2001 - Baggott & Jerome - 3,4-Methylenedioxymethamphetamine - MDMA Clinical Guide.pdf - MDMA - Majster128

lenedioxymethamphetamine (MDMA):

A Review of the English-Language Scientific and Medical Literature

Matthew Baggott, B.A. ( matt@baggott.net )

Lisa Jerome, Ph.D. ( ljerome@bigplanet.com )

Reid Stuart, M.A.

August 1, 2001

3,4-Meth

INTRODUCTION............................................................................................................. 1

CONCLUSIONS AND SUMMARY ............................................................................... 3

C ONCLUSIONS .................................................................................................................. 3

S UMMARY OF C HAPTER 2: C LINICAL MDMA S TUDIES ................................................... 4

S UMMARY OF C HAPTER 3: D EMOGRAPHICS AND S ELF -R EPORTED E FFECTS OF I LLICIT

E CSTASY U SE ................................................................................................................... 5

S UMMARY OF C HAPTER 4: N EUROTOXICITY R ESEARCH IN A NIMALS .............................. 6

S UMMARY OF C HAPTER 5: N EUROTOXICITY R ESEARCH IN H UMANS ............................... 7

S UMMARY OF C HAPTER 6: A DVERSE E VENTS IN I LLICIT U SERS ...................................... 9

R ECOMMENDATIONS FOR F UTURE P SYCHOTHERAPY R ESEARCH ................................... 11

C ONCLUDING R EMARK .................................................................................................. 11

PREVIOUS HUMAN EXPERIENCE: CONTROLLED CLINICAL TRIALS AND

PHARMACOLOGY....................................................................................................... 13

I NTRODUCTION AND O VERVIEW .................................................................................... 13

A N OTE ON U SE OF MDMA IN T HERAPY ...................................................................... 14

Table 2.1: Peak Acute Physiological Effects of MDMA ........................................... 15

Figures 2.1 & 2.2: Peak Acute Increase in Diastolic BP and Heart Rate ............... 16

A CUTE P HYSIOLOGICAL E FFECTS .................................................................................. 17

A CUTE AND S UBACUTE S IDE E FFECTS OF MDMA ........................................................ 18

Table 2.2: Acute Side Effects of MDMA .................................................................. 19

Table 2.3: Subacute (Up To Post 24 H) Side Effects Of MDMA ............................. 20

Table 2.4: Late Subacute (72 H+) Side Effects Of MDMA ..................................... 21

A CUTE H ORMONAL /N EUROENDOCRINE E FFECTS .......................................................... 21

A CUTE S ELF -R EPORTED /S UBJECTIVE MDMA E FFECTS ................................................ 22

Table 2.5: Unaltered Neurocognitive Performance after Two MDMA Exposures .. 24

N EUROCOGNITIVE AND P SYCHOMOTOR P ERFORMANCE E FFECTS OF MDMA ............... 24

A CUTE AND S UBACUTE I MMUNOMODULATING E FFECTS OF MDMA............................. 25

A CUTE AND C HRONIC F UNCTIONAL C EREBRAL I MAGING S TUDIES ............................... 26

G ENDER D IFFERENCES IN THE P SYCHOLOGICAL AND P HYSIOLOGICAL E FFECTS OF

MDMA.......................................................................................................................... 26

D RUG I NTERACTION S TUDIES AND THE N EUROTRANSMITTER S YSTEMS M EDIATING THE

E FFECTS OF MDMA ...................................................................................................... 27

P HARMACOKINETICS OF MDMA ................................................................................... 28

Table 2.6: MDMA Pharmacokinetic Parameters ..................................................... 29

Figure 2.3: Metabolic Pathways of MDMA in Humans ........................................... 31

DEMOGRAPHICS AND SELF-REPORTED EFFECTS OF ILLICIT ECSTASY

USE................................................................................................................................... 33

I NTRODUCTION AND O VERVIEW .................................................................................... 33

Table 3.1: Estimated Prevalence of Ecstasy Use in the United States ..................... 34

D EMOGRAPHICS OF E CSTASY U SE : H ISTORY AND C URRENT T RENDS ............................ 34

Table 3.2: Demographics of Ecstasy Users (Age 19-32) in the United States ......... 36

Table 3.3: Estimated Frequency of Ecstasy Use by U.S. High School Students ...... 37

A N O VERVIEW OF R ETROSPECTIVE OR U NCONTROLLED S TUDIES A DDRESSING D RUG

E FFECTS ......................................................................................................................... 38

A CUTE P SYCHOLOGICAL E FFECTS R EPORTED IN R ETROSPECTIVE S TUDIES ................... 40

Table 3.4: Effects of Ecstasy Reported by 100 Undergraduates .............................. 40

A CUTE P HYSIOLOGICAL E FFECTS OF E CSTASY R EPORTED IN R ETROSPECTIVE S TUDIES 42

S UB -A CUTE AND L ONG - TERM E FFECTS OF E CSTASY R EPORTED IN R ETROSPECTIVE

S TUDIES ......................................................................................................................... 43

S UB - ACUTE S EQUELAE R EPORTED A FTER E CSTASY U SE .............................................. 43

L ONG - TERM S EQUELAE R EPORTED A FTER E CSTASY U SE .............................................. 44

C OMPARISONS B ETWEEN E CSTASY , H ALLUCINOGENS AND P SYCHOSTIMULANTS ......... 46

Table 3.5: Frequently Reported Effects of Ecstasy, Amphetamines, and

Hallucinogens ........................................................................................................... 47

D ECLINE IN D RUG E FFECTS A FTER R EPEATED U SE OR “L OSS OF M AGIC ” .................... 48

C OADMINISTRATION OF E CSTASY WITH SSRI S IN I LLICIT E CSTASY U SERS ................... 49

O THER A VENUES OF I NVESTIGATING THE E FFECTS OF E CSTASY / MDMA ................... 49

MDMA NEUROTOXICITY: STUDIES IN NONHUMAN ANIMALS ................... 51

I NTRODUCTION AND O VERVIEW .................................................................................... 51

D EFINITIONS .................................................................................................................. 52

MDMA C AN I NDUCE L ONG - TERM S EROTONERGIC C HANGES ...................................... 52

S EROTONERGIC C HANGES ARE A CCOMPANIED BY S TRUCTURAL C HANGES TO A XONS . 53

N ON - SEROTONERGIC I NDICATORS OF C ELL D AMAGE ARE I NCONSISTENTLY A FFECTED

BY MDMA .................................................................................................................... 54

T HE R OLE OF O XIDATIVE S TRESS IN MDMA NEUROTOXICITY ..................................... 55

P ROPOSED S OURCES OF O XIDATIVE S TRESS .................................................................. 56

E NERGY E XHAUSTION OR I MPAIRMENT AS A S OURCE OF O XIDATIVE S TRESS ............... 57

MDMA M ETABOLITES AS A S OURCE OF O XIDATIVE S TRESS ........................................ 57

Table 4.1. Studies of the Neurotoxicity of Putative MDMA Metabolites.................. 58

D OPAMINE M ETABOLITES AS A S OURCE OF O XIDATIVE S TRESS .................................... 64

T HERE IS C URRENTLY L ITTLE E VIDENCE THAT 5HT M ETABOLITES A CT AS T OXINS .... 66

G LUTAMATE D OES N OT A PPEAR TO P LAY A M AJOR R OLE IN MDMA NEUROTOXICITY 66

A P OSSIBLE R OLE FOR C A 2+ IN MDMA N EUROTOXICITY ............................................. 67

E XTENT OF N EUROTOXICITY D EPENDS ON D OSE , R OUTE OF A DMINISTRATION , A NIMAL

A GE , AND S PECIES . ........................................................................................................ 67

S PECIES AND S TRAIN D IFFERENCES IN V ULNERABILITY ................................................ 68

W HY A RE S UCH H IGH D OSES U SED I N N EUROTOXICITY R ESEARCH ? ........................... 70

E XTENT OF N EUROTOXICITY IN R ATS IS I NFLUENCED BY E NVIRONMENT , E SPECIALLY

A MBIENT T EMPERATURE ............................................................................................... 72

Table 4.2. Studies of Drugs Modifying MDMA Neurotoxicity and Hyperthermia ... 73

D RUGS M ODIFYING MDMA N EUROTOXICITY .............................................................. 88

T IME C OURSE OF C HANGES AND E XTENT OF R ECOVERY ............................................... 88

MDMA-I NDUCED A POPTOSIS (P ROGRAMMED C ELL D EATH )........................................ 90

N ON - SEROTONERGIC MDMA N EUROTOXICITY IN THE S OMATOSENSORY C ORTEX ...... 90

B EHAVIORAL AND F UNCTIONAL C ORRELATES OF MDMA E XPOSURE IN A NIMALS ...... 91

Table 4.3. Studies of Long-term Behavioral or Functional Changes after MDMA

Exposure in Animals ................................................................................................. 92

B EHAVIORAL E FFECTS OF O THER S EROTONERGIC N EUROTOXINS ................................. 98

H OW C AN N EUROTOXIC D AMAGE BE W ITHOUT D ETECTABLE B EHAVIORAL

C ONSEQUENCES ? ........................................................................................................... 99

NEUROTOXICITY RESEARCH IN HUMANS ...................................................... 101

I NTRODUCTION AND O VERVIEW .................................................................................. 101

L IMITATIONS OF T HE R ESEARCH L ITERATURE ............................................................. 104

Table 5.1: Summary of Common Study Limitations .............................................. 105

Table 5.2: Comparison of PET and Autoradiography Measures of SERT Density109

I NTERPRETING S TUDIES FOR R ISK A SSESSMENT .......................................................... 109

E VIDENCE OF S EROTONERGIC D IFFERENCES BETWEEN E CSTASY U SERS AND N ONUSERS

..................................................................................................................................... 111

Table 5.3: Cerebral Spinal Fluid Levels of 5HIAA in Ecstasy Users and Nonusers

................................................................................................................................. 111

Figure 5.1: Relationship between ecstasy exposure and CSF 5HIAA in 4 studies. 113

O THER (P OSSIBLY N ONSEROTONERGIC ) N EUROFUNCTIONAL D IFFERENCES BETWEEN

E CSTASY U SERS AND N ONUSERS ................................................................................. 116

Table 5.4: Reported Neurofunctional Differences Between Ecstasy Users and

Nonusers ................................................................................................................. 118

M OOD , P ERSONALITY , B EHAVIORAL , AND N EUROCOGNITIVE U SER -N ONUSER

D IFFERENCES ............................................................................................................... 121

Table 5.5: Mood Alterations in Ecstasy Users ...................................................... 122

N EUROCOGNITIVE D IFFERENCES BETWEEN ECSTASY USERS AND NONUSERS ............... 124

Table 5.6: Summary of Significant Neurocognitive Findings................................ 124

Table 5.7: Immediate Verbal Memory in Ecstasy Users Compared to Nonusers. 126

Table 5.8: Delayed Verbal Memory in Ecstasy Users Compared to Nonusers..... 127

Table 5.9: Executive Functioning in Ecstasy Users Compared to Nonusers. ...... 128

Figure 5.2: Relationship between Number of Exposures and Executive Function 131

Figure 5.3: Relationship between Abstinence from Ecstasy and Executive Function

................................................................................................................................. 131

Table 5.11. Memory Performance in Chronic Cocaine Users .............................. 134

P OSSIBLE S IGNIFICANCE OF N EUROCOGNITIVE D IFFERENCES AND MDMA

N EUROTOXICITY .......................................................................................................... 136

R ISKS OF N EUROTOXICITY IN C LINICAL MDMA S TUDIES .......................................... 139

M ONITORING FOR C HRONIC N EUROTOXICITY IN C LINICAL MDMA S TUDIES ............. 144

MEDICAL EMERGENCIES AND ADVERSE EVENTS IN ECSTASY USERS. 147

I NTRODUCTION AND O VERVIEW .................................................................................. 147

E MERGENCY D EPARTMENT (ED) V ISITS A FTER E CSTASY U SE ................................... 148

Figure 6.1: Emergency Department (ED) cases involving MDMA........................ 149

E STIMATING THE F REQUENCY OF E MERGENCY D EPARTMENT V ISITS A FTER E CSTASY

U SE .............................................................................................................................. 149

Table 6.1. Relationship Between Ecstasy Exposures and ED Visits in 329 Users . 150

W HAT T YPES OF A DVERSE E VENTS A RE M OST C OMMON ? ......................................... 151

Table 6.2: Features of 48 Sequential Ecstasy-related ED Visits............................ 152

U SE OF O THER H EALTH C ARE S ERVICES BY E CSTASY U SERS ..................................... 153

D EATHS A FTER E CSTASY U SE ..................................................................................... 154

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