology, Biochemistry and Behavior, 97, 627-31. PMC3018238
Bedi, G., K.L. Preston, D.H. Epstein, S.J. Heishman, G.F Marrone, Y. Shaham, & de Wit, H. (2011) Incubation of cue-induced cigarette craving during abstinence in human smokers. Biological Psychiatry, 69, 708-11 PMID: 20817135
Hamidovic, A. A.M. Dlugos, A.A. Palmer, & de Wit (2010) Polymorphisms in dopamine transporter (SLC6A3) are associated with stimulant effects of d-amphetamine: an exploratory pharmacogenetic study using healthy volunteers. Behavior Genetics 40, 255-260. PMID: 20091113
Childs, E., Van Dam, N. T., & de Wit, H. (2010) Effects of acute progesterone administration uopn responses to accute psychosocial stress in men. Experimental Clinical Psychopharmacology, 18, 78-86. PMID: 20158297
Dlugos, A.M., A. Hamidovic, C.A. Hodgkinson, D. Goldman, A.A. Palmer, & de Wit (2010) More aroused, less fatigued: FAAH gene polymorphisms influence acute response to amphetamine. Neuropsychopharmacology , 35, 613-22. PMID: 19890266
Porcu, P, T.K. OBuckley, S.E. Alward, K.A. Grant, H. de Wit, & A.L. Morrow (2010) Differential effects of ethanol on serum GABAergic 3α,5α/3α,5β neuroactive steroids in mice, rats, Cynomolgus monkeys and humans. Alcoholism: Clinical Experimental Research, 34, 432-42 PMID: 20028362
McCloskey, M., A.A. Palmer,& de Wit, H. (2010) Is self-reported liking of d-amphetamine related to impulsivity? Psychopharmacology, 208, 201-9. PMID: 19936714
Hamidovic, A., E. Childs, M. Conrad, A. King, & H. de Wit (2010) Stress-induced changes in mood and cortisol release predict mood effects of amphetamine. Drug and Alcohol Dependence, 109 175-180. PMC2875349
Yang, A., Palmer, A. A., & de Wit, H (2010) Genetics of caffeine consumption and caffeine response. Psychopharmacology, 211, 245-257. PMID: 20532872
Childs, E., A.M. Dlugos, & de Wit, H. (2010) Cardiovascular, hormonal, and emotional responses to the TSST in relation to sex and menstrual cycle phase. Psychophysiology, 47 550-55. PMID: 20070572
Hamidovic, A. A.M. Dlugos, A.A. Palmer, & de Wit, H. (2010). Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine. Psychiatric Genetics, 25, 85-92. PMC2875066
Childs, E., & de Wit, H. (2010). Acute psychosocial stress increases cigarette craving and smoking pleasure. Nicotine and Tobacco Research, 12, 449-453. PMC2847070
Lejuez, C.W., J.R. Magidson, S.H. Mitchell, R. Sinha, M. Stevens, & de Wit, H. (2010). Behavioral and biological indicators of impulsivity in the development of alcohol use disorders. Alcoholism: Clinical and Experimental Research, 34, 1334- 45. PMID: 20491733
Mueller, D., & de Wit, H. (2011). Conditioned place preference in rodents and humans. Neuromethods, 50, 133-152.
Mahler, S.V., & de Wit, H. (2010). Cue-Reactors: Individual differences in cue-induced craving after food or smoking abstinence. PLoS ONE, 5:e15475 PMID: 21085667
Bedi, G., D. Hyman, & de Wit, H. (2010). Is ecstasy an "empathogen"? MDMA increases social feelings but blunts identification of negative emotions in others. Biological Psychiatry, 68, 1134-40. PMID: 20947066
Wardle, M., K. Cederbaum, & de Wit, H. (2010) Quantifying talk: Developing reliable measures of verbal productivity. Behavior Research Methods, 43:168-178 PMID: 21287128
Publications: 2006 - 2009
Terner, J. M., & de Wit, H. (2006). Menstrual cycle phase and responses to drugs of abuse. Drug and Alcohol Dependence, 84, 1-13.
Reynolds, B., Ortengren, A., Richards, J. B., & de Wit, H. (2006). Dimensions of impulsive behavior: Personality and behavioral measures. Personality and Individual Differences, 40, 305-315.
Acheson, A., Mahler, S. V., Chi, H., & de Wit, H. (2006) Differential effects of nicotine on alcohol consumption in men and women. Psychopharmacology, 186(1):54-63.
King, A., Munisamy, G., de Wit, H. & Lin, S. (2006) Attenuated cortisol response to alcohol in heavy social drinkers. International Journal of Psychophysiology, 59, 203-209.
Reynolds, B., Richards, J. B., & de Wit, H. (2006) Acute-alcohol effects on the Experiential Discounting Task (EDT) and a question-based measure of delay discounting. Pharmacology, Biochemistry and Behavior, 83(2):194-202
de Wit, H., Vicini, L., Haig, G., Hunt, T., & Feltner, D. (2006) Evaluation of the abuse potential of pagoclone, a partial GABA a agonist. Journal of Clinical Psychopharmacology, 26(3):268-73.
Acheson A., Farrar A.M., Patak M., Hausknecht, K.A., Kieres, A.K., Choi, S. de Wit H., Richards, J.B. (2006) Nucleus accumbens lesions decrease sensitivity to rapid changes in the delay to reinforcement. Behav Brain Research, 173, 217-228.
Flanagin, B. A., de Wit, H., & Cook, Jr, E. H. (2006) Association study of the brain-derived neurotrophic factor Val66Met polymorphism and amphetamine response. Neuropsychiatric Genetics, 141B(6), 576-583.
Lott, D. C., Kim, S. J., Cook, E. H., & de Wit, H. (2006) Serotonin transporter genotype and acute subjective response to amphetamine. American Journal on Addictions, 15(5):327-35.
King, A., de Wit, H., Riley, R. C., Cao, D., Niaura, R., & Hatsukami, D. (2006) Efficacy of naltrexone in smoking cessation: A preliminary study and an examination of sex differences. Nicotine and Tobacco Research, 8(5):671-82.
Acheson, A., Reynolds, B., Richards, J. B., & de Wit, H. (2006) Diazepam impairs behavioral inhibition but not delay discounting or risk taking in healthy adults. Experimental and Clinical Psychopharmacology, 14(2):190-8.
Childs, E., Vicini, L., & de Wit, H. (2006) Responses to the Trier Social Stress Test (TSST) in single versus grouped participants. Psychophysiology, 43(4):366-71.
de Wit, H., Vicini, L., Childs, E., Sayla, M., Terner, J. (2006) Does stress reactivity or response to d-amphetamine predict progression to smoking in young adults? A preliminary study. Pharmacol Biochem Behav, 2007 Feb;86(2):312-9
White, T.L., Grover, V.K., de Wit, H. (2006) Cortisol effects of d-amphetamine relate to traits of fearlessness and aggression but not anxiety in healthy humans. Pharmacol Biochem Behav, 85, 123-131.
Childs, E., & de Wit, H. (2006) Subjective, behavioural and physiological effects of acute caffeine administration in light, non-dependent caffeine users. Psychopharmacology, 185(4):514-23.
Hariri, A.R., Brown, S.M., Williamson, D.E., Flory, J.D., de Wit, H., S.B. Manuck (2006) Preference for immediate over delayed rewards is associated with magnitude of ventral striatal activity. The Journal of Neuroscience, 26, 13213-7.
de Wit, H., J.D. Flory, A. Acheson, M. McCloskey, S.B. Manuck. (2007) IQ and Nonplanning Impulsivity are independently associated with delay discounting in middle-aged adults. Personality and Individual Differences, 42, 111-121.
Dlugos, A., C. Freitag, C. Hohoff, J. McDonald, E.H. Cook, J. Deckert, H. de Wit (2007) Norepinephrine transporter gene variation modulates acute response to d-amphetamine. Biological Psychiatry 61, 1296-1305.
Acheson, A., Richards, J.B., de Wit H. (2007) Effects of sleep deprivation on impulsive behaviors in men and women. Physiology and Behavior, 91, 579-587.
White, T.L., C. W. Lejuez and H. de Wit (2007) Personality and gender differences in effects of d-amphetamine on risk-taking. Journal of Clinical and Experimental Psychopharmacology, 15, 599-609.
Childs E, de Wit H. (2008) Enhanced mood and psychomotor performance by a caffeine-containing energy capsule in fatigued individuals. Exp Clin Psychopharmacol, 16, 13-21.
Hamidovic, A., Kang, U., de Wit, H. (2008) Effects of low to moderate acute doses of pramipexole on impulsivity and cognition in healthy volunteers. Journal of Clinical Psychopharmacology, 28, 45-51.
Childs A., C. Hohoff, C., J. Deckert, X. Ke, J. Badner, H. de Wit (2008) Association between A1, A2a and DRD2 receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology, 33(12), 2791-2800.
Phan, K.L., M. Angstadt, J. Golden, I. Onyewuenyi, A. Popovska, H. de Wit (2008) Cannabinoid modulation of amygdala reactivity to social signals of threat in humans. J Neurosci, 28, 2313-2319.
Acheson, A., H. de Wit (2008) Bupropion improves attention but does not affect impulsive behavior in healthy men and women. J Exp Clin Psychopharmacol, 16, 113-123.
Miczek, K.A., H. de Wit (2008) Challenges for translational psychopharmacology research - Some basic principles. Psychopharmacology, 199, 291-301.
Bornovalova M.A., Cashman-Rolls A., O'Donnell J.M., Ettinger K., Richards J.B., de Wit H, Lejuez CW (2008) Risk taking differences on a behavioral task as a function of potential reward/loss magnitude and individual differences in impulsivity and sensation seeking. Pharmacol Biochem Behav, [Epub ahead of print].
White, T.L., C.W. Lejuez, H. de Wit (2008) Test-retest characteristics of the Balloon Analogue Risk Task (BART). Exp and Clin Psychopharmacol, 16, 565-570.
Childs, E., H. de Wit (2009) Hormonal, cardiovascular and subjective responses to acute stress in smokers. Psychopharmacology, 203, 1-12.
de Wit, H. (2009) Impulsivity as a determinant and consequence of drug use: A review of underlying processes. Addiction Biology, 1, 22-31.
Childs, E., H. de Wit (2009) Amphetamine-induced place preference in humans. Biological Psychiatry.
Hamidovic, A., H. de Wit (2009) Sleep deprivation increases smoking. Pharmacology, Biochemistry and Behavior.
de Wit, H. and L. Phan (2009) "Positive reinforcement theories of drug use." In: Substance Abuse and Emotion. Ed. Jon D. Kassel, American Psychological Association, Washington DC.
de Wit, H. and S. Mitchell (2009) "Drug Effects on Delay Discounting." In: Impulsivity: The behavioral and neurological science of discounting. Eds: G. J. Madden, W. K. Bickel, & T. S. Critchfield American Psychological Association, Washington DC.