MDMA and social context

Harriet de Wit and Anya Bershad

Department of Psychiatry and Behavioral Neuroscience University of Chicago Disclosure

• No conflicts related to this presentation

• HdW has received research support from Insys Therapeutics, Pfizer and Indivior; consulting fee from Jazz Pharmaceuticals. Drugs are used in social contexts Coffee house, Istanbul 19th C Bidirectional relationship 1. Drugs increase enjoyment of social setting 2. Social contexts increase enjoyment of drugs

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SOCIAL DRUG CONTEXT

+++ Drugs in social settings

• Social settings influence responses to drugs – Laboratory animals – Controlled studies with humans • Drugs influence social interactions

• Yet, most psychopharmacology research is conducted under isolated conditions, and we know little about effects of drugs in social contexts. “Socio-pharmacology”

[sōsēˈo fahr-muh-kol-uh-jee]

• from Latin socius a fellow, companion, comrade; Greek pharmakon, "drug”

• the scientific study of the effects drugs have on mood, sensation, thinking, and behavior in the presence of others MDMA, Ecstasy MDMA: A prototypic pro-social drug

‘Entactogens’; MDMA ±3,4 methylenedioxymethamphetamine; MDA, MDEA

• Increase NE, DA, 5-HT: – Stimulate release – Block reuptake – Inhibit metabolism • 5-HT2A,B agonists • Release oxytocin MDMA vs prototypic stimulants

MDMA, MDA, MDEA d-amphetamine, methamphetamine, • Increase NE, DA, 5-HT: methylphenidate – Stimulate release – Block reuptake •Increase NE, DA, 5-HT: – Inhibit metabolism –Stimulate release • –Block reuptake 5-HT2A agonist –Inhibit metabolism • Release oxytocin MDMA vs other stimulants: Effects on social processes?

1. Self-reports of feeling sociable, desire to socialize 2. Emotional response to positive or negative, social or nonsocial images 3. Perception of social stimuli; detecting positive or negative emotions 4. Response to acute stress 5. Sexual or nonsexual Our studies • Double blind, placebo controlled • MDMA (0.5-1.5 mg/kg oral), d- amphetamine or methamphetamine (10 or 20 mg oral) • Healthy men and women 18-35 – No psychiatric diagnoses or substance dependence – Minimum high school – Lifetime ecstasy use: 4-40 occasions – Menstrual cycle phase controlled Typical Session Protocol 1. Self-reports of feeling sociable

• Both MDMA and methamphetamine increase ratings of feeling sociable • Rating scales: e.g., feeling friendly, sociable, loving, playful, talkative

(Bedi et al, 2009; Wardle et al 2014a;b Kirkpatrick et al 2014) VAS ‘Sociable’ VAS ‘Loving’ VAS ‘Playful’ 2. Ratings of positivity or negativity of images (Wardle et el, 2011; Kirkpatrick et al, 2014) • IAPS images – Positive and negative – Social (with two or more people) or nonsocial (no people) • Amphetamine increased positivity ratings of all positive images • MDMA increased positivity ratings of positive social images only 3. Perception of emotion

• MDMA and other stimulants differentially affect ability to detect emotions in others – Fearful – Angry – Happy – Sad – Neutral

(Wardle et al 2014a;b Kirkpatrick et al 2014) Emotion Identification MDMA decreases recognition of anger d-amphetamine improves recognition of all emotions Neural responses to emotions

• Do either MDMA or amphetamine alter neural responses to emotional faces? – MDMA decreased amygdala response to negative faces – amphetamine increased amygdala response to negative stimuli

(Bedi et al, 2010; Wardle et al 2014a;b Kirkpatrick et al 2014) Emotion Perception Task

Perception: Match Faces Contrast:

Faces: Angry/Fear – Happy

Angry Faces Happy Faces

Control task MDMA (1.5 mg/kg) reduced anger-induced activation in the left amygdala D-amphetamine increased amygdala response to fearful and angry faces Hariri et al, 2002 4. Effects on social stress

• Trier Social Stress Test (public speaking) – MDMA (0 or 0.5 mg/kg) – D-amphetamine (0, 5, 10 mg) • Measures – Mood ratings – Heart rate – Cortisol

(Childs et al, in press; Bershad et al unpublished) MDMA increased stress-induced ratings of ‘tense’ (Bershad et al, ECNP Poster) TSST

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( -20 -30 -20 -10 0 10 20 40 60 80 Time post-task (min) D-Amphetamine had little effect on stress-induced ‘tense’ rating (Childs et al, 2016) 5. Effects on sexual responses? (Liechti et al, 2015; Schmid et al, 2015) • Subjects rated erotic images as ‘arousing’/ ‘exciting’, after MDMA (75 mg), methylphenidate (40 mg) or placebo • Images were either implicitly sexual or explicitly sexual • Methylphenidate increased arousal ratings to sexually explicit images • MDMA did NOT increase ratings in response to explicit images Appraisal of Erotic Stimuli (Schmid et al. 2015) INTERIM Summary MDMA Amph

Self report of sociability Increase Increase

Ratings of positive images Only social images All more more positive positive

Perception of emotions Worse detection Better all of anger emotions

Amygdala response, threat Decrease Increase faces Acute stress response Increase Minimal effect

Explicit sexual stimuli No effect Increase Behaviors for which there are data for MDMA but not other stimulants

1. Autobiographical memories 2. Speech content 3. Trustworthiness 4. Generosity 5. Social rejection Bidirectional relationship 1. Drugs increase enjoyment of social setting 2. Social contexts increase enjoyment of drugs

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SOCIAL DRUG CONTEXT

+++ Future research

• Behavioral constructs • Pharmacological specificity • Neural mechanisms of behavioral effects (serotonin, oxytocin?) • Relationship to drug consumption? • Develop field of ‘socio-pharmacology’ Acknowledgments Emma Childs, Melissa Miller, Matthew Kirkpatrick, Margaret Wardle, Gillinder Bedi, Matthew Baggott, Royce Lee, Jacob Seiden, Brooke Slawinski, National Institute on Drug Abuse