BrainBrain serotoninserotonin functionfunction inin MDMAMDMA (( ““ecstasyecstasy ””)) usersusers
Boris B. Quednow 1, Felix Hasler 1, Valerie Treyer 2, Matthias T. Wyss 2, Katharina M. Rentsch 3, Gerrit Westera 4, Schubiger PA 4, Alfred Buck 2, Franz X. Vollenweider 1
1University Hospital of Psychiatry, Zurich, Switzerland 2Department of Nuclear Medicine, University Hospital Zurich, Switzerland 3Department of Clinical Chemistry, University Hospital Zurich, Switzerland 4Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland EcstasyEcstasy
• The use of Ecstasy is increasingly spreading since the end of the 1980s.
• Lifetime prevalence of Ecstasy use in European adolescents and young adults is about 4-5%.
• In Europe, Ecstasy is the second most popular illicit drug in adolescents and young adults following cannabis.
• Over the past 15 years, in Germany and Switzerland more than 90% of the confiscated Ecstasy pills contained exclusively the substituted amphetamine derivative MDMA.
• Ecstasy pills comprise of 60-65 mg MDMA on average, but with a great range (0-360 mg). SerotonergicSerotonergic neurotransmissionneurotransmission
Holmes, Neurosci Biobehav 2008
MDMA SelectiveSelective serotonergicserotonergic neurotoxicityneurotoxicity ofof MDMAMDMA
Sagittal plane of 5-HT immunoreaktive axons in the frontal cortex of squirrel monkeys after a treatment of 5 mg/kg MDMA 2x/die for 4 days.
Control 2 weeks after MDMA 7 years after MDMA
Hatzidimitriou et al., J Neurosci 1999 TheThe serotoninserotonin systemsystem
Birbaumer & Schmidt, 1999 SerotoninSerotonin isis involvedinvolved inin nearlynearly allall brainbrain functionsfunctions
•• MotorMotor activity activity •• MoodMood • • • CircadianCircadian rhythm rhythmSerotoninSerotonin isis anan enigma;enigma;• AnxietyAnxiety •• SleepSleep •• StressStress itit isis atat onceonce implicatedimplicated inin virtuallyvirtually everythingeverything •• AppetiteAppetite •• AggressionAggression •• SexualSexual regulation regulationbutbut responsibleresponsible forfor•• nothingnothingLearningLearning an .an. Memory Memory • • • PainPain processing processing JacobsJacobs && FornalFornal 19991999• ImpulseImpulse control control •• NeuroendocrineNeuroendocrine •• ExecutiveExecutive functions functions functions functions •• SocialSocial behavior behavior PsychopathologyPsychopathology andand MDMAMDMA useuse
• MDMA user display an elevated risk for psychiatric comorbidities such as depression and anxiety disorders (Schifano et al., 1998, 2000 ).
• However, the onset of comorbid psychiatric diseases mostly precedes the onset of the MDMA use (Lieb et al., 2002 ).
• Psychiatric symptoms of MDMA users are associated rather with cannabis co- consume or polytoxic drug use patterns (Daumann et al., 2004; Thomasius et al., 2003; Parrott et al., 2001; Roisier et al., 2004 ).
• Whether MDMA use increases the risk for psychiatric diseases is not clear so far (Gouzoulis-Mayfrank & Daumann, 2006).
• In contrast, MDMA users consistently exhibit memory deficits and impaired executive functions (see meta-analysis of Kalechstein et al., 2007 ). AuditoryAuditory VerbalVerbal LearningLearning TestTest (RAVLT)(RAVLT)
RAVLT recall
18 *** ••• *** *** ••• ••• 16
14
12
10
8 Words
6
4
2 MDMA Cannabis Controls
0
2 4 5 6 l l l B l l 7 st a ria ria ria ria Trial 1 T Trial 3 T T Li T Tri Helmstaedter et al., 2001 Quednow et al., J Psychopharmacol 2006 Means and SD CompositeComposite measuresmeasures ofof thethe RAVLTRAVLT Correlation of drug use patterns and performance
MDMA Cannabis Controls F df/df err p Years of MDMA use (n=19,learning ♂) (n=19,performance ♂) (n=19, ♂) r=-0.56 Learning performance delayed recall r=-0.70 56,2 (±8,16) 64,8 (±6,21) 64,7 (±5,72) 10,09 2/54 0,0002
Σ trials 1-5 loss after consolidation r= 0.63 Recall consistency 86,6 (±8,61) 94,8 (±3,94) 95,1 (±4,8) 11,85 2/54 0,00005 in percent recognition list A r=-0.62 Retroactive interference 2,26 (±2,47) 0,32 (±0,89) 0,58 (±0,90) 8,28 2/54 0,001 Lifetimetrial 5 minus dosetrial 6 MDMA recall after interference r=-0.55 Loss after consolidation 2,05 (±2,04)delayed 0,05recall (±0,85) 0,52 (±1,02) 10,51r=-0.61 2/54 0,0001 trial 5 minus trial 7 Adjusted recognition A 0,85 (±0,10) 0,93 (±0,05) 0,90 (±0,08) 4,60 2/54 0,015 Peakp(A) list dose A MDMA recall after interference r=-0.66 Adjusted recognition B 0,74 (±0,03)delayed 0,84recall (±0,02) 0,81 (±0,03) 4,64r=-0.65 2/54 0,014 p(A) list B retroactive interference r= 0.57 loss after consolidation r= 0.65 Means and SD Quednow et al., J Psychopharmacol 2006 (all p<.0005) IOWAIOWA --GamblingGambling --TaskTask
Bechara et al., Neuropsychologia 2001 IOWAIOWA --GamblingGambling --TaskTask
IOWA-Gambling-Task ** p< 0.01 *** p< 0.001 30 25 ANOVA Interaction: Quartile*Group 20 MDMA vs. Kont.: p < 0.05 15 10 *** 5 ** 0 -5 good vs. bad decks bad vs. good -10 -15 1.Quartile 2. Quartile 3. Quartile 4. Quartile Difference
MDMA Cannabis Controls
Means and SEM Quednow et al., Psychopharmacology 2007 Neuropsychological performance in MDMA users
Psychopharmacology 2007 Confounding factors in MDMA research
Cannabis? Co-use?
Content of Ecstasy pills?
Lifestyle?
Predispositions?
Gouzoulis-Mayfrank & Daumann, Addiction 2006 Positron Emission Tomography PETPET imagingimaging studiesstudies suggestingsuggesting serotonergicserotonergic neurotoxicityneurotoxicity ofof MDMA:MDMA: serotoninserotonin transportertransporter
SERT density measured by [ 11 C]McN5652 and [ 11 C]DASB
Methodological concerns:
⇒ Selectivity of the radiotracer?
⇒ Low density of SERT in cortical regions resulting in a
worse signal-to-noise ratio
⇒ Decreased SERT density is not necessarily correlated
with loss of serotonin axon terminals
⇒ SERT density can be up- and down-regulated
McCann et al., Neuropsychopharmacology 2005 PETPET imagingimaging studiesstudies suggestingsuggesting serotonergicserotonergic neurotoxicityneurotoxicity ofof MDMA:MDMA: serotoninserotonin receptorsreceptors
Mapping 5-HT 2A receptor density
Methodological concerns:
⇒ Changes of a mostly postsynaptic expressed receptor
may not reflect loss of (presynaptic) axon terminals ⇒ 5-HT 2A receptor density can be up- and down-regulated
Reneman et al., Neuropsychopharmacology 2002 MagneticMagnetic resonanceresonance spectroscopyspectroscopy inin MDMAMDMA usersusers
Methodological concerns:
⇒ Low inherent sensitivity
⇒ Spatial resolution
⇒ Not specific for serotonin neurotoxicity
Cowan et al., Psychopharmacology 2007 HowHow cancan wewe measuremeasure serotoninserotonin functionfunction inin vivo?vivo?
Serotonin
18F-Altanserin Hypothetical normal state: Dexfenfluramine 60% of the serotonin receptors are occupied
Forced serotonin release by dexfenfluramine: 90% of the serotonin receptors are occupied
Serotonin release capacity: Normal state minus dexfenfluramine-condition in percent AreAre MDMAMDMA usersusers sufferingsuffering fromfrom lowlow serotoninserotonin levels?levels?
Serotonin
18F-Altanserin
Dexfenfluramine
Impaired serotonin release capacity: Hypothesis: Compared to drug-naïve controls, MDMA users should display more available serotonin receptors under dexfenfluramine challenge. Assessment of serotonin release capacity in the living human bra in using dexfenfluramine challenge and [ 18 F]altanserin positron emission tomography (PET)?
Idea: Combination of a forced 5-HT release with a subsequent measurement
of postsynaptic 5-HT 2A receptors with PET.
Procedure: 1. Forced 5-HT release by dexfenfluramine compared to placebo. 2. Two hours later, injection of the radioligand [ 18 F]altanserin to assess the
density of postsynaptic 5-HT 2A receptors with PET.
Hypothesis: If MDMA users suffer from a loss of serotonin axon terminals they should release less serotonin after dexfenfluramine challenge and more postsynaptic receptors should be available for the [ 18 F]altanserin in comparison to drug-naive controls. PositronPositron EmissionEmission TomographyTomography (PET)(PET) imagingimaging
[18 F]altanserin PET:
• Selective 5-HT 2A antagonist • Injection: slow bolus (250 Mbq, 30 s) • Aquisition: 90 min in rest • Arterial blood sampling • Total distribution volume (DV) calculated Dexfenfluramine challenge: by Logan Plot model • Serotonin releaser (metabolite corrected). • Negligible affinity for the 5-HT 2A receptor (K i <10,000) • Dosage: 40 mg vs. 60 mg
F-18 • Administration: 2 h before PET-Scan • Placebo-controlled, double-blind, and randomized (2 PET-Scans per subject) [18 F]altanserin PositronPositron EmissionEmission TomographyTomography (PET)(PET) imagingimaging
Advance General Electrics PET-CT MeasuringMeasuring serotoninserotonin releaserelease capacitycapacity inin healthyhealthy malemale humanhuman volunteersvolunteers Placebo: n = 13 40 mg (+)FEN: n = 6 Placebo 60 mg (+)FEN: n = 7
2.7 ~8% decrease in 40mg (+)FEN cortical V tot
~17% DV log decrease in
cortical V tot
60mg (+)FEN 0.5
Logan plot model voxel-based Quednow et al. in preparation MeasuringMeasuring regionalregional serotoninserotonin releaserelease capacitycapacity inin healthyhealthy malemale humanhuman volunteersvolunteers Quednow et al. in preparation
Percent reduction of [ 18 F]Altanserin binding after dexfenfluramine challenge
25 *** ** * 20
Pla/Pla 15 40 mg 60 mg 10
5 Vtot Vtot reduction in %
0
-5 Prefrontal Insula Occipital Thalmus Caudatum Total
Pla/Pla: n = 3 Distribution volumes Means and SEM 40 mg (+)FEN: n = 6 calculated with the Significant drug effects: 60 mg (+)FEN: n = 7 Logan plot model *p<.05, **p<.01 SampleSample characteristicscharacteristics
current MDMA Ex-MDMA* Controls (n=15, ♂) (n=12, ♂) (n=15, ♂) Age 27.7 (±7.2) 27.0 (±5.1) 26.1 (±5.1) BMI 22.7 (±1.5) 23.1 (±2.4) 24.2 (±2.1) Verbal IQ 100.7 (±8.3) 99.2 (±5.3) 103.4 (±12.2) Years of education 11.5 (±3.2) 11.5 (±3.0) 12.7 (±2.8) MDMA pills per week 1.0 (±0.9) 0.0 (±0.0) - MDMA years of use 7.9 (±4.4) 5.7 (±3.3) - MDMA pills lifetime 521 (±592) 388 (±360) - Cannabis occasions per week 2.0 (±2.7) 1.2 (±2.2) 0.2 (±0.6) Cannabis years of use 5.9 (±5.2) 3.9 (±5.9) 0.8 (±3.0) Cannabis occasions lifetime 1025 (±1294) 1406 (±1260) 389 (±799)
* Ex-users were abstinent for at least one year. Means and SD
⇒⇒⇒ 42 von 68 subjects were matched study criteria and gave informed consent. Means and SD, NeuropsychologicalNeuropsychological performanceperformance Post hoc test vs. controls: *p<.05, **p<.01, ***p<.001 DecreasedDecreased serotonergicserotonergic releaserelease capacitycapacity inin malemale currentcurrent MDMAMDMA usersusers
Change in [ 18 F]altanserin binding after 60mg dexfenfluramine
Serotonin release capacity
20 ** (*) ** (*)(*) * * 15
10
5 % reduction in tracer DV tracer in reduction % 0
C FC C TC O A mus M LTC Total LPFC la Insula D a Pall/Put cipital C. Caudatum Th Parietal C. c Current MDMA vs. Controls: O Controls current MDMA Ex-MDMA *p<.05; (*)p<.10 Means and SEM Controls : n = 12; current MDMA user : n = 14; Ex-MDMA user : n = 10 DecreasedDecreased serotoninserotonin --2A2A receptorreceptor densitydensity inin currentcurrent andand formerformer MDMAMDMA usersusers
Controls Controls : n = 12 Current MDMA : n = 14 Ex-MDMA : n = 10 2.0
Current MDMA
DV
Ex-MDMA
0.4
Logan plot model voxel-based DecreasedDecreased serotoninserotonin --2A2A receptorreceptor densitydensity inin currentcurrent andand formerformer MDMAMDMA usersusers
[18 F]altanserin binding at baseline (placebo)
3 * ° * * * ° * ° * * * ° * ° * ° * ° * ° * ° * ° * 2.5 * ° * ° * ° * ° * * ° * ° 2 * * °* ° 1.5 * * * ° * ° 1
0.5 Distribution volume [Vtot] volume Distribution
0
C t s la C tal u T o PFC L l C. T OFC AC ll/Pu m MTC a DL a Insu et P ri Current MDMA vs. Controls Caudatum Thala Pa ***p<.001 Occipital C. Ex-MDMA vs. Controls Controls current MDMA Ex-MDMA °p<.05, °°p<.01 Means and SEM
Controls : n = 12; current MDMA user : n = 14; Ex-MDMA user : n = 10 MemoryMemory performanceperformance underunder dexfenfluraminedexfenfluramine challengechallenge Means and SEM
1 1 Memory Index Declarative Memory 0.5 0.5
0 0
-0.5 -0.5
-1 -1
-1.5 -1.5 Group*treatment interaction: p<.05 Group*treatment interaction: p<.05 -2 -2 Baseline Defenfluramine Baseline Dexfenfluramine
1 1 Recognition Working Memory 0.5 0.5
0 0
-0.5 -0.5
-1 -1 Controls -1.5 -1.5 Current MDMA users Former MDMA users -2 -2 Baseline Dexfenfluramine Baseline Dexfenfluramine NeuroendocrineNeuroendocrine responseresponse afterafter dexfenfluraminedexfenfluramine challengechallenge
Prolactin response under 60mg dexfenfluramine
15 ** Controls °°° current MDMA * Ex-MDMA 10
5 µg/l
*Cont. vs. current MDMA: p<.05 0
** Cont. vs. current Time*group interaction: p<.05 MDMA: p<.01 -5 t0-15 t0+60 t0+120 t0+180 t0+240 °°° Cont. vs. Ex- min MDMA.: p<.001 Corrected for placebo (Means und SEM) SummarySummary
•Preliminary data imply that current MDMA users display a decreased serotonin release capacity. •In contrast, former MDMA users display a largely recovered serotonin release capacity.
•Current and former MDMA users show a decreased 5-HT2A receptor density in all investigated brain regions. •Memory performance was enhanced under dexfenfluramine in current and former MDMA users.
•Prolactin response to dexfenfluramine is blunted in both current and former MDMA users. •In sum, this data suggest that the changes in the serotonin system of MDMA users are only in part reversible. AcknowledgementsAcknowledgements
University Hospital of Psychiatry Zurich Felix Hasler Nadja Dörig Carmen Ghisleni Franz X. Vollenweider
Department of Nuclear Medicine University Hospital Zurich Matthias Wyss Valerie Treyer Alfred Buck Gerrit Westera P. August Schubiger GrantsGrants
Project grants: Schweizerischer Nationalfonds (SNF) Olga Mayenfisch-Stiftung Fürstentum Liechtenstein Hartmann Müller-Stiftung
Personal grants: Deutsche Forschungsgemeinschaft (DFG) Nachwuchsförderungskredit der Universität Zürich KokainkonsumentenKokainkonsumenten gesucht!gesucht!
Neurosocial consequences of cocaine use Wir suchen gelegentliche und chronische Kokainkonsumenten für eine längsschnittliche Studie zu der sozio-kognitiven Folgen des Kokainkonsums.
Ausschlusskriterien: schwere Achse I-Störung (SZ, BP, OCD), Opiat-Abhängigkeit, Polytoxikomanie
Kontakt: [email protected] [email protected] DesignDesign • Placebo-controlled, double-blind, randomized, and counterbalanced • Two assessments with an interval of 14 days • Three experimental groups: Placebo/Placebo (Pla/Pla, p.o.) Placebo/40 mg dexfenfluramine (40mg Dexfen, p.o.) Placebo/60 mg dexfenfluramine (60mg Dexfen, p.o.) • 30 sec bolus of 250 MBq [ 18 F]altanserin on each test day • Arterial blood samples for quantification and plasma metabolite correction: -5 min, 0,20,40,60,90 sec, 2,3,5,8,10,15,20,30,45,60,75,90 min • Plasma levels for dexfenfluramine, prolactin, and cortisol
Placebo/drug 30s bolus, 250 MBq List of 2x List of administration [18 F]altanserin Complaints Complaints
-45 min t0 +60 min +120 min +180 min +240 min +24 h +72 h
PET-Scan 90 min Prolactin Prolactin Prolactin Prolactin Prolactin Cortisol Cortisol Cortisol Cortisol Cortisol Dexfenfluramine Dexfenfluramine Dexfenfluramine RegionsRegions --ofof --InterestInterest
Six Regions-of-Interest*:
Three with Occipital high 5-HT 2A density: Nucleus cortex caudatus • Prefrontal cortex • Occipital cortex • Insula
Three with
low 5-HT 2A density:
• Nucleus caudatus • Thalamus Thalamus • Cerebellum Prefrontal cortex
Cerebellum Insula *Drawn on the raw data of each subject WhyWhy dexfenfluraminedexfenfluramine andand [[ 18 F]altanserin?F]altanserin?
[18 F]altanserin PET:
• Selective 5-HT 2A antagonist
(K i =0.3 nM)
• Only residual binding to 5-HT 2C ,
5-HT 7, alpha-1, and histamine-1 Dexfenfluramine challenge: receptors • Potent serotonin releaser
• Displaceable by high 5-HT concentrations • Negligible affinity for the 5-HT 2A
receptor ( K i >11`000 nM) and the 5-
HT 2C receptor (K i >6000 nM). • The main metabolite
F-18 nordexfenfluramine has also low affinty
for the 5-HT 2A ( K i >1`500 nM) and 5-
HT 2C receptor (K i >300 nM). SafetySafety andand tolerabilitytolerability ofof dexfenfluraminedexfenfluramine
List of Complaints corrected for placebo (von Zerrsen, 1971) The 10 most frequent of 65 symptoms 12 within 72 h (in percent) Pla/Pla (n=13) 10 40mg Dexfen (n=6) (+)-FEN Plac p 60mg Dexfen (n=7) 8 Tiredness 48.7 36.8 0.57 6 Faintness 28.2 10.5 0.11
4 Lack of energy 23.1 19.3 0.80 Headache 20.5 10.5 0.26 2 Weakness 20.5 3.5 0.02 0
Number Number of complaints Feeling cold 20.5 5.3 0.06 -2 Cold feet 17.9 0.0 0.003 Time: p<.05 LSD Pla vs. 40 mg: n.s. -4 Lack of concentration 15.4 8.8 0.52 Time*dose: n.s. LSD Pla vs. 60 mg: p<.05 Dose: p=.06 LSD 40 mg vs. 60 mg: n.s. Diarrhea 15.4 1.8 0.04 -6 t0+4h t0+24h t0+72h Strong thirst 15.4 1.8 0.04 means and SEM Dexfenfluramine was generally well tolerated. All side -effects were transient and mild, and disappeared after 72 h