methamphetamines and other stimulants - results...

Methamphetamines Methamphetamines and other stimulantsand other stimulants

Risk factors for pulmonary arterial Risk factors for pulmonary arterial hypertension?hypertension?

Kelly Chin, MDKelly Chin, MDUT Southwestern Medical CenterUT Southwestern Medical Center

Dallas, TXDallas, TX

IntroductionIntroduction

Methamphetamines probably cause PAHMethamphetamines probably cause PAHMechanism: like Mechanism: like fenfluraminefenfluramine, probably , probably acts on the serotonin transporteracts on the serotonin transporterRates of methamphetamine use Rates of methamphetamine use

Vary by geographical areaVary by geographical areaIncreased during the 1990sIncreased during the 1990s

Methylphenidate Methylphenidate ≠≠ amphetamine amphetamine ≠≠methamphetaminemethamphetamine

Drugs and toxins associated with PAHDrugs and toxins associated with PAHEvian meeting 1998, as Evian meeting 1998, as referencedreferenced by by SimonneauSimonneau et al. (et al. (JACCJACC 2004;43:5S2004;43:5S--12S)12S)

PossiblePossibleMetaMeta--amphetaminesamphetaminesCocaineCocaineChemotherapeutic agentsChemotherapeutic agents

UnlikelyUnlikelyAntidepressantsAntidepressantsOCPOCP’’ssEstrogenEstrogenSmokingSmoking

DefiniteDefiniteAminorexAminorexFenfluramineFenfluramineDexfenfluramineDexfenfluramineToxic rapeseed oilToxic rapeseed oil

Very likelyVery likelyAmphetaminesAmphetaminesLL--tryptophantryptophan

Cocaine: Collazos J. Respir Med. 1996;90:171, Yakel DL Jr Am Heart J. 1995;130:398. Methamphetamine: Schaiberger PH Chest. 1993;104:614.

MethamphetamineNH

CH3

CH3

NH2

CH3

NH

CH3

CH3F3CFenfluramine

Amphetamine

Substrate type releasers: Increase release of NE, DA, 5HT through substrate mediated exchangeDisrupt intracytoplasmic storage vesicles

Amphetamine and methamphetamine: more potent releasers of dopamine and norepinephrineFenfluramine: more potent releaser of serotonin

Background: Background: FenfluramineFenfluramine and and DexfenfluramineDexfenfluramine

IPPHS: PPH (N=95) IPPHS: PPH (N=95) vsvs Normal ControlNormal ControlFenfluramineFenfluramine >3 >3 mosmos: 23.1 (6.9: 23.1 (6.9--77.7)77.7)FenfluramineFenfluramine <3 <3 mosmos: 1.8 (0.5: 1.8 (0.5--5.7)5.7)AmphetamineAmphetamine--like appetite suppressant: 8.4% like appetite suppressant: 8.4% vsvs 2.3%, but 2.3%, but only 2 cases and 3 controls did not also have only 2 cases and 3 controls did not also have fenfluraminefenfluramineexposureexposure

SNAPH: PPH (N=205) SNAPH: PPH (N=205) vsvs SPHSPHFenfluramineFenfluramine >6 >6 mosmos: 7.5 (1.7: 7.5 (1.7--32.4)32.4)FenfluramineFenfluramine <6 <6 mosmos: 1.3 (0.5: 1.3 (0.5--3.9)3.9)Amphetamines: 1.4 (0.6Amphetamines: 1.4 (0.6--3.3)3.3)Antidepressants: 12.2% PPH Antidepressants: 12.2% PPH vsvs 17.1% SPH17.1% SPH

SN hest 2000;117:870APH: Rich S C

IPPHS: Abenhaim NEJM 1996;335:609

SerotoninSerotonin5HT transporter: growth 5HT receptors: 5HT receptors:

vasoconstrictionvasoconstriction

http://www.cnsforum.com/content/pictures/imagebank/hirespng/Drug_SSRI_2.png

Methamphetamine and PHMethamphetamine and PH

32 year old male referred for dyspneaLaid off from a maintenance job 6 months ago –unable to perform physical activity, loses insurance Develops syncope, echo suggests elevated RVSPInitial SHx: cocaine very remotely, occ MJ and prior amphetamines. “The amphetamine use was very rare”.

Initial Work-up

RA 10 PA 80/46 (48) PCWP 8 CO 2.7 PVR 22 RA 10 PA 80/46 (48) PCWP 8 CO 2.7 PVR 22 wuwuNo vasodilator responseNo vasodilator responseMRI: MRI:

LVEDV 73 ml LVEF 61%LVEDV 73 ml LVEF 61%RVEDV 179 ml RVEF 32%RVEDV 179 ml RVEF 32%

Walks 436 metersWalks 436 metersInsurance issues; prescribed Viagra 100mg Insurance issues; prescribed Viagra 100mg ¼¼ tab tab tidtid and diureticsand diuretics

More + More + toxtox screensscreens

1 month later admitted with volume overload1 month later admitted with volume overload+ + toxtox screen: amphetamines, MJscreen: amphetamines, MJAdmits to MJ; denies amphetamines Admits to MJ; denies amphetamines –– reports reports pseudoephedrinepseudoephedrine

4 months later: severe volume overload, admitted4 months later: severe volume overload, admittedUtoxUtox: amphetamines: amphetaminesNot taking his medicationsNot taking his medicationsFamily reports Family reports ““irrational behaviorirrational behavior””

Denies drug use: confirmatory sendDenies drug use: confirmatory send--out out toxtox screen screen positive for methamphetamine and amphetaminepositive for methamphetamine and amphetamineClinic followClinic follow--up at 5 months: doing better, volume well up at 5 months: doing better, volume well controlled, continues to deny drug usecontrolled, continues to deny drug use

Motivation for the studyMotivation for the study

Women Men1. Fenfluramine 1. Stimulants2. CTD 2. HIV (almost all used stimulants)3. Congenital Heart 3. Familial / CTD

0

10

20

30

40

50

60

IPAH Fenfluramine CTD Amphetamine /Cocaine Alone

Congenital HeartDisease

HIV Portal HTN Familial Amphetamine /Cocaine Total

Men

Women

Total

Study: stimulant use in idiopathic PAH compared with other forms of PH

UCSD (La Jolla)Only amphetamine, methamphetamine, cocaine Categorized as:

Idiopathic PAHPAH with known risk factors (familial PAH, CVD, CHD, anorexigen)CTEPH (chronic thromboembolic PH)

Excluded: PAH due to HIV, liver disease

Screened: 614 Other PHLung diseaseLeft heart diseaseHIV with PAH / CTEPHPortal hypertension with PAHOther PA obstruction*Acute / recent PE

4242

9 / 1564

No pulmonary hypertension found

50

Incomplete work-up 16

Age<18 8

183 ineligible

91 missing stimulant histories 15 IPAH (13%)28 APAH (21%)48 CTEPH (26%)

Pulmonary HTN: 431

Stimulant history complete: 340

137 CTEPH97 idiopathic PAH 106 associated PAH

DemographicsDemographicsIdiopathic PAH (97)

PAH with known risk factors (106)

CTEPH (137)

Mean Age 47.2 49.1 53.0Mean PAP (mm Hg) 50.2 42.2 46.5Gender (% female) 72% 89% 56%Race

White 74% 76% 82%Black 5% 4% 13%Hispanic 11% 7% 2%Asian / Pacific Island 3% 9% 2%Other or Unknown 6% 5% 0.7%

Results: Stimulant UseResults: Stimulant Use

0

.05

.1

.15

.2

.25

.3

.35

.4

Pro

por

tion

Rep

orti

ng

Stim

ula

nt

Use

Idiopathic Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension with Known Risk Factors

Chronic ThromboembolicPulmonary Hypertension

28.9%

3.7% 4.4%

Specific StimulantsSpecific Stimulants

Idiopathic PAH

(N=97)

PAH known risk factors

(N=106)

CTEPH (N=137)

Methamphetamine alone 16 4 2

Amphetamine alone 3 0 0

Cocaine alone 1 0 2

Methamphetamine + cocaine 7 0 1

Amphetamine + cocaine 1 0 1

Total 28 4 6

Most patients reported heavy useMost patients reported heavy use

49 M 1998 Cocaine, methamphetamine, heroin IV for 25 years.

53 F 1998 Methamphetamine and cocaine use for 20 years.

47 F 2000 Methamphetamine use for 15 years, last use 1998.

40 M 1999 Amphetamines for 20 years.

38 F 1999 Inhaled methamphetamine use for 17 years, last ~1994.

43 M 2004 Crystal methamphetamine and cocaine for 15 years

46 F 2003 Cocaine and methamphetamine for 13 years

41 M 2001 Methamphetamine use for approximately seven years.

Uncertain DurationUncertain Duration

30 F 2003 Methamphetamine use continuing up until diagnosis, none IV34 F 2000 Methamphetamine use40 M 1999 Inhaled crystal methamphetamine use41 F 2004 Methamphetamine, cocaine use last use one year prior to dx42 F 2002 Methamphetamine use45 F 1999 Amphetamine history, none in many years51 F 2004 Methamphetamine use (snorted) up until <1 mo prior to dx54 M 1999 Methamphetamine use, “none for four years”57 M 2004 Crystal methamphetamine use67 F 2003 Amphetamine containing diet pills in her twenties

Odds RatioOdds Ratio

Idiopathic PAH vs. PAH with known risk factors

Idiopathic PAH vs. CTEPH

Any Stimulant UseUnadjusted

10.4 (3.5-31) p<0.001 8.9 (3.5-22) p<0.001

Full model (includes Age, gender, race)

10.1 (3.3-30) p<0.001 8.1 (3.1-21) p<0.001

Final model 10.1 (3.4-30) p<0.001 7.6 (3-20) p<0.001

Methamphetamine, final model

7.7 (2.6-24) p<0.001 11.6 (3.3-40) p<0.001

ProblemsProblems

RetrospectiveRetrospectiveMissing data: more data missing in the IPAHMissing data: more data missing in the IPAH

?Less likely to ask someone with CTEPH / risk ?Less likely to ask someone with CTEPH / risk factor for PAHfactor for PAHOr some stimulant histories reported as Or some stimulant histories reported as ““noncontributorynoncontributory”” were likely negativewere likely negative

Geography and control group issuesGeography and control group issues

Past year use of methamphetamine by persons 12 years or older by region and gender: 2002-2005

Lifetime rates: ~5%

Source: The NSDUH Report January 26, 2007Source: The NSDUH Report January 26, 2007

Percentages of Persons Aged 12 or Older Reporting Past Year Methamphetamine Use, by State: 2002, 2003, 2004, and 2005

www.oas.samhsa.gov/2k6/stateMeth/stateMeth.htm

http://www.oas.samhsa.gov/2k6/stateMeth/stateMeth.htm

Primary Amphetamine/Methamphetamine Primary Amphetamine/Methamphetamine TEDS Admission Rates: 1992TEDS Admission Rates: 1992

(per 100,000 aged 12 and over)(per 100,000 aged 12 and over)

SOURCE: SAMHSA Treatment Episode Data Set (TEDS); maps from Thomas E. Freese, Ph.D

35 - 5812 - 35

< 12No data

> 58


< 12

35 - 5812 - 35

< 12No data

> 58




< 1212 - 35

35 -58150-199 200 or more100-149

SOURCE: 2002 SAMHSA Treatment Episode Data Set (TEDS).

35 - 5812 - 35

< 12No data

58-99100-149150-199

> 200

Treatment is a lagging Treatment is a lagging indicatorindicator

Clandestine Lab Incidents: 2000Clandestine Lab Incidents: 2000

2

127

26

283

889

243399

429

641

36

7

12334

12

142

50384

209

28

283

2,198

351

110414

2494

15

5484

126

15

829

21

3633

944

1

2

1270

00

00 1

1

5

26<100

100-499

500-999

>1000

Source: national Clandestine Laboratory Database (http://www.dea.gov/concern/map_lab_seizures.html)


8

319

45

578

2,180

404806

619

852

208

18

15485

30

240

103312

162

65

259

1,883

587

517532

49510

35

59166

224

16

1789

122

52117

1,480

2

2

1310

11

12 0

1

3

14<100

100-499

500-999

>1000



26

552

79

861

2,767

431883

547

769

357

34

250207

61

450

121253

121

89

105

1,743

525

1037347

60836

157

127264

462

133

3097

225

72352

1,443

1

0

1190

01

31 0

2

10

33<100

100-499

500-999

>1000



18

751

101

1,272

2,885

7761,068

677

641

253

40

309252

26

352

195140

85

73

131

1,287

419

30485168

95365

240

250341

319

94

62124

267

97975

1,011

1

0

910

11

02 2

1

3

40<100

100-499

500-999

>1000



48

1,058

78

1,335

2,788

800659

452

584

205

31

168234

21

228

120122

72

65

79

764

472

75571318

1,327170

276

261285

267

123

106286

295

1074 165

947

1

3

422

10

01 3

0

20

66<100

100-499

500-999

>1000


More on potential mechanisms

MonamineMonamine transporters: clear the synaptic cleft transporters: clear the synaptic cleft of NE, DA, 5HTof NE, DA, 5HTSerotonin transporter is present in other tissues:Serotonin transporter is present in other tissues:

Lungs: endothelium and Lungs: endothelium and smooth musclesmooth musclePlacentaPlacentaPlatelets Platelets Other vesselsOther vesselsGI tractGI tract

Smooth muscle growth: serotonin Smooth muscle growth: serotonin receptor vs. serotonin transporterreceptor vs. serotonin transporter

Serotonin leads to greater smooth muscle Serotonin leads to greater smooth muscle proliferation in PPH than controlproliferation in PPH than control

• Blocked by fluoxetine (Prozac: SSRI)

• Not blocked by ketanserin, 5HT receptor antagonist

Eddahibi J Clin Invest 108:1141

More on the 5HT Transporter in PHMore on the 5HT Transporter in PH

Levels of the serotonin transporter protein are Levels of the serotonin transporter protein are increased in idiopathic PAH increased in idiopathic PAH

Idiopathic PAH > Secondary PAH > ControlIdiopathic PAH > Secondary PAH > Control

LL LL polymorphism accounts polymorphism accounts for some of the increasefor some of the increase

Marcos Circ Res. 2004;94:1263

OverexpressionOverexpression of the 5HT transporterof the 5HT transporter

BMPR2 +/BMPR2 +/-- mice increase RVSP with mice increase RVSP with serotoninserotoninaa

OverexpressionOverexpression alone is sufficient to cause alone is sufficient to cause elevated pulmonary pressures in elevated pulmonary pressures in animalsanimalsbb

More susceptible to chronic hypoxic and More susceptible to chronic hypoxic and monocrotalinemonocrotaline induced induced PHPHcc

Less susceptible to acute hypoxic Less susceptible to acute hypoxic vasoconstrictionvasoconstriction

a. Long Circ Res. 2006;98:818b. MacLean MR Circulation 2004;109:2150c. Guignabert Circ Res. 26 2006;98:1323

Does Methamphetamine lead to Does Methamphetamine lead to serotonin release?serotonin release?

•• In vitro IC50 values for In vitro IC50 values for release release ((nanomolarnanomolar): ): •• Higher values = less potent Higher values = less potent •• Methamphetamine: nine times less potent then Methamphetamine: nine times less potent then fenfuraminefenfuramine•• Amphetamine: twentyAmphetamine: twenty--two times less potent than two times less potent than fenfluraminefenfluramine

Negus SS J Pharmacol Exp Ther. 2007;320:627-36

Drug levels among arrestees in Bakersfield, CaliforniaDrug levels among arrestees in Bakersfield, CaliforniaTypical dosesTypical doses

Amphetamine for ADHD: 5Amphetamine for ADHD: 5--40 mg40 mgAbuse: 50 to several 1000 mg reported with illicit useAbuse: 50 to several 1000 mg reported with illicit use

Cocaine halfCocaine half--life: 1 hourslife: 1 hoursMethamphetamine halfMethamphetamine half--life: 11life: 11--12 hours hours12 hours hours

Melega Synapse 2007;61:216

How much methamphetamine is How much methamphetamine is enough to cause PAH?enough to cause PAH?

Methamphetamine/Amphetamine treatment admissionsMethamphetamine/Amphetamine treatment admissionsRoute of administration: 1993Route of administration: 1993--20032003

Source: 2003 SAMHSA Treatment Episode Data Set (TEDS).

What about ADHD?What about ADHD?

Amphetamine (prior study) 22 times less potent Amphetamine (prior study) 22 times less potent than than fenfluraminefenfluramineMethylphenidate: minimal 5HT activityMethylphenidate: minimal 5HT activity

Rothman RB J Pharmacol Exp Ther. 2003;307:138

What about ephedrine?What about ephedrine?

Rothman RB Rothman RB J J PharmacolPharmacol Exp Exp TherTher.. 2003 Oct;307(1):138 2003 Oct;307(1):138

MethMeth UsersUsers

UrbanUrbanRuralRuralPerformance enhancementPerformance enhancement

Longer hours of workLonger hours of workWeight lossWeight lossBetter sexBetter sex

HIV in MSMHIV in MSM““RecreationalRecreational”” methmeth: 26%: 26%Outpatient, drug free: 62%Outpatient, drug free: 62%Residential treatment: 90%Residential treatment: 90% Molitor et al., 1998; Shoptaw et al.,

2002; VNRH, unpublished data

California: 2002California: 2002--20032003

35,947 individuals were admitted to treatment in 35,947 individuals were admitted to treatment in California under the Substance Abuse and Crime California under the Substance Abuse and Crime Prevention Act funding.Prevention Act funding.Of this group, 53% reported MA as their primary Of this group, 53% reported MA as their primary drug problemdrug problemTreatment: equally successful to that of other Treatment: equally successful to that of other drugs: 40drugs: 40--60% relapse rate60% relapse rate

SSRI AntidepressantsSSRI Antidepressants

Do increase local levels of serotoninDo increase local levels of serotoninAntidepressants in general (SNAPH) not associated with Antidepressants in general (SNAPH) not associated with PAHPAHaa

SSRIsSSRIs block rather than promote serotonin induced smooth block rather than promote serotonin induced smooth muscle cell growth muscle cell growth in in vitrovitrobb

Use of Use of SSRIsSSRIs is not associated with increased mortality in is not associated with increased mortality in patients with established patients with established PAHPAHcc. . BUT maternal use of BUT maternal use of SSRIsSSRIs has been linked to persistent has been linked to persistent pulmonary hypertension of the newborn; the cause for this pulmonary hypertension of the newborn; the cause for this discrepancy remains discrepancy remains unclearuncleardd. .

a. Rich S Chest 2000;117:870b. b. EddahibiEddahibi S. S. Circulation. Circulation. Apr 18 2006;113(15):1857Apr 18 2006;113(15):1857--1864.; Marcos E 1864.; Marcos E Circ ResCirc Res. 2004;94:1263. 2004;94:1263--1270.1270.c. c. KawutKawut SM SM PulmPulm PharmacolPharmacol TherTher. . 2006;19(5):3702006;19(5):370--374.374.d. Chambers CD d. Chambers CD N N EnglEngl J Med. J Med. Feb 9 2006;354(6):579Feb 9 2006;354(6):579--587.587.

Conclusions: MethamphetaminesConclusions: Methamphetamines

Use increased significantly through the 1990Use increased significantly through the 1990’’s, now s, now primarily inhaled or smoked.primarily inhaled or smoked.Long halfLong half--life life

Acutely: Acutely: catecholaminescatecholamines may lead to hypertension, may lead to hypertension, dehydration, renal failure, MIdehydration, renal failure, MICan have paranoia for daysCan have paranoia for days

10 times higher rates of use among IPAH: suggests 10 times higher rates of use among IPAH: suggests associationassociationRisk, minimum dose / duration of use unknown but Risk, minimum dose / duration of use unknown but usually years of abuseusually years of abuseMethamphetamine epidemic began on the West CoastMethamphetamine epidemic began on the West Coast

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