Clinical trial NCT03707951
Conditions: Alcohol Use Disorder
Keywords: alcohol youth adolescent pharmacotherapy medication N-acetylcysteine
Sponsor: Medical University of South Carolina
Start date: 2019-02-27; Completion date: 2024-02-26
Enrollment: 126 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 8-week randomized, placebo-controlled trial testing the effects of N-acetylcysteine (NAC), on a platform of weekly evidence-based brief alcohol intervention for 120 adolescents with alcohol use disorder (AUD). The primary efficacy endpoint is reduction in alcohol use (total standard drinks), compared between NAC and placebo groups.

Detailed description:
Adolescence is a critical developmental stage involving marked elevation in alcohol initiation, progression to AUD, and development of significant, lasting adverse outcomes from use. Effective treatments must be developed for AUD in this especially vulnerable age range. The identification of a well-tolerated, effective pharmacological treatment would represent a significant advance and could yield tremendous public health impact. The proposed trial will provide critical data to evaluate NAC as a highly promising pharmacotherapy for adolescent AUD, and regardless of NAC versus placebo outcomes will provide key methodological guidance for future randomized controlled trials of pharmacotherapies for adolescent AUD. Randomized participants will be provided and instructed to take their assigned medication at 1200 mg twice daily, in approximately twelve-hour intervals.

Arms: arm 1: N-acetylcysteine 1200 mg twice daily for 8 weeks; administered orally arm 2: Placebo (matched in appearance to N-acetylcysteine to preserve double-blind) twice daily for 8 weeks; administered orally
Interventions: intervention 1: N-acetylcysteine intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: N-acetylcysteine 1200 mg twice daily for 8 weeks (administered orally) intervention 2: Placebo (matched in appearance to N-acetylcysteine to preserve double-blind) twice daily for 12 weeks (administered orally)

Protocol documents:
Prot_SAP_001.pdf: 
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N -A c et yl c y st ei n e f or Y o ut h Al c o h ol U s e Di s or d er  
 
St u d y Pr ot o c ol  
 
N C T 0 3 7 0 7 9 5 1  
 
M o st re c e nt I R B -a p pr o v e d Pr ot o c o l, d at ed J ul y 1 1, 2 0 2 3 ( n o u p d at e s si n c e)  
 
S u b mitt e d t o Cli ni c al Tri al s. g o v o n D e c e m b er 3 0 , 2 0 2 4 
 


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1. 0  O bj e cti v e s  / S p e cifi c Ai m s  
A d olesce nce is a ke y peri o d i n t he de vel o p me nt of pr o ble matic alc o h ol use, wit h a p pr o xi matel y 1 5 % 
of 1 8- year- ol ds meeti n g criteria f or alc o h ol use dis or der ( A U D). Eff orts t o pre ve nt or di mi nis h a d olesce nt 
hea v y alc o h ol use ha ve bee n o nl y m o destl y effecti ve, wit h u p t o 8 6 % of y o ut h ret ur ni n g t o use wit hi n 1 2 
m o nt hs f oll o wi n g treat me nt. I na de q uate treat me nt f or a d olesce nts is a n i m p orta nt p u blic healt h c o ncer n 
gi ve n t hat alc o h ol use d uri n g t his ti me is hi g hl y pre dicti ve of l o n g-ter m pr o ble matic dri n ki n g. Effecti ve 
treat me nt  d uri n g  t his  v ul nera ble  peri o d  c o ul d  hel p  pre ve nt  m ore  se vere,  treat me nt-resista nt  A U D  i n 
a d ult h o o d.  W hile  se veral  me dicati o ns  ha ve  de m o nstrate d  efficac y  f or  a d ult  A U D,  mi ni mal 
p har mac ot hera p y  researc h  has  f oc use d  o n  a d olesce nts.  E val uati o n  of  alter nati ve  a n d  m ore  efficaci o us 
treat me nts f or a d olesce nts wit h A U D is warra nte d. 
A m o n g ca n di date p har mac ot hera pies f or a d olesce nt A U D, t he o ver-t he-c o u nter a nti o xi da nt s u p ple me nt 
N -acet ylc ystei ne ( N A C) is partic ularl y c o m pelli n g.  A n easil y accessi ble a n d aff or da ble c o m p o u n d wit h 
esta blis he d  safet y  acr oss  a ge  gr o u ps,  N A C  has  s h o w n  pr o mise  i n  treati n g  a  variet y  of  s u bsta nce  use 
dis or ders b y rest ori n g gl uta mate h o me ostasis disr u pte d b y a d dicti o n.  O ur tea m has de m o nstrate d, via a 
place b o-c o ntr olle d  ra n d o mize d  trial,  t hat  N A C  pr o m otes  a bsti ne nce  i n  a d olesce nts  wit h  ca n na bis  use 
dis or der ( C U D).  S pecific t o alc o h ol, a n u m ber of rece nt precli nical st u dies ha ve de m o nstrate d s u peri orit y 
of  N A C,  c o m pare d  t o  place b o,  i n  re d uci n g  alc o h ol  self-a d mi nistrati o n.    T hese  fi n di n gs,  c o u ple d  wit h 
fi n di n gs of alc o h ol re d ucti o ns i n o ur tea m’s N A C trials f or C U D, i n dicate t hat a trial t o directl y assess t he 
effects of N A C o n a d olesce nt A U D is warra nte d. 
I n a d diti o n t o e val uati n g t he effects of N A C, t he pr o p ose d P hase II pr o of- of-c o nce pt st u d y is desi g ne d 
t o gat her ke y data t o i nf or m f ut ure P hase III treat me nt efficac y trials f or a d olesce nt A U D, i ncl u di n g effect 
size  esti mates.    T here  is  n o  c urre ntl y  esta blis he d  te m plate  f or  a d olesce nt  A U D  p har mac ot hera p y  trials.  
W hile  a d ult  trials  ma y  be  i nf or mati ve,  a d olesce nts  wit h  A U D  ofte n  differ  fr o m  a d ults  i n  alc o h ol  use 
patter ns,  use-ass ociate d  pr o ble ms,  a n d  rece pti ve ness  t o,  as  well  as  a d here nce  wit h,  treat me nt.  Bef ore 
pr ocee di n g t o a P hase III efficac y trial i n a d olesce nts, a n u m ber of de vel o p me ntall y-i nf or me d met h o ds m ust 
be e m be d de d a n d e val uate d f or feasi bilit y a n d val ue i n a pr o of- of-c o nce pt trial.  I n a d diti o n t o tra diti o nal, 
esta blis he d, office- base d cli nical trial pr oce d ures, we pr o p ose utilizi n g m o bile tec h n ol o g y t o i m pr o ve data 
c ollecti o n,  e n ga ge me nt,  a n d  me dicati o n  a d here nce.    We  a d diti o nall y  pr o p ose  c o m pari n g  t he  val ue  of  a 
cr oss-secti o n of self-re p ort a n d bi ol o gical meas ures of alc o h ol use a n d relate d be ha vi ors, t o deter mi ne t he 
m ost a p pr o priate meas ures f or i ncl usi o n as efficac y o utc o mes i n P hase III trials. 
Wit h t hese met h o d ol o gical c o nsi derati o ns i n mi n d, a n d i n res p o nse t o Nati o nal I nstit ute o n Alc o h ol 
A b use a n d Alc o h olis m ( NI A A A) R F A- A A - 1 8- 0 0 9 Me dic ati o ns Devel o p me nt f or t he Tre at me nt of Alc o h ol 
Use Dis or der , we pr o p ose preli mi naril y testi n g t he effects of N A C, c o m pare d t o place b o, o n a platf or m of 
wee kl y e vi de nce- base d brief alc o h ol i nter ve nti o n f or a d olesce nts wit h A U D ( N = 1 2 0). We will ( 1) c o n d uct 
a n 8- wee k, i nte nt- t o-treat, d o u ble- bli n d, parallel- gr o u p, ra n d o mize d, place b o-c o ntr olle d trial of N A C ( 2 4 0 0 
m g  per  da y);  ( 2)  e xa mi ne  sta n dar dize d,  re peate d  de pe n de nt  meas ures  of  cli nical  o utc o mes  at  baseli ne, 
t hr o u g h o ut treat me nt, a n d at p ost-treat me nt f oll o w- u p; a n d ( 3) e m pl o y m o bile tec h n ol o g y t o i m pr o ve data 
c ollecti o n, e n ga ge me nt, a n d me dicati o n a d here nce. T he f oll o wi n g s pecific ai ms are pr o p ose d: 
S pecific Ai m 1 . T o e val uate t he effect of N A C, as c o m pare d t o place b o, i n re d uci n g alc o h ol use (t otal 
sta n dar d dri n ks) a m o n g treat me nt-see ki n g a d olesce nts wit h A U D. 
S pecific  Ai m  2 .  T o  e val uate  t he  feasi bilit y  a n d  utilit y  of  i m ple me nti n g  de vel o p me ntall y-i nf or me d 
met h o ds, i ncl u di n g t h ose t hat le vera ge m o bile tec h n ol o g y, t o c o n d uct a ra n d o mize d, place b o-c o ntr olle d 
trial of a p har mac ot hera p y f or a d olesce nt A U D. 
S pecific  Ai m  2 a:   E xa mi ne  a gree me nt  bet wee n  self-re p ort  ( m o bile  tec h n ol o g y- deli vere d  dail y  self-
re p ort, Ti meli ne F oll o w- Bac k) a n d bi o mar kers (et h yl gl uc ur o ni de, car b o h y drate deficie nt tra nsferri n, 
p h os p hati d ylet ha n ol, alc o h ol breat hal yzer) of alc o h ol use. 


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S pecific Ai m 2 b:  E xa mi ne a gree me nt bet wee n meas ures of me dicati o n a d here nce ( m o bile tec h n ol o g y-
deli vere d vi de o of me dicati o n ta ki n g, Me dicati o n E ve nt M o nit ori n g S yste m, pill c o u nt, self-re p ort). 
A d olesce nce is a critical de vel o p me ntal sta ge i n v ol vi n g mar ke d ele vati o n i n alc o h ol i nitiati o n, pr o gressi o n 
t o A U D, a n d de vel o p me nt of si g nifica nt, lasti n g a d verse o utc o mes fr o m use. Effecti ve treat me nts m ust be 
de vel o pe d f or A U D i n t his es peciall y v ul nera ble a ge ra n ge. T he i de ntificati o n of a well-t olerate d, effecti ve 
p har mac ol o gical treat me nt w o ul d re prese nt a si g nifica nt a d va nce a n d c o ul d yiel d tre me n d o us p u blic healt h 
i m pact.  T he  pr o p ose d  trial  will  pr o vi de  critical  data  t o  e val uate  N A C  as  a  hi g hl y  pr o misi n g 
p har mac ot hera p y f or a d olesce nt A U D, a n d re gar dless of N A C vers us place b o o utc o mes will pr o vi de ke y 
met h o d ol o gical g ui da nce f or f ut ure ra n d o mize d c o ntr olle d trials of p har mac ot hera pies f or a d olesce nt A U D. 
2. 0  B ac k gr o u n d  
A d olesce nt Alc o h ol Use Dis or der 
A d olesce nce is a ke y peri o d i n t he de vel o p me nt of alc o h ol use dis or der ( A U D), wit h nearl y 1 5 % of 
y o ut h meeti n g dia g n ostic criteria f or A U D b y a ge 1 8. 1 Hea v y a d olesce nt alc o h ol use is relate d t o seri o us 
ps yc h os ocial pr o ble ms, i ncl u di n g c o m or bi d ps yc h o pat h ol o g y, 2, 3 p o orer aca de mic s uccess,4 a n d detri me ntal 
ne ur oc o g niti ve  c o nse q ue nces. 5- 7  F urt her m ore,  bi n ge  alc o h ol  use  patter ns  i nitiate d  d uri n g  a d olesce nce 
persist i nt o a d ult h o o d a n d si g nifica ntl y i ncrease ris k f or s u bse q ue nt A U D a n d relate d pr o ble ms. 8- 1 0 
Li mit ati o ns i n C urre nt Tre at me nts 
Decreasi n g  alc o h ol  use  at  t his  earl y  sta ge  c o ul d  ha ve  si g nifica nt  l o n g-ter m  i m plicati o ns;  h o we ver, 
eff orts t o pre ve nt or decrease hea v y alc o h ol use d uri n g a d olesce nce ha ve o nl y bee n m o destl y effecti ve, 1 1, 1 2 
wit h  u p  t o  8 6 %  of  y o ut h  ret ur ni n g  t o  use  wit hi n  1 2  m o nt hs  f oll o wi n g  treat me nt. 1 3, 1 4  W hile  se veral 
me dicati o ns ha ve bee n a p pr o ve d b y t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) as efficaci o us i n treati n g 
a d ult A U D, mi ni mal p har mac ot hera p y researc h has f oc use d o n a d olesce nts, a n d t here are n o F D A a p pr o ve d 
me dicati o ns f or a d olesce nt A U D. 1 5 T his li mits treat me nt o pti o ns f or t his es peciall y v ul nera ble a ge gr o u p, 
as safet y a n d efficac y of me dicati o ns f or a d olesce nts ca n n ot be i nferre d fr o m a d ult st u dies. 1 6 E val uati o n of 
alter nati ve a n d m ore efficaci o us treat me nts f or a d olesce nt A U D  is warra nte d. 
N- Acet ylc ystei ne as a C a n di d ate P h ar m ac ot her a p y 
S afety, Accessi bility, a n d Aff or d a bility  
N-acet ylc ystei ne  ( N A C),  a  pr o dr u g  of  t he  a mi n o  aci d  c ystei ne,  p ossesses  a  l o n g-esta blis he d  safet y 
rec or d, wit h pe diatric a n d a d ult F D A a p pr o val si nce 1 9 6 3. N A C has bee n use d safel y f or se veral deca des 
i n c hil dre n a n d a d ults, ofte n at d oses greatl y e xcee di n g t h ose pr o p ose d f or o ur st u d y. A meta-a nal ysis of 
N A C  st u dies  f o u n d  t hat  t his  s u p ple me nt  was  well  t olerate d,  wit h  ge nerall y  mil d,  m ost  c o m m o nl y 
gastr oi ntesti nal, a d verse effects t hat di d n ot re q uire treat me nt i nterr u pti o n. 1 7 S yste mic aller gic reacti o ns t o 
N A C ha ve bee n o bser ve d, b ut o nl y wit h i ntra ve n o us a d mi nistrati o n. 1 8 Reflecti n g its safet y pr ofile, N A C is 
a vaila ble o ver-t he-c o u nter as a s u p ple me nt, w hic h f urt her i ncreases its p ote ntial acce pta bilit y, accessi bilit y, 
a n d aff or da bilit y. O ur tea m’s e xte nsi ve e x perie nce wit h N A C i n s u bsta nce usi n g a d olesce nts a n d a d ults, 
ma n y of w h o m als o dra n k alc o h ol fre q ue ntl y, has f urt her s u p p orte d its acce pta bilit y a n d t olera bilit y i n t he 
pr o p ose d trial’s tar get p o p ulati o n. 1 9 -2 6 
Mec h a nis m i n S u bst a nce Use Dis or ders  
Gl uta mate  has  e mer ge d  as  a  t hera pe utic  tar get  i n  t he  treat me nt  of  a d dicti o ns. 2 7  Re peate d  use  of  a n 
a d dicti ve  s u bsta nce  res ults  i n  gl uta mate  d ysre g ulati o n  i n  vari o us  brai n  re gi o ns,  i ncl u di n g  t he  n ucle us 
acc u m be ns,  a  striatal  str uct ure  critical  t o  m oti vati o n  a n d  lear ni n g. 2 8, 2 9  N A C  a d mi nistrati o n  rest ores 
gl uta mate h o me ostasis via u pre g ulati o n of t he gl uta mate G L T 1 tra ns p orter, cleari n g e xcess gl uta mate fr o m 
t he acc u m be ns a n d re d uci n g s u bsta nce see ki n g a n d self-a d mi nistrati o n.3 0, 3 1 A rece nt meta-a nal ysis of se ve n 
cli nical  trials  f o u n d  t hat  N A C  was  s u peri or  t o  place b o  f or  cra vi n g  re d ucti o n  acr oss  s u bsta nce  use 
dis or ders, 3 2 a n d cli nical fi n di n gs fr o m o ur gr o u p (see Preli mi nar y Fi n di n gs) i n dicate t hat N A C re d uces use 
acr oss a ra n ge of s u bsta nces, i ncl u di n g ca n na bis, alc o h ol, t o bacc o, a n d c ocai ne. 1 9 -2 6  T he str o n gest cli nical 


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fi n di n gs t o date are a d olesce nt-s pecific, wit h N A C m ore t ha n d o u bli n g rates of a bsti ne nce c o m pare d t o 
place b o i n a d olesce nts wit h ca n na bis use dis or der ( C U D). 2 1 
Alc o h ol- S pecific Fi n di n gs  
A rece nt pr o misi n g precli nical st u d y f o u n d t hat alc o h ol-c o ns u mi n g rats w h o were a d mi nistere d N A C 
i n hi bite d  alc o h ol  i nta ke  u p  t o  7 0 %  c o m pare d  t o  sali ne-treate d  rats  (p <. 0 0 0 1). 3 3  T he  effect  of  treat me nt 
re mai ne d f or 4 da ys p ost-treat me nt, s h o wi n g t hat N A C a d mi nistrati o n ge nerates a ne ur oc he mical effect 
e xte n di n g well past its 1- h o ur half-life i n r o de nts. A s u bse q ue nt trial st u d yi n g t he effects of N A C o n alc o h ol 
self-a d mi nistrati o n  i n  rats  s h o we d  a n  8 1 %  decrease  i n  alc o h ol  c o ns u m pti o n  f or  t he  N A C-treate d  gr o u p 
c o m pare d t o place b o, as well as re d uce d rates of reac q uisiti o n i n rats t hat ha d bee n a bsti ne nt fr o m alc o h ol 
f or 1 7 da ys.3 4 I n a st u d y of rats w h o u n der we nt 3 0 da ys of c hr o nic alc o h ol i n gesti o n, N A C pre ve nte d a n 
i ncrease  i n  pr o-i nfla m mat or y  c yt o ki nes  a n d  a  decrease  i n  a nti-i nfla m mat or y  c yt o ki nes  i n  fr o ntal  a n d 
hi p p oca m pal re gi o ns. 3 5 I n a st u d y of ze brafis h, N A C pre ve nte d t he effects of ac ute alc o h ol e x p os ure o n 
be ha vi oral a n d o xi dati ve stress para meters. 3 6 T o date, n o h u ma n A U D cli nical trials of N A C ha ve bee n 
p u blis he d; h o we ver, sec o n dar y a nal yses fr o m o ur pri or ca n na bis cessati o n trials s u g gest N A C effects ma y 
ge neralize t o ot her s u bsta nces i ncl u di n g alc o h ol (see Preli mi nar y St u dies secti o n). 
I n n o v ati o n 
Directly Testi n g N- Acetylcystei ne f or A d olesce nt A U D 
Alc o h ol is t he m ost c o m m o nl y use d s u bsta nce i n a d olesce nce. Des pite t he s uccess of N A C i ncreasi n g 
ca n na bis  a bsti ne nce  rates  t w o-f ol d  i n  a d olesce nts  wit h  ca n na bis  use  dis or der, 2 1  a n d  rece nt  precli nical 
fi n di n gs s u g gesti n g N A C re d uces alc o h ol use i n r o de nts b y u p t o 8 1 %, t here are n o st u dies e xa mi ni n g t he 
effect of N A C o n a d olesce nt A U D. Effecti ve i nter ve nti o ns d uri n g a d olesce nce c o ul d ha ve s u bsta ntial l o n g-
ter m i m plicati o ns b y re d uci n g ac ute a n d e n d uri n g ne gati ve s ocial, aca de mic, a n d c o g niti ve c o nse q ue nces 
relate d t o hea v y tee n dri n ki n g.5 Earlier treat me nt d uri n g t his v ul nera ble peri o d c o ul d hel p pre ve nt m ore 
se vere, treat me nt-resista nt A U D i n a d ult h o o d. 
Pr o of- of- C o nce pt of R a n d o mize d C o ntr olle d Tri al Met h o d ol o gy f or A d olesce nt A U D 
T here is n o c urre ntl y esta blis he d te m plate f or a d olesce nt A U D p har mac ot hera p y efficac y trials.  O nl y 
a ha n df ul of trials ha ve bee n c o n d ucte d i n a d olesce nts, wit h var yi n g met h o d ol o g y a n d s mall sa m ple sizes, 
lea di n g t o diffic ult y wit h i nter pretati o n.  W hile a d ult trials ma y be i nf or mati ve, a d olesce nts wit h A U D ofte n 
differ  fr o m  a d ults  i n  alc o h ol  use  patter ns,  use-ass ociate d  pr o ble ms,  a n d  rece pti ve ness  t o, as  well  as 
a d here nce  wit h,  treat me nt.  Bef ore  pr ocee di n g  t o  a  P hase  III  efficac y  trial  i n  a d olesce nts,  a  n u m ber  of 
de vel o p me ntall y-i nf or me d met h o ds m ust be e m be d de d a n d e val uate d f or feasi bilit y a n d val ue i n a pr o of-
of-c o nce pt trial.  I n a d diti o n t o tra diti o nal, esta blis he d, office- base d cli nical trial pr oce d ures, we pr o p ose 
utilizi n g  m o bile  tec h n ol o g y  t o  i m pr o ve  data  c ollecti o n,  e n ga ge me nt,  a n d  me dicati o n  a d here nce.    We 
a d diti o nall y  pr o p ose  c o m pari n g  t he  val ue  of  a  cr oss-secti o n  of  self-re p ort  a n d  bi ol o gical  meas ures  of 
alc o h ol  use  a n d  relate d  be ha vi ors,  t o  deter mi ne  t he  m ost  a p pr o priate  meas ures  f or  i ncl usi o n  as  efficac y 
o utc o mes i n P hase III trials. 
Rese arc h Te a m 
T he  m ulti disci pli nar y  i n vesti gati ve  tea m  c o nsists  of  e x perie nce d  cli nical  researc hers  wit h 
c o m ple me ntar y  e x pertise  i n  a d olesce nt  alc o h ol  a n d  ot her  s u bsta nce  use  dis or ders,  m o bile  tec h n ol o g y, 
de vel o p me ntal ps yc h o pat h ol o g y, ne ur o ps yc h ol o gical testi n g, a n d h u ma n la b orat or y para di g ms, as well as 
e xte nsi ve  e x perie nce  c o n d ucti n g  ra n d o mize d  c o ntr olle d  trials  e val uati n g  p har mac ol o gical  a n d  be ha vi oral 
i nter ve nti o ns f or alc o h ol a n d ot her s u bsta nce use dis or ders. S o me scie ntific c o ntri b uti o ns of direct rele va nce 
t o t he pr o p ose d w or k are s u m marize d bel o w. 
 
 
 
 


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Preli mi n ar y St u dies 
N- Acetylcystei ne Tre at me nt of S u bst a nce Use Dis or ders 
A d olesce nt C a n n a bis Use Dis or der 
O ur researc h tea m c o m plete d a d o u ble- bli n d ra n d o mize d place b o-c o ntr olle d trial of N A C f or a d olesce nt 
C U D. 2 1  Treat me nt-see ki n g y o ut h wit h C U D ( N = 1 1 6) were ra n d o mize d, i n 1: 1 parallel gr o u p all ocati o n, t o 
recei ve a d o u ble- bli n d 8- wee k c o urse of N A C ( 1 2 0 0 m g) or place b o t wice dail y, a d de d t o a c o nti n ge nc y 
ma na ge me nt i nter ve nti o n a n d brief wee kl y cessati o n c o u nseli n g.  A p ost-treat me nt f oll o w- u p visit occ urre d 
4 wee ks after treat me nt c o ncl usi o n.   
T he pri mar y st u d y h y p ot hesis was t hat partici pa nts ra n d o mize d t o N A C w o ul d ha ve hi g her o d ds t ha n 
t h ose ra n d o mize d t o place b o t o s u b mit ne gati ve wee kl y uri ne ca n na bi n oi d tests ( U C Ts) d uri n g treat me nt.  
A n  i nte nt- t o-treat  (I T T)  a p pr oac h  i ncl u di n g  all  ra n d o mize d  partici pa nts  was  use d.    I n  all  a nal yses, 
partici pa nts l ost t o f oll o w u p or a bse nt f or visits were c o de d as ha vi n g a p ositi ve U C T at e ver y misse d visit.  
T he  pr o p orti o n  of  ne gati ve  U C Ts  i n  t he 
N A C  a n d  place b o  gr o u ps  at  eac h  visit  (I T T 
sa m ple) is s h o w n i n t he a dj oi ni n g fi g ure.  T he 
relati o ns hi p bet wee n treat me nt a n d t he o d ds of 
a ne gati ve U C T was O R = 2. 4 ( 9 5 % CI: 1. 1- 5. 4), 
p = 0. 0 2 1.  T hr o u g h  t he  fi nal  treat me nt  visit, 
4 0. 9 %  ( 1 9 0/ 4 6 4)  of  t he  U C Ts  a m o n g 
partici pa nts  i n  t he  N A C  gr o u p  were  ne gati ve, 
c o m pare d t o 2 7. 2 % ( 1 2 6/ 4 6 4) a m o n g t h ose i n 
t he  place b o  gr o u p.    At  t he  p ost-treat me nt 
f oll o w- u p  visit  (f o ur  wee ks  after  me dicati o n 
disc o nti n uati o n),  1 9. 0 %  ( 1 1/ 5 8)  of  t he  U C Ts 
a m o n g  partici pa nts  i n  t he  N A C  gr o u p  were 
ne gati ve,  c o m pare d  t o  1 0. 3 %  ( 6/ 5 8)  a m o n g 
t h ose i n t he place b o gr o u p.  W hile still n u mericall y fa v ori n g N A C, t he o verall treat me nt effect l ost statistical 
si g nifica nce  at  p ost-treat me nt  f oll o w- u p  ( O R = 2. 2  [ 9 5 %  CI:  0. 7- 6. 5], p = 0. 1 5 5),  t h o u g h  t he  trial  was  n ot 
p o were d f or t his o utc o me.  
A p ost  h oc   se nsiti vit y  a nal ysis  was  perf or me d  o n  o d ds  of  ne gati ve  U C Ts  d uri n g  treat me nt,  usi n g 
m ulti ple met h o ds t o ma na ge missi n g data a n d partici pa nt dr o p o uts.  T he selecti o n of missi n g data ha n dli n g 
ha d little effect o n o utc o mes. 
E ver y efficac y o utc o me a p pr oac h e x pl ore d, i ncl usi ve of b ot h U C T a n d self-re p ort data sets, c o nsiste ntl y 
yiel de d fi n di n gs n u mericall y fa v ori n g N A C o ver place b o.  Statisticall y si g nifica nt differe nces were n ote d 
i n t he st u d y’s a pri ori  o utc o me a nal ysis ( o d ds of ne gati ve wee kl y U C T o ver t he c o urse of treat me nt) a n d 
i n t he e n d- of-treat me nt bi nar y U C T o utc o mes (last 2 wee ks [ O R 2. 5 5, p = 0. 0 3 6] a n d last 4 wee ks [ O R 2. 5 9, 
p = 0. 0 4 5]).  O d ds rati os were greater t ha n 2 f or all e n d- of-treat me nt (last 2 a n d last 4 wee ks) U C T a n d self-
re p ort o utc o mes.  F urt her m ore, t here was str o n g a gree me nt bet wee n U C T a n d self-re p ort.  O verall, fi n di n gs 
de m o nstrate d c o nsiste ntl y fa v ora ble o utc o mes f or N A C vers us place b o acr oss a wi de variet y of a p pr oac hes. 
Alc o h ol Use Dis or der 
T o date, n o p u blis he d cli nical trials ha ve e xa mi ne d t he effect of N A C o n A U D . T heref ore, sec o n dar y 
a nal yses were perf or me d o n t he a d olesce nt ca n na bis cessati o n dataset descri be d a b o ve t o e xa mi ne t he effect 
of N A C o n c o -occ urri n g alc o h ol use o ver t he 8 -wee k treat me nt c o urse. 2 5 Less ca n na bis  use ( base d o n uri ne 
ca n na bi n oi d tests a n d creati ni ne a dj uste d ca n na bi n oi d le vels) was ass ociate d wit h less alc o h ol use i n t he 
N A C treate d gr o u p b ut n ot i n t he place b o treate d gr o u p (i nteracti o n t8 6= 2. 4 4, p = 0. 0 1 6). I n s u m, partici pa nts 
w h o re d uce d ca n na bis use w hile usi n g N A C als o ha d a si g nifica nt re d ucti o n i n alc o h ol use; t his was n ot t he 
case i n t he place b o c o n diti o n, s u p p orti n g t he asserti o n t hat N A C ma y be e xerti n g effects acr oss s u bsta nces, 
i ncl u di n g alc o h ol. Fi n di n gs are n ota ble c o nsi deri n g t his sa m ple was n ot atte m pti n g t o re d uce alc o h ol use a n d 
was n ot recei vi n g a c o m bi ne d be ha vi oral treat me nt f or alc o h ol use.  
 
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St u d y W e e k s
Pr o p orti o n ( %) of N e g ati v e Uri n e 
C a n n a bi n oi d T e st s 
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N A C 
 
N e g ati v e Uri n e C a n n a bi n oi d T e st ( %) 
 
N A C ( n = 5 8)       8. 6      3 1. 0    3 9. 7     4 3. 1     4 4. 8    4 1. 4     4 3. 1     3 9. 7    4 4. 8                 1 9. 0 
Pl a c e b o ( n = 5 8) 1 0. 3   
  1 7. 2     2 9. 3     2 9. 3     3 1. 0    2 7. 6     2 5. 9     2 4. 1    3 2. 8                 1 0. 3 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 6 of 2 8  
 
We rece ntl y c o m plete d  a 1 2 -wee k, m ulti -site ca n na bis cessati o n trial e xa mi ni n g t he effects of N A C  
vers us place b o o n a d ults wit h C U D. 2 2 Partici pa nts ( N = 3 0 2, a ges 1 8 -5 0) were ra n d o mize d t o d o u ble -bli n d 
N A C  ( 1 2 0 0 m g,  t wice  dail y)  or  place b o.  Neit her  alc o h ol  use  n or  desire  f or  alc o h ol  cessati o n  were 
re q uire me nts f or partici pati o n. Partici pa nts t hat ret ur ne d f or at least o ne treat me nt visit a n d ha d rec or de d 
alc o h ol use data (n = 2 7 7) were i ncl u de d i n sec o n dar y a nal ysis of alc o h ol use. 2 6 C o m pare d t o t he place b o 
gr o u p, partici pa nts i n t he N A C gr o u p ha d i ncrease d o d ds of bet wee n visit alc o h ol a bsti ne nce [ O R = 1. 3 7; 
9 5 % CI = 1. 0 6 -1. 7 8; p = 0. 0 1 9], fe wer dri n ks per wee k [ R R = 0. 6 7; 9 5 % CI = 0. 4 8 -0. 9 9; p = 0. 0 4 5], a n d fe wer 
dri n ki n g  da ys  per  wee k  [ R R = 0. 6 9;  9 5 %  CI = 0. 5 1 -0. 9 2;  p = 0. 0 1 4].  C ha n ges  i n  c o nc urre nt  ca n na bis  use 
a m o u nts were n ot c orrelate d t o a n y  of t he alc o h ol use varia bles. T hese fi n di n gs i n dicate t hat , e ve n wit h o ut 
alc o h ol treat me nt-see ki n g or ps yc h os ocial i nter ve nti o ns tar geti n g alc o h ol use, N A C ma y be effecti ve at 
re d uci n g c o ns u m pti o n of alc o h ol b y ~ 3 0 %  a m o n g i n di vi d uals see ki n g treat me nt f or  C U D . 
A pil ot cli nical trial at M U S C e xa mi ne d t he effects of N A C f or re d ucti o n of alc o h ol a n d dr u g cra vi n g 
a n d  p osttra u matic  stress  a m o n g  Vetera ns  ( N = 3 5)  wit h  c o m or bi d  s u bsta nce  use  dis or der  a n d  tra u ma. 1 9 
T h o u g h a n A U D dia g n osis was n ot re q uire d f or i ncl usi o n, 8 2 % of t he sa m ple met criteria f or a n A U D. 
N A C yiel de d a vera ge re d ucti o ns i n t he a m o u nt a n d fre q ue nc y of alc o h ol a n d dr u g cra vi n g t hat were m ore 
t ha n 2. 5 ti mes t he ma g nit u de of place b o effects.  
I n a n ot her d o u ble- bli n d, place b o-c o ntr olle d trial of N A C i n a d ults wit h c ocai ne use dis or der ( N = 1 1 1), 
N A C was ass ociate d wit h si g nifica ntl y l o n ger ti me t o rela pse a n d l o wer cra vi n g as c o m pare d t o place b o 
a m o n g partici pa nts e nteri n g t he trial a bsti ne nt. 2 3 Sec o n dar y a nal ysis of i n di vi d uals i n t he st u d y w h o met 
criteria f or A U D ( n = 2 8/ 1 1 1) re veale d t hat t he N A C treate d gr o u p c o ns u me d a p pr o xi matel y 9 fe wer dri n ks 
per wee k (i.e., 4 6 % less) t ha n t he place b o treate d gr o u p ( N A C = 1 0. 4 sta n dar d dri n ks per wee k vs. place b o 
=  1 9. 3  sta n dar d  dri n ks  per  wee k)  ( Gr o u p  ×  Ti me  Wal d  C hi- S q uare  =  1 5. 9, df = 8, p < 0. 0 5).  T his  w or k 
pr o vi des f urt her s u p p ort f or t he t hera pe utic p ote ntial of N A C i n re d uci n g alc o h ol use. 
B olstere d b y t he af ore me nti o ne d preli mi nar y fi n di n gs, o ur tea m is e xa mi ni n g N A C m ore directl y f or 
A U D, i n a wit hi n-s u bjects cr oss o ver mec ha nistic/ ne ur oi ma gi n g st u d y of n o n-treat me nt-see ki n g a d olesce nt 
hea v y dri n kers ( K 2 3 A A 0 2 5 3 9 9) a n d i n a n ot her trial i n a d ults wit h c o- occ urri n g A U D a n d p osttra u matic 
stress dis or der ( R 0 1 A A 0 2 5 0 8 6).  T he pr o p ose d trial d oes n ot d u plicate or o verla p wit h t he met h o ds of t hese 
t w o st u dies, a n d i nstea d will ser ve t o c o m ple me nt t he m t o better i nf or m f ut ure w or k, i ncl u di n g p ote ntial 
P hase III trials wit h N A C i n A U D.  C o n d ucti n g t his w or k i n parallel, rat her t ha n i n series, will yiel d s y ner g y 
t o m ore efficie ntl y pr ocee d wit h i m p orta nt ne xt ste ps i n treat me nt de vel o p me nt. 
I n s u m, o ur w or k wit h N A C has de m o nstrate d si g nifica nt treat me nt effects f or C U D i n a d olesce nts, a n d 
sec o n dar y e xa mi nati o n acr oss m ulti ple trials of N A C f or s u bsta nce use dis or ders has re veale d re d ucti o ns 
i n alc o h ol use o ver t he c o urse of treat me nt, rei nf orci n g pr o misi n g alc o h ol-s pecific precli nical fi n di n gs (see 
Alc o h ol- S pecific Fi n di n gs ).  C o m bi ne d, t hese res ults i n dicate t hat a pr o of- of-c o nce pt cli nical trial of N A C 
f or a d olesce nt A U D is warra nte d. 
I nc or p or ati o n of M o bile Tec h n ol o gy t o E n h a nce Cli nic al Tri als 
Alc o h ol use is ofte n u n deresti mate d o ver l o n ger peri o ds of recall. 3 7, 3 8 O ur tea m has e x perie nce utilizi n g 
m o bile  s ur ve ys  as  a  mea ns  of  dail y  data  c ollecti o n  t hat 
i nte grates wit h a n e xisti n g data base ma na ge me nt a n d data 
ca pt ure  s yste m,  Researc h  Electr o nic  Data  Ca pt ure 
( R E D Ca p).3 9 I n se veral o n g oi n g pr ot oc ols ( R 0 1 D A 0 4 2 1 1 4, 
R 3 4 D A 0 4 2 2 2 8,  U G 3 D A 0 4 3 2 3 1;  K 2 3 A A 0 2 5 3 9 9)  we 
o btai n dail y m or ni n g re p orts of past- da y s u bsta nce use via 
R E D Ca p. 4 0  Partici pa nts  recei ve  a  s ur ve y  li n k  via  te xt 
messa ge  a n d  e mail  o nce  per  m or ni n g  d uri n g  t he  st u d y 
pr ot oc ol  as ki n g  t he m  t o  re p ort  t heir  alc o h ol  a n d  ot her 
s u bsta nce use o ver t he past 2 4 h o urs t o mi ni mize bias d ue 
t o retr os pecti ve recall.  
A d diti o nall y,  me dicati o n  a d here nce  is  si g nifica ntl y  o ver-esti mate d  w he n  rel yi n g  o n  partici pa nt self-
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S elf  R e p ort
Pill c o u nt
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Vi d e o C a pt ur e


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 7 of 2 8  
 
re p ort.4 1, 4 2 Me dicati o n n o n-a d here nce is e xtre mel y detri me ntal t o t he s uccess of p har mac ol o gical cli nical 
trials, as p o or a d here nce ( partic ularl y w he n o veresti mate d) ma y lea d i n vesti gat ors t o i nc orrectl y ass u me 
t hat a p ote ntiall y usef ul me dicati o n is i neffecti ve. Als o usi n g R E D Ca p, we ha ve s uccessf ull y i m ple me nte d 
vi de o  ca pt ure  t o  o bser ve  me dicati o n-ta ki n g  i n  o ur  cli nical  trials  ( R 0 1 D A 0 4 2 1 1 4,  R 3 4 D A 0 4 2 2 2 8, 
U G 3 D A 0 4 3 2 3 1, K 2 3 A A 0 2 5 3 9 9). See fi g ure f or wee k - b y- wee k c o m paris o n of me dia n perce nta ge of d oses 
re p orte d  as  ta ke n  a m o n g  a d here nce  assess me nts  fr o m  U G 3 D A 0 4 3 2 3 1  (a  cli nical  trial  of  a  t wice-a- da y 
me dicati o n f or C U D i n a d ults), i n dicati n g t hat tra diti o nal meas ures ma y o veresti mate a d here nce, c o m pare d 
t o t he o bjecti ve vi de o ca pt ure met h o d. F or t he vi de o ca pt ure pr oce d ure, partici pa nts recei ve a li n k t wice 
dail y t o t heir m o bile p h o ne. T he y rec or d t he msel ves ta ki n g t he me dicati o n i n real-ti me a n d t he vi de o is 
u pl oa de d f or later staff verificati o n. C o m pleti o n rates are o ver 7 0 % i n o ne st u d y 4 0 a n d c o nsi deri n g t hat t he 
me dicati o n vi de o is li kel y a c o nser vati ve esti mate of me dicati o n a d here nce (i.e., partici pa nts ma y ta ke t he 
me dicati o n  wit h o ut  rec or di n g  a  vi de o),  we  belie ve  t his  re prese nts  a  si g nifica nt  i m pr o ve me nt  o ver  ot her 
cli nical trials i n w hic h bi o mar kers s u g gest st u d y- defi ne d me dicati o n n o n-a d here nce ma y s o meti mes be as 
hi g h  as  4 0- 5 5 %. 4 1, 4 3  T he  sa me  pr oce d ures  will  t h us  be  utilize d  i n  t he  pr o p ose d  trial  t o  c o nfir m  a n d 
e nc o ura ge me dicati o n a d here nce. 
S u m m ary 
T he w or k o utli ne d a b o ve de m o nstrates t he e x pertise of t he i n vesti gati ve tea m i n a n u m ber of areas 
directl y  rele va nt  t o  t he  pr o p ose d  pr oject.  T he res ults  of  t he preli mi nar y   st u dies  are e nc o ura gi n g  a n d 
i n dicate t hat f urt her i n vesti gati o n of N A C i n a d olesce nts wit h A U D is warra nte d.  B uil di n g o n t he pre vi o us 
N A C st u dies b y o ur gr o u p, we  pr o p ose t o c o n d uct a cli nical trial f oc use d s pecificall y o n a d olesce nts wit h 
A U D.  T his e x perie nce d tea m bri n gs t o get her a u ni q ue set of s kills a n d a str o n g trac k rec or d of pr o d ucti vit y 
t o e ns ure t he s uccess of t he pr o p ose d pr oject. 
3. 0  I nter ve nti o n t o be st u die d 
N-acet ylc ystei ne  ( N A C),  a  pr o dr u g  of  t he  a mi n o  aci d  c ystei ne,  p ossesses  a  l o n g-esta blis he d  safet y 
rec or d, wit h pe diatric a n d a d ult F D A a p pr o val si nce 1 9 6 3. N A C has bee n use d safel y f or se veral deca des 
i n c hil dre n a n d a d ults, ofte n at d oses greatl y e xcee di n g t h ose pr o p ose d f or o ur st u d y. A meta-a nal ysis of 
N A C  st u dies  f o u n d  t hat  t his  s u p ple me nt  was  well  t olerate d,  wit h  ge nerall y  mil d,  m ost  c o m m o nl y 
gastr oi ntesti nal, a d verse effects t hat di d n ot re q uire treat me nt i nterr u pti o n. 1 7 S yste mic aller gic reacti o ns t o 
N A C ha ve bee n o bser ve d, b ut o nl y wit h i ntra ve n o us a d mi nistrati o n. 1 8 Reflecti n g its safet y pr ofile, N A C is 
a vaila ble o ver-t he-c o u nter as a s u p ple me nt, w hic h f urt her i ncreases its p ote ntial acce pta bilit y, accessi bilit y, 
a n d aff or da bilit y. O ur tea m’s e xte nsi ve e x perie nce wit h N A C i n s u bsta nce usi n g a d olesce nts a n d a d ults, 
ma n y of w h o m als o dra n k alc o h ol fre q ue ntl y, has f urt her s u p p orte d its acce pta bilit y a n d t olera bilit y i n t he 
pr o p ose d trial’s tar get p o p ulati o n. 1 9 -2 6 
Gl uta mate  has  e mer ge d  as  a  t hera pe utic  tar get  i n  t he  treat me nt  of  a d dicti o ns. 2 7  Re peate d  use  of  a n 
a d dicti ve  s u bsta nce  res ults  i n  gl uta mate  d ysre g ulati o n  i n  vari o us  brai n  re gi o ns,  i ncl u di n g  t he  n ucle us 
acc u m be ns,  a  striatal  str uct ure  critical  t o  m oti vati o n  a n d  lear ni n g. 2 8, 2 9  N A C  a d mi nistrati o n  rest ores 
gl uta mate h o me ostasis via u pre g ulati o n of t he gl uta mate G L T 1 tra ns p orter, cleari n g e xcess gl uta mate fr o m 
t he acc u m be ns a n d re d uci n g s u bsta nce see ki n g a n d self-a d mi nistrati o n.3 0, 3 1 A rece nt meta-a nal ysis of se ve n 
cli nical  trials  f o u n d  t hat  N A C  was  s u peri or  t o  place b o  f or  cra vi n g  re d ucti o n  acr oss  s u bsta nce  use 
dis or ders, 3 2 a n d cli nical fi n di n gs fr o m o ur gr o u p (see Preli mi nar y Fi n di n gs) i n dicate t hat N A C re d uces use 
acr oss a ra n ge of s u bsta nces, i ncl u di n g ca n na bis, alc o h ol, t o bacc o, a n d c ocai ne. 1 9 -2 6  T he str o n gest cli nical 
fi n di n gs t o date are a d olesce nt-s pecific, wit h N A C m ore t ha n d o u bli n g rates of a bsti ne nce c o m pare d t o 
place b o i n a d olesce nts wit h ca n na bis use dis or der ( C U D). 2 1 
C o nsiste nt wit h o ur esta blis he d pr oce d ures, U nite d States P har mac o peia ( U S P ) gra de N A C p o w der will 
be e nca ps ulate d i n 6 0 0 m g q ua ntities (t w o 6 0 0 m g ca ps ules per d ose).  Matc he d place b o ca ps ules will als o 
be  pre pare d.    Ra n d o mize d  partici pa nt  will  be  i nstr ucte d  t o  ta ke  1 2 0 0  m g  t wice  dail y,  i n  a p pr o xi matel y 
t wel ve- h o ur i nter vals.  T his d ose was c h ose n d ue t o its de m o nstrate d t olera bilit y a n d e vi de nce of effect o n 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 8 of 2 8  
 
s u bsta nce use i n o ur pri or trials.  Partici pa nts will be e x pecte d t o c o nti n ue ta ki n g st u d y me dicati o n u ntil 
t he y c o me i n f or t he Wee k 8 ( E n d- of- Treat me nt) Visit. 
4. 0  St u d y E n d p oi nts  
T he pri mar y efficac y e n d p oi nt is re d ucti o n i n alc o h ol use (t otal sta n dar d dri n ks), c o m pare d bet wee n 
N A C a n d place b o gr o u ps. A d diti o nal o utc o mes of i nterest i ncl u de a gree me nt bet wee n self-re p ort ( m o bile 
tec h n ol o g y- deli vere d  dail y  self-re p ort,  Ti meli ne  F oll o w- Bac k)  a n d  bi o mar kers  (et h yl  gl uc ur o ni de, 
car b o h y drate  deficie nt  tra nsferri n,  p h os p hati d ylet ha n ol,  alc o h ol  breat hal yzer)  of  alc o h ol  use,  as  well  as 
a gree me nt bet wee n meas ures of me dicati o n a d here nce ( m o bile tec h n ol o g y- deli vere d vi de o of me dicati o n 
ta ki n g, Me dicati o n E ve nt M o nit ori n g S yste m, pill c o u nt, self-re p ort). 
5. 0  I ncl usi o n a n d E xcl usi o n Criteri a/ St u d y P o p ul ati o n 
I ncl usi o n Criteri a 
Partici pa nts  m ust  be  a ge  1 3  t o 2 5 , m ust  be  a ble  t o 
u n dersta n d t he st u d y a n d pr o vi de writte n i nf or me d c o nse nt 
(f or t h ose u n der a ge 1 8, pare nt/le gal g uar dia n m ust be a ble 
t o pr o vi de c o nse nt a n d partici pa nt m ust be a ble t o pr o vi de 
asse nt),  m ust  be  a  c urre nt  m o derate  or hea v y  dri n ker  b y 
esta blis he d  a d olesce nt  criteria  (see  fi g ure ),4 9 m ust  meet 
criteria f or c urre nt A U D a n d e x press i nterest i n A U D treat me nt , a n d (i n di vi d uals assi g ne d fe male at birt h) 
m ust  a gree  t o  use  a p pr o priate  birt h  c o ntr ol  met h o ds  d uri n g  st u d y  partici pati o n:  oral  c o ntrace pti ves, 
c o ntrace pti ve patc h, barrier ( dia p hra g m or c o n d o m), le v o n or gestrel i m pla nt, me dr o x y pr o gester o ne acetate, 
c o m plete a bsti ne nce fr o m se x ual i nterc o urse, or h or m o nal c o ntrace pti ve va gi nal ri n g.  Partici pa nts m ust 
als o ha ve s uccessf ull y c o m plete d t he Y C I nta ke Pr ot oc ol ( P R O # 9 4 7 4 3) wit hi n  a p pr o xi matel y 3 0 da ys of 
f or mal st u d y scree ni n g. 
Excl usi o n Criteri a 
Partici pa nts m ust n ot sc ore > 1 0 o n t he Cli nical I nstit ute Wit h dra wal Assess me nt f or Alc o h ol, 5 0 as t his 
w o ul d warra nt m ore ac ute me dical i nter ve nti o n t ha n offere d i n t he trial.  Partici pa nts m ust n ot ha ve k n o w n 
aller g y  or  i nt olera nce  t o  N A C,  n o  c urre nt  use  of N -acet ylc ystei ne  or  a n y  s u p ple me nt  c o ntai ni n g N -
acet ylc ystei ne  ( m ust  a gree  n ot  t o  ta ke  a n y  s uc h  s u p ple me nt  t hr o u g h o ut  st u d y  partici pati o n),  i n di vi d uals 
w h o  are  pre g na nt,   lactati n g,  or  c o nte m plati n g  pre g na nc y/lactati n g  o ver  t he  ne xt  6  m o nt hs,  m ust  n ot  be 
c urre ntl y e nr olle d i n o n g oi n g treat me nt f or A U D, a n d a n y ot her me dical or ps yc hiatric c o n diti o n or ot her 
si g nifica nt c o ncer n t hat i n t he I n vesti gat or’s o pi ni o n w o ul d i m pact partici pa nt safet y or c o m plia nce wit h 
st u d y i nstr ucti o ns, or p ote ntiall y c o nf o u n d t he i nter pretati o n of fi n di n gs. 
C o- Occ urri n g Dis or ders 
C o nsiste nt wit h o ur esta blis he d i ncl usi o n/e xcl usi o n pr ot oc ols acr oss a d olesce nt s u bsta nce use dis or der 
treat me nt trials, we electe d n ot t o e xcl u de n o n-ac ute c o- occ urri n g me ntal or s u bsta nce use dis or ders, as 
t hese  are  s o  c o m m o n  a m o n g  a d olesce nts  wit h  A U D.5 1  I ncl usi o n  will  all o w  f or  m ore  p ote ntial 
ge neraliza bilit y of t he st u d y’s fi n di n gs, a n d o ur esta blis he d p olicies a n d pr oce d ures ha ve de m o nstrate d t he 
tea m’s  a bilit y  t o  safel y  ma na ge  a d olesce nt  partici pa nts  wit h  c o- occ urri n g  dis or ders.    We  will  m o nit or 
me ntal healt h a n d s u bsta nce use meas ures t hr o u g h o ut t he trial, a n d partici pa nts will meet wit h t he me dical 
cli nicia n  f or  safet y  assess me nts  at  all  visits.  We  will  a d diti o nall y  pr o vi de  c o nsiste nt  a vaila bilit y  a n d 
i n v ol ve me nt of t he M PIs a n d cli nicia n C o-Is (all wit h a d olesce nt me ntal healt h a n d s u bsta nce use e x pertise). 
A ge R a n ge  
T he partici pa nt a ge ra n ge f or t he pr o p ose d st u d y ( 1 3- 2 5 years ol d) has br oa d a gree me nt a n d s u p p ort, 
a n d was c h ose n f or m ulti ple reas o ns.  T he Mater nal C hil d Healt h B urea u defi nes a d olesce nce as a ge 1 1- 2 1, 
a n d t he Ce nter f or Disease C o ntr ol a n d Pre ve nti o n defi nes it as a ges 1 0- 2 4.  It is i ncreasi n gl y u n derst o o d 
t hat a d olesce nt brai n de vel o p me nt c o nti n ues t hr o u g h a ge 2 5.6 9 W hile s o me y o ut h i nitiate alc o h ol use bef ore 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 9 of 2 8  
 
a ge 1 3, fe w e x hi bit s ufficie nt s y m pt o ms of A U D t o merit st u d y i ncl usi o n, s o we c o ncl u de d t hat a ra n ge of 
1 3- 2 5 w o ul d be a p pr o priate.   
We rec o g nize t hat t he de vel o p me ntal c o nte xt varies c o nsi dera bl y e ve n wit hi n t he narr o we d ra n ge of 1 3-
2 5.  T o a d dress t his, we pla n t o stratif y ra n d o mizati o n b y sec o n dar y sc h o ol stat us, e ns uri n g t hat e q ui vale nt 
pr o p orti o ns  of  t h ose  i n  sec o n dar y  sc h o ol  (e. g.,  mi d dle  sc h o ol,  hi g h  sc h o ol)  a n d  t h ose  n ot  i n  sec o n dar y 
sc h o ol  (e. g.,  dr o p pe d  o ut,  gra d uate d,  w or ki n g,  atte n di n g  c olle ge)  are  re prese nte d  i n  t he  treat me nt 
ra n d o mizati o n gr o u ps.  We dee me d t he ps yc h os ocial de vel o p me ntal differe nces bet wee n t hese gr o u ps as 
m ore  mea ni n gf ul  t ha n  t h ose  bet wee n  ar bitrar y  a ges  wit hi n  t he  i ncl usi o n  ra n ge  t o  ser ve  as  a  p oi nt  of 
stratificati o n. Gi ve n o ur pri or s uccess, we a ntici pate recr uiti n g si milar pr o p orti o ns of y o ut h acr oss t hese 
strata, a n d we will a dj ust strate gies if t he pr o p orti o ns bec o me s ke we d.  T his stratifie d a p pr oac h will c o n ve y 
t he  a d de d  o p p ort u nit y  t o  c o m pare  o utc o mes  (i n  e x pl orat or y  fas hi o n)  bet wee n  t hese  de vel o p me ntal 
s u b gr o u ps. 
I ncl usi o n of W o me n a n d Mi n orities 
1.  T ar gete d/ pl a n ne d  distri b uti o n  of  p artici p a nts  b y  ge n der  a n d  r aci al/et h nic  gr o u ps. T he 
e nr oll me nt de m o gra p h y was ai me d t o matc h t he de m o gra p hic c o m p ositi o n of C harlest o n C o u nt y. 
Of t he t otal 1 2 0 partici pa nts t o be recr uite d a n d f oll o we d i n t his st u d y, 5 0 % are fe male; 1 0 % are 
Lati n o/a et h nicit y.  
2.  S u bject  selecti o n  criteri a  a n d  r ati o n ale  f or  selecti o n  of  se x/ ge n der  a n d  r aci al/et h nic  gr o u p 
me m bers . A d olesce nts will be recr uite d base d o n pre vi o usl y s uccessf ul tec h ni q ues use d f or se veral 
lar ge-scale  a d olesce nt  s u bsta nce  use  dis or der  cli nical  trials  c o n d ucte d  b y  t he  researc h  tea m, 
i ncl u di n g  a  mi x  of  c o m m u nit y  a n d  m ulti me dia  a d vertisi n g as  well  as  cli nical  recr uit me nt.  T he 
ge n der, et h nic, a n d racial c o m p ositi o n of t he sa m ple will be base d o n t he de m o gra p h y of C harlest o n 
C o u nt y. Racial c o m p ositi o n is: 6 7 % W hite, 2 9 % Africa n A merica n, 2 % m ultiracial, 1 % Asia n, < 1 % 
A merica n I n dia n/ Alas ka n Nati ve, a n d < 1 % Nati ve Ha waiia n or Ot her Pacific Isla n der.  
3.  N o ge n der or r aci al/et h nic gr o u p will be e xcl u de d.  
4.  O utre ac h  pr o gr a ms  f or  recr uiti n g  se x/ ge n der  a n d  r aci al/et h nic  gr o u p  me m bers :  T o  recr uit 
re prese ntati ve  n u m bers  i n  eac h  de m o gra p hic  cate g or y,  we  ca n  f oc us  recr uit me nt  eff orts  at 
c o m m u nities t hat ha ve hi g her pr o p orti o ns of a n y u n derre prese nte d de m o gra p hic gr o u p.  
I ncl usi o n of C hil dre n 
1.  R ati o n ale f or t he s pecific a ge r a n ges of c hil dre n t o be i ncl u de d. All partici pa nts i n t his st u d y will 
ra n ge i n a ge fr o m 1 3 t o 2 5 a n d will t heref ore i ncl u de a s u bsta ntial p orti o n of c hil dre n ( NI H defi niti o n 
of < 1 8 years ol d).  E val uati o n of alter nati ve a n d m ore efficaci o us treat me nts f or a d olesce nt s u bsta nce 
users is warra nte d. N-acet ylc ystei ne ( N A C) is a n o ver-t he-c o u nter s u p ple me nt wit h a str o n g safet y 
a n d t olera bilit y pr ofile f or s u bsta nce- usi n g a d olesce nts. T his st u d y is a ste p i n deter mi ni n g if N A C 
c o ul d be a p ote ntial treat me nt o pti o n f or a d olesce nts wit h alc o h ol use dis or der.  
2.  E x pertise of st u d y te a m f or c o n d ucti n g rese arc h wit h c hil dre n.  PI Dr. Ke vi n Gra y is a b oar d-
certifie d  ps yc hiatrist  a n d  nati o nall y  rec o g nize d  e x pert  i n  t he  area  of  a d olesce nt  s u bsta nce  use 
dis or ders a n d treat me nt. Dr . Gra y will be res p o nsi ble f or res p o n di n g t o a n y me ntal healt h or me dical 
referrals t hat ma y arise. 
3.  F acilities  a v ail a ble  t o  acc o m m o d ate  c hil dre n. T he  i n vesti gati ve  tea m  has  a  str o n g  rec or d  of 
a d olesce nt s u bsta nce use researc h usi n g t he descri be d tec h ni q ues, i ncl u di n g cli nical trials usi n g N-
acet ylc ystei ne. St u dies are perf or me d i n a n e n vir o n me nt t hat is a p pr o priate a n d safe f or y o ut h. T he 
office s uite is a l oc ke d facilit y wit h 2 4- h o ur sec urit y m o nit ori n g. Pri vate testi n g areas, i ncl u di n g a 
p h ysical e xa m r o o m, are a vaila ble f or st u d y use. T here is a se parate waiti n g area t o acc o m m o date 
fa milies. 
4.  S ufficie nt n u m ber of c hil dre n t o c o ntri b ute t o a me a ni n gf ul a n al ysis. 1 2 0 partici pa nts will be 
e nr olle d  i n  t his  8- wee k,  i nte nt- t o-treat,  d o u ble- bli n d,  ra n d o mize d  place b o-c o ntr olle d  pr o of- of-


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 1 0 of 2 8  
 
c o nce pt  trial  of  N-acet ylc ystei ne.  T his  sa m ple  size  is  s ufficie nt  t o  ac hie ve  t he  statistical  p o wer 
necessar y t o t he meet t he st u d y ai ms.  
6. 0  N u m ber of S u bjects  
We pla n f or 1 2 0 t otal ra n d o mize d partici pa nts i n t he st u d y (e xcl u di n g scree n fail ures a n d i n di vi d uals 
dr o p pi n g o ut pri or t o ra n d o mizati o n). 
7. 0  Setti n g  
T he st u d y will be c o n d ucte d i n o ur o ut patie nt researc h cli nic at M U S C or re m ote/ h y bri d via d o x y. me, 
We b E x, or Z o o m. 
8. 0  Recr uit me nt Met h o ds  
Recr uit me nt Str ate gies 
All partici pa nts will be recr uite d fr o m a p o ol of partici pa nts w h o ha ve c o m plete d a n o n g oi n g E ntr y wa y 
I nta ke  st u d y  ( P R O  # 9 4 7 4 3).  Partici pa nts  w h o  ha ve  c o m plete d  t his  pr ot oc ol  a n d  w h o  a p pear  t o  meet 
eli gi bilit y criteria will be offere d partici pati o n i n t his pr ot oc ol. I n di vi d uals w h o partici pate i n t he E ntr y wa y 
I nta ke  c o nse nt  f or  t heir  data  t o  be  carrie d  f or war d  i nt o  t he  st u d y  i n  w hic h  t he y  ulti matel y  e nr oll.  T he 
E ntr y wa y I nta ke i ncl u des, b ut is n ot li mite d t o, a c o m pre he nsi ve s u bsta nce use hist or y assess me nt a n d a 
str uct ure d  dia g n ostic  i nter vie w  f or  ps yc hiatric  c o n diti o ns,  i ncl u di n g  assess me nt  of  A U D  a n d  ot her 
s u bsta nce  use  dis or ders,  as  well  as  bi oassa y  c ollecti o n.  After  c o m pleti o n  of  t he  E ntr y wa y  I nta ke, 
partici pa nts w h o are eli gi ble f or t he c urre nt st u d y will be offere d partici pati o n. T he y will c o nse nt t o s hari n g 
data c ollecte d acr oss b ot h pr ot oc ols f or a nal ysis. E xa m ples of s hare d data i ncl u de, b ut are n ot li mite d t o 
vitals,  st u d y  e nr oll me nt  a n d  st u d y  c o m pleti o n  stat us.  Si nce  la u nc hi n g  t he  s hare d  E ntr y wa y  I nta ke  i n 
Se pte m ber 2 0 2 0, we ha ve a vera ge d 3 3 referrals per m o nt h of y o ut h (a ges 1 6- 2 2) i ntereste d i n partici pati n g 
i n alc o h ol st u dies. O ur tea m is hi g hl y e x perie nce d i n recr uiti n g a n d retai ni n g at-ris k a n d s u bsta nce- usi n g 
y o ut h. A d olesce nts ( N = 1 2 0) will be recr uite d fr o m t he c o m m u nit y, sc h o ols, a n d cli nical setti n gs. T h o u g h 
t his p o p ulati o n is n ot ori o usl y diffic ult t o e n ga ge, o ur cli nical trials ( 5 c o m plete d p har mac ot hera p y trials t o 
date tar geti n g a d olesce nt s u bsta nce use dis or ders, wit h c ollecti ve N = 4 6 0) ha ve c o nsiste ntl y e nr olle d a n d 
retai ne d partici pa nts well a hea d of g oal rates ( ge nerall y ≥4 a d olesce nts per m o nt h). We ha ve a n a g gressi ve 
pla n  f or  recr uit me nt  a n d  are  c o nfi de nt  t hat  o ur  pre vi o usl y  esta blis he d  strate gies  will  e ns ure  s uccess. 
Ass u mi n g  a n  i nitial 3- m o nt h  peri o d  f or  st u d y  set u p,  per -partici pa nt  st u d y  d urati o n  of  6  m o nt hs,  a n d  a 
c o ncl u di n g 3- m o nt h  peri o d  f or  data  a nal ysis  a n d  p u blicati o n,  we  a ntici pate  a  recr uit me nt  wi n d o w  of 4 8  
m o nt hs. T o meet t he recr uit me nt g oal, we m ust e nr oll 6 partici pa nts per m o nt h, w hic h is feasi ble, realistic, 
a n d  c o nsiste nt  wit h  o ur  past  eff orts.  St u d y  staff  ma y  als o  use  t he  f oll o wi n g  met h o ds  of  a d vertisi n g  t o 
pr o m ote recr uit me nt: l ocal p u blicati o ns, p h ysicia n offices/l ocal cli nics, M U S C ca m p us, l ocal c olle ge a n d 
hi g h sc h o ol ca m p uses as per missi o ns are gra nte d b y t he aca de mic i nstit uti o n, i nter net, s ocial me dia, T V 
c o m mercials, a n d ot her l ocati o ns (e. g., resta ura nts, m o vie t heaters, malls, b uses/tra ns p ortati o n ser vices) i n 
t he c o m m u nit y t hat a gree t o p ost Bra n d a n d I R B a p pr o ve d recr uit me nt materials f or t his st u d y a n d t hat ma y 
reac h o ur tar get p o p ulati o n. 
 
O ur c o nfi de nce i n s uccessf ul recr uit me nt ste ms fr o m a c o m ple me nt of strate gies de vel o pe d o ver t he past 
1 5 years of e x perie nce wit h ra n d o mize d c o ntr olle d trials of p har mac ot hera pies a n d be ha vi oral treat me nts f or 
a d olesce nts wit h s u bsta nce use dis or ders. We ha ve ha d c o nsiste nt s uccess via m ulti me dia a n d i nter net /s ocial 
me dia  a d vertise me nts,  referrals  fr o m  cli nics,  a n d  res p o n de nt -dri ve n  sa m pl i n g/ partici pa nt  peer  referral.  
Acr oss  lar ge -scale  st u dies  of  a d olesce nts  wit h  t o bacc o  (R 0 1 D A 1 7 4 6 0,  U 0 1 D A 0 3 1 7 7 9 ),  ca n na bis 
(R 0 1 D A 0 2 6 7 7 7, R 0 1 D A 0 4 2 1 1 4 ), a n d alc o h ol (K 2 3 A A 0 2 5 3 9 9 ) use dis or ders, we ha ve c o nsiste ntl y met or 
e xceede d t he g oal e nr oll me nt rate pla n ne d f or t he pr o p ose d trial.   F or t he pr o p ose d st u d y, we pla n t o c o nti n ue 
o ur  esta blis he d  c o m bi ne d  a p pr oac h,  w hic h  we  ar e  c o nfi de nt  will  be  s uccessf ul.   A d diti o nall y,  a  Y o ut h 
C olla b orati ve of a d olesce nt s u bsta nce use st u dies wit hi n t he Di visi o n has bee n de vel o pe d t hat will n ot o nl y 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 1 1 of 2 8  
 
all o w f or t he c ost s hari n g nee ds of a d vertisi n g a n d st u d y pr o m oti o n b ut als o ma ke t he pr ocess of i de ntif yi n g 
o p p ort u nities  at  M U S C  easier  f or  partici pa nts,  pare nts/fa mil y,  a n d  c o m m u nit y  part ners.    B y  mar keti n g  a 
ce ntral p oi nt of c o ntact f or i ntereste d parties t o see k a d diti o nal i nf or mati o n, callers ca n be tria ge d t o t he 
a p pr o priate  st u d y  or  directe d  t o  cli nical  ser vices  base d  o n  t heir  e x presse d  i nterest  le vel  a n d/ or  prescree n 
o utc o mes .  T his is partic ularl y a p pr o priate f or i nc or p orati o n si nce t here is a hi g h li keli h o o d of p ol ys u bsta nce 
use.  B y strea mli ni n g t he referral pr ocess, it lesse ns t he b ur de n o n t he caller t o d u plicate t heir eff orts a n d 
p ote ntiall y bec o me fati g ue d a n d disill usi o ne d wit h t he pr ocess a n d ulti matel y n ot recei ve t he ser vice deli ver y 
t hat t he y desire. 
9. 0  C o nse nt Pr ocess  
Pre - Scree ni n g Assess me nt 
I n di vi d uals res p o n di n g t o recr uit me nt materials or ot her wise referre d t o t he st u d y will be pre-scree ne d 
o n t he p h o ne or i n pers o n t o ascertai n preli mi nar y eli gi bilit y stat us.  A series of q uesti o ns will deter mi ne 
preli mi nar y  eli gi bilit y,  a n d  f or mal  scree ni n g  a p p oi nt me nts  will  be  sc he d ule d  f or  t h ose  w h o  meet  t hese 
eli gi bilit y criteria.  N o i nf or mati o n o btai ne d d uri n g t he pre-scree ni n g will be use d as researc h data. 
I nf or me d C o nse nt Pr oce d ures 
Pri or t o t he i nitiati o n of a n y st u d y pr oce d ures, writte n i nf or me d c o nse nt a n d HI P A A a ut h orizati o n will 
be o btai ne d b y t he desi g nate d researc h staff. I nf or me d c o nse nt/asse nt ma y be o btai ne d eit her i n pers o n i n 
t he  researc h  office,  or  re m otel y  via  R E D Ca p  a n d  d o x y. me,  We b E x,  or  Z o o m.  Pare nts/ g uar dia ns  of 
partici pa nts  u n der  1 8  years  ol d  will  partici pate  wit h  t he  a d olesce nt  i n  t he  scree ni n g,  e val uati o n,  a n d 
i nf or me d  c o nse nt/asse nt  pr oce d ure.    Partici pa nts  1 8  years  a n d  ol der  will  be  a ble  t o  pr o vi de  t heir  o w n 
i nf or me d  c o nse nt.    T he  i nf or me d  c o nse nt  pr ocess  will  i ncl u de  a  t h or o u g h  disc ussi o n  of  p ote ntial  ris ks 
ass ociate d wit h partici pati o n, i ncl u di n g p ote ntial a d verse effects of st u d y me dicati o n. T he c o m ple x iss ues 
of i nf or me d c o nse nt a n d asse nt, a n d relate d li mitati o ns of c o nfi de ntialit y, as t he y a p pl y t o a d olesce nts a n d 
t heir pare nts/ g uar dia ns, are u n derst o o d b y t he i n vesti gati ve tea m a n d will be c o m m u nicate d clearl y d uri n g 
t he tele p h o ne scree ni n g a n d assess me nt visit.  I n t he case of a d olesce nts i n S o ut h Car oli na De part me nt of 
S ocial  Ser vices  c ust o d y,  state  g ui deli nes  re gar di n g  c o nse nt  f or  cli nical  researc h  partici pati o n  will  be 
f oll o we d. 
P ote ntial partici pa nts (a n d pare nts/ g uar dia ns, as a p pr o priate) will be gi ve n a c o p y of t he I R B-a p pr o ve d 
c o nse nt f or m a n d as ke d t o rea d it eit her o n site or at h o me i n acc or da nce wit h t he c o nse nt pr ocess.  T h ose 
w h o de m o nstrate u n dersta n di n g of t he st u d y a n d v ol u ntaril y a gree t o partici pate will be as ke d t o si g n t he 
i nf or me d c o nse nt f or m a n d pr ocee d wit h t he scree ni n g assess me nts. 
1 0. 0  St u d y Desi g n  / Met h o ds 
Overvie w  
T he pr o p ose d  st u d y is a P hase II, 8-w e e k, d o u ble -bli n d,  ra n d o mize d, pl a c e b o - c o ntr olle d, pr o of-of -
c o n c e pt trial  of N A C  f or A U D i n a d olesce nts (N = 1 2 0) . O utc o me  meas ures  will   all o w  assess me nt of 
N A C  effects  o n  alc o h ol 
use,  w hile t he  st u d y  will  a d diti o nall y e val uate  t he  feasi bilit y  a n d  utilit y  of 
i m ple me nti n g de vel o p me ntall y-i nf or me d met h o ds f or a d olesce nt A U D p har mac ot hera p y trials. 
 
 
 
Scree ni n g/ B aseli ne Assess me nt  
After  c o nse nti n g  t o  partici pate  i n  t he  st u d y,  partici pa nts  will  start  t he  scree ni n g/ baseli ne  assess me nt 
p hase.   I deall y, t he scree ni n g/ baseli ne assess me nt pr oce d ures will be c o m plete d i n o ne i n- pers o n or re m ote 
M o bile tec h n ol o g y d eli v ere d d ail y e n ga ge me nt, d ata c ollecti o n, a n d me dicati o n a d h ere n ce 
m o nit ori n g  
C o nse nt & 
Eli gi bilit y 
Assess m e nt 
W ee ks 1- 8  
N A C 1 2 0 0 m g or pl ac e b o t wi ce dail y 
Wee kl y brief alc o h ol i nter v e nti o n a n d m e dicati o n m a n a g e m e nt  
W k. 1 2 
St art m e di cati o n 
E n d of tr eat m e nt 
 
P ost -tre at m e nt 
Ra n d o miz ati o n 
N A C  
n = 6 0  
Pla c e b o   
n = 6 0  
W k. 2 6 


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Pa ge 1 2 of 2 8  
 
visit, b ut t he y ca n be c o m plete d i n m ore visits if necessar y.  Partici pa nts will pr o vi de ge neral de m o gra p hic 
i nf or mati o n  a n d  c o m plete  a  l ocat or  f or m  t o  o pti mize  bet wee n- visit  c o ntact  a n d  c o m m u nicati o n.    T he 
c o m pre he nsi ve  assess me nt  will  i ncl u de  a  me dical  hist or y  a n d  p h ysical  e xa mi nati o n,  uri ne  dr u g  testi n g, 
se mi-str uct ure d ps yc hiatric dia g n ostic i nter vie w, a n d detaile d assess me nt of alc o h ol a n d ot her s u bsta nce 
use  hist or y.   S h o ul d  a  partici pa nt  ha ve  scree n  faile d  f or  pr ot oc ol  # 5 4 4 9 9,  N- Acet ylc ystei ne  f or  Y o ut h 
Ca n na bis  Use  Dis or der,  t he  data/i nf or mati o n  t hat was c o m plete d  as  part  of  t hat  pr ot oc ol  c o ul d  be 
i nc or p orate d i nt o t his pr ot oc ol if t he partici pa nt prese nte d as a li kel y eli gi ble ca n di date.  T he partici pa nt 
w o ul d nee d t o c o nfir m i nterest a n d c o nse nt t o s uc h partici pati o n a n d data s hari n g.   Data/i nf or mati o n fr o m 
P R O # 9 4 7 4 3 is als o tra nsfera ble as it ser ves as t he p oi nt of i nta ke i nt o t he Y o ut h C olla b orati ve, of w hic h 
t his pr ot oc ol is a me m ber st u d y.  T he scree ni n g pr oce d ures of t hese pr ot oc ols cl osel y mirr or eac h ot her, a n d 
t his data s hari n g w o ul d re m o ve t he nee d f or d u plicati o n of pr oce d ures as well as u n d ue b ur de n a n d testi n g 
fati g ue.    
R a n d o miz ati o n  
F oll o wi n g  c o m pleti o n  of  scree ni n g/ baseli ne  assess me nts  a n d  deter mi nati o n  of  st u d y  eli gi bilit y, 
partici pa nts w h o ret ur n f or t he ra n d o mizati o n visit a n d c o nti n ue t o be eli gi ble will be ra n d o ml y assi g ne d t o 
o ne of t he t w o c o n diti o ns ( N A C or place b o) f or 8 wee ks of treat me nt.  Ra n d o m assi g n me nt will be o n a 1: 1 
rati o t o o ne of t he t w o c o n diti o ns.  Ra n d o mizati o n will be stratifie d b y sc h o ol stat us [i n sec o n dar y sc h o ol 
(i.e.,  mi d dle  or  hi g h  sc h o ol)  vers us  n ot]  a n d  b y  se x  (fe male  vers us  male).    A d olesce nts  n o  l o n ger  i n 
sec o n dar y  sc h o ol  (i.e.,  dr o p pe d  o ut,  gra d uate d,  w or ki n g,  a n d/ or  e nr olle d  i n  c olle ge)  ma y  ha ve  differe nt 
ps yc h os ocial c o nte xts a n d c o nti n ge ncies relate d t o alc o h ol use, c o m pare d t o t h ose still i n sec o n dar y sc h o ol. 
T he se x stratificati o n will hel p a v oi d si g nifica ntl y discre pa nt re prese ntati o n of se x acr oss treat me nt gr o u ps, 
all o wi n g  f or  e x pl orati o n  of  p ote ntial  se x  differe nces  i n  st u d y  o utc o mes.    We  c o nsi dere d  a d diti o nal 
stratificati o n  varia bles  (e. g.,  se verit y  of A U D , c o- occ urri n g  ot her  s u bsta nce  use  dis or ders,  hist or y  of 
atte nti o n- deficit/ h y peracti vit y dis or der), b ut, a mi d c o ncer n o ver e xcessi ve di visi o n of partici pa nts a m o n g 
m ulti ple cells, j u d ge d t hat t hese c o ul d be a de q uatel y e x pl ore d as c o variates d uri n g efficac y a nal yses.  
Mr. Ba ker, t he st u d y statisticia n, will ge nerate t he ra n d o mizati o n sc he d ule usi n g a stratifie d per m ute d 
ra n d o m  bl oc k  desi g n wit h   bl oc k  sizes  of  2,  4  a n d  6  t o  e ns ure  lac k  of  pre dicta bilit y  al o n g  wit h  relati ve 
e q ualit y of assi g n me nt acr oss treat me nt gr o u ps.  All st u d y staff, t he i n vesti gati ve tea m, a n d partici pa nts will 
re mai n  bli n d  t o  st u d y  assi g n me nts  u ntil  t he  c o m pleti o n  of  t he  st u d y,  u nless  a n  u n bli n di n g  is  dee me d 
me dical l y necessar y.  Mr. Ba ker will re vie w ra n d o mizati o n data o n a re g ular basis t o e ns ure t hat t he sc he me 
is bei n g i m ple me nte d acc or di n g t o pla n.  A ra n d o mizati o n sl ot, o nce use d, will n ot be re-all ocate d. 
Tre at me nt 
Psyc h os oci al I nterve nti o n 
All  partici pa nts  will  recei ve 8 wee kl y brief alc o h ol i nter ve nti o n sessi o ns fr o m NI A A A’s brief alc o h ol 
i nter ve nti o n,5 2  w hic h  i ncl u des  m oti vati o nal  i nter vie wi n g  a n d  setti n g  i n di vi d ual  g oals  a n d  acti o n  pla ns, 
c o nsiste nt wit h t he c urre nt sta n dar d- of-care treat me nt. 
P h ar m ac ol o gic al I nterve nti o n 
C o nsiste nt wit h o ur esta blis he d pr oce d ures, U nite d States P har mac o peia ( U S P ) gra de N A C p o w der will 
be e nca ps ulate d i n 6 0 0 m g q ua ntities (t w o 6 0 0 m g ca ps ules per d ose).  Matc he d place b o ca ps ules will als o 
be pre pare d.  If assess me nt pr oce d ures re veal t hat a partici pa nt meets i ncl usi o n criteria a n d n o ne of t he 
e xcl usi o n  criteria,  t he  partici pa nt  will  be  ra n d o mize d  t o  d o u ble- bli n d  N A C  or  matc he d  place b o.    T he 
partici pa nt  will  be  gi ve n a s u p pl y  of  me dicati o n,  wit h  i nstr ucti o n  t o  ta ke  1 2 0 0  m g  t wice  dail y,  i n 
a p pr o xi matel y t wel ve- h o ur i nter vals. Re m ote partici pa nts will recei ve me dicati o n s u p pl y i n t he mail.   T his 
d ose was c h ose n d ue t o its de m o nstrate d t olera bilit y a n d e vi de nce of effect o n s u bsta nce use i n o ur pri or 
trials.  S u bse q ue nt me dicati o n s u p pl y will be gi ve n o ut or maile d a wee k i n a d va nce t o decrease t he ris k of 
t he  partici pa nt  r u n ni n g  o ut  of  st u d y  me dicati o n.    Partici pa nts  will  be  e x pecte d  t o  c o nti n ue  ta ki n g  st u d y 
me dicati o n u ntil t he y t heir Wee k 8 ( E n d- of- Treat me nt) Visit. 


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Pa ge 1 3 of 2 8  
 
M ulti ple met h o ds f or me dicati o n a d here nce assess me nt ma y be i m ple me nte d, i ncl u di n g partici pa nt 
self-re p ort via m o bile dail y diaries, wee kl y pill c o u nts, re m ote a d here nce m o nit ori n g s yste m (e. g. 
Pills y ®), a n d m o bile tec h n ol o g y- deli vere d vi de o ca pt ure of me dicati o n ta ki n g (see Preli mi nar y 
St u dies). 4 0 Pills y ca ps fit sec urel y o n me dicati o n b ottles a n d pr o vi de a ti me-sta m p eac h ti me t he b ottle is 
o pe ne d.  T he Pills y ca p als o dis pla ys t he n u m ber of ti mes t he b ottle has bee n o pe ne d wit hi n a 2 4- h o ur 
peri o d t o assist partici pa nts i n re me m beri n g t o ta ke b ot h dail y d oses. Partici pa nts will be re mi n de d t o ta ke 
me dicati o n a n d u pl oa d me dicati o n-ta ki n g vi de os via t wice- dail y m o bile tec h n ol o g y- deli vere d te xt 
messa ges, ge nerate d usi n g t he R E D Ca p s yste m a n d ti me d base d o n t he partici pa nt’s t y pical dail y 
sc he d ule. 4 0 If partici pa nts d o n ot ha ve a c o m pati ble m o bile p h o ne, o ne will be pr o vi de d f or use i n 
c o m pleti n g m o bile tec h n ol o g y-facilitate d pr oce d ures. 
Me dicati o n t olera bilit y a n d effects will be s yste maticall y assesse d.  Partici pa nts will be e nc o ura ge d t o 
c o ntact st u d y pers o n nel bet wee n visits t o a d dress a n y i m me diate c o ncer ns re gar di n g a d verse effects.  If a 
partici pa nt e x perie nces i nt olera ble me dicati o n-relate d a d verse effects at a n y p oi nt d uri n g t he st u d y, a d ose 
re d ucti o n t o 6 0 0 m g t wice dail y ma y be u n derta ke n.  T he d osa ge ma y be i ncrease d bac k t o 1 2 0 0 m g t wice 
dail y at t he discreti o n of t he me dical cli nicia n.  H o we ver, if a partici pa nt is u na ble t o t olerate t he re d uce d 
d ose, me dicati o n will be disc o nti n ue d, a n d t he partici pa nt will c o nti n ue t o c o me i n f or st u d y visits. 
 
 
P ost- Tre at me nt F oll o w- U p  
P ost-treat me nt f oll o w- u p visits will be c o n d ucte d at a p pr o xi matel y 1 2 wee ks a n d 2 6 wee ks fr o m i nitial 
ra n d o mizati o n. 
Rete nti o n Str ate gies  
Rete nti o n,  li ke  recr uit me nt,  is  a  c o nsi dera ble  c halle n ge i n  cli nical  trials  f or a d olesce nt  s u bsta nce  use 
dis or ders. Gi ve n i nte nt -t o-treat a nal ysis (i ncl u di n g all ra n d o mize d partici pa nts a n d ass u mi n g t hat partici pa nts 
are usi n g alc o h ol at eac h misse d visit), p o or rete nti o n ma y res ult i n a n u n deresti mate of treat me nt effects  a n d 
t he nee d t o i m p ute missi n g data. It als o li mits partici pa nt e x p os ure t o treat me nt, w hic h f urt her atte n uates 
treat me nt effects.  
O ur  tea m  has  bee n  s uccessf ul  wit h  o pti mizi n g  partici pa nt  rete nti o n  via  a  n u m ber  of  well -esta blis he d 
strate gies. O ur researc h cli nic is ce ntrall y l ocate d a n d o pe n f or e xte n de d (i ncl u di n g after-sc h o ol) h o urs, wit h 
free  par ki n g  i m me diatel y  i n  fr o nt  of  t he  b uil di n g. All  of  o ur  visits  ca n  als o be  c o m plete d  re m otel y  via 
d o x y. me, We b E x, or Z o o m. We mai ntai n acti ve c o m m u nicati o n wit h partici pa nts bet wee n visits via t heir 
preferre d m o de of c o ntact (e. g., te xt messa ge, tele p h o ne, e -mail). We als o strictl y mai ntai n c o nfi de ntialit y, 
a  partic ularl y  si g nifica nt  iss ue  i n  st u dies  f oc use d  o n  i nter ve nti o ns  f or  alc o h ol  a n d  ot her  s u bsta nce  use  i n 
y o ut h. Dr. Gra y  (PI), a b oar d-certifie d c hil d, a d olesce nt, a n d ge neral ps yc hiatrist, is  well verse d i n ma na gi n g 
c o m m u nicati o n  wit h  a d olesce nts  a n d  pare nts/ g uar dia ns  w hile  mai ntai ni n g  a p pr o priate  b o u n ds  of 
c o nfi de ntialit y a n d ma na gi n g iss ues of safet y; t he res ulta nt tr ust a n d ra p p ort s u p p orts partici pa nt a d here nce 
a n d  rete nti o n.  A d diti o nall y,  we  stri ve  t o  rei nf orce  partici pa nts  a p pr o priatel y  f or  atte n di n g  visits  a n d 
c o m pleti n g  st u d y  pr oce d ures. H i g her  ma g nit u de rei nf orce me nt  is  ass ociate d  wit h  si g nifica ntl y  i m pr o ve d 
rete nti o n,4 4 -4 6 a n d cas h re war ds (relati ve t o gift car ds or ot her t o ke ns) are ass ociate d wit h i m pr o ve d sessi o n 
atte n da nce. 4 7 A d ult  a n d a d olesce nt st u dies  re veal  t hat  hi g h-ma g nit u de  re war ds  are  ge nerall y  n ot  use d  t o 
p urc hase  s u bsta nces  of  a b use .4 7, 4 8 I n  t he  pr o p ose d  trial,  partici pa nts  will  be  c o m pe nsate d  $ 2 0  f or  eac h 
sta n dar d visit a n d $ 4 0 f or visits t hat i n v ol ve c o g niti ve testi n g. Partici pa nts will als o be eli gi ble f or as m uc h 
as $ 2 0 per wee k d uri n g t he 8 wee ks of acti ve treat me nt f or c o m pleti o n of re m ote data e ntr y via s mart p h o ne, 
i ncl u di n g  vi de o  u pl oa ds  c o nfir mi n g  t wice- dail y  me dicati o n  a d here nce.   A  b o n us  of  $ 6 0  is  a vaila ble  f or 
c o m pleti n g  t he  Wee k  8  e n d- of-treat me nt  visit  a n d  c o m pleti n g  st u d y  re q uire me nts  of  p h o ne  use.  If  t he 
partici pa nt  is  e nr olle d  directl y  fr o m  t he  Y o ut h  C olla b orati ve  I nta ke  ( P R O  9 4 7 4 3)  wit h  data  fr o m  t hat 
pr ot oc ol bei n g utilize d f or t he c urre nt ai ms, t his st u d y ma y be res p o nsi ble f or t he $ 4 0 I nta ke Scree ni n g 


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Pa ge 1 4 of 2 8  
 
c o m pe nsati o n. Partici pa nts will be eli gi ble f or a ma xi m u m of $ 6 0 0 f or u ni nterr u pte d c o m pleti o n of all st u d y 
visits a n d pr oce d ures. 
Re m ote Visits – T he i nf or me d c o nse nt/asse nt pr oce d ure ca n be c o n d ucte d re m otel y via R E D Ca p a n d 
Z o o m. Partici pa nts will c o m plete direct-e ntr y R E D Ca p s ur ve ys re m otel y. T he st u d y me dical cli nicia n 
will ha ve t he o pti o n t o c o n d uct assess me nts a n d cessati o n c o u nseli n g re m otel y via Z o o m or p h o ne. All 
visits ta ki n g place ca n be c o n d ucte d e ntirel y re m otel y via R E D Ca p, Z o o m, or p h o ne. Partici pa nts ma y  
recei ve st u d y me dicati o n b y mail. T he partici pa nt will als o be pr o vi de d s u p plies re q uire d t o c o m plete a n 
offsite/at h o me uri ne c ollecti o n a n d C LI A wai ve d q ualitati ve Et G test, U D S, a n d pre g na nc y test f or 
partici pa nts assi g ne d fe male at birt h, t he res ults of w hic h will be verifie d usi n g vi de o a n d p h ot o ca pt ure. 
T he alc o h ol breat hal yzer test a n d t he bl o o d dra w will n ot occ ur d uri n g re m ote visits. 
I n a d diti o n, a h y bri d m o del ca n be utilize d if a n i n- pers o n partici pa nt has a n u ne x pecte d c o nflict wit h 
atte n di n g a n i n- pers o n visit (e. g., tra ns p ortati o n iss ue or tra vel), arra n ge me nts ma y be ma de t o re m otel y 
c o m plete visit pr oce d ures, i n or der t o mai ntai n data c ollecti o n a n d st u d y e n ga ge me nt.   I n ver y rare i nsta nces, 
st u d y me dicati o n ma y be s hi p pe d t o a partici pa nt w he n e xte n de d or i n defi nite rel ocati o n fr o m t he st u d y 
ce nter  w o ul d  pre ve nt  re g ularl y  pla n ne d  me dicati o n  ma na ge me nt  ( dis pe nsi n g/acc o u nta bilit y  a n d 
c o m plia nce) at a n i n-cli nic visit.  F or re m ote or h y bri d partici pa nts me dicati o ns will be s hi p pe d i n pr o per 
pac ki n g  wit h  trac ki n g  t o  pr otect  me dicati o n  as  well  as  partici pa nt  pri vac y.  Pri or  t o  t he  maili n g  of  a n y 
materials,  o n g oi n g  partici pa nt  i nterest  i n  c o nti n ue d  st u d y  partici pati o n  will  be  c o nfir me d,  d osi n g 
i nstr ucti o ns  a n d  safet y  nee ds  will  be  re vie we d,  a n d  de pe n di n g  o n  t he  a bilit y  t o  p h ysicall y  ret ur n  st u d y 
me dicati o n/ blister pac ks, a p pr o priate destr ucti o n meas ures will be pr o vi de d.  If s uc h re m ote meas ures are 
e m pl o ye d, partici pa nts will be directe d t o ha ve m ore e xte n de d vis ualizati o n of t heir me dicati o n blister pac ks 
i n t heir vi de o rec or di n g of st u d y me dicati o n d osi n g t o all o w st u d y pers o n nel t o pr o perl y m o nit or me dicati o n 
acc o u nta bilit y. 
I n  o ur  pri or  N A C  trial  f or  C U D,  wit h  t he  a b o ve-me nti o ne d  strate gies  i n  place,  a m o n g  partici pa nts 
prese nti n g  f or  a n y  visits  after  me dicati o n  i nitiati o n,  8 4 %  c o m plete d  t he  e ntire  c o urse  of  treat me nt.  We 
mai ntai n si milar s uccess i n o ur o n g oi n g st u dies f oc use d o n a d olesce nt t o bacc o ( U 0 1 D A 0 3 1 7 7 9), ca n na bis 
( R 0 1 D A 0 4 2 1 1 4), a n d alc o h ol (K 2 3 A A 0 2 5 3 9 9 ) use dis or ders. 
 
I nstr u me nts/ Me as ures/ M ateri als (see St u d y Ti met a ble  f or a n o verall s u m mar y) 
Cli nic al Assess me nts 
T he i nstr u me nts t o  be  use d were  selecte d beca use   ma n y are sta n dar dize d, ha ve   g o o d ps yc h o metric  
pr o perties,   are wi del y   use d,  a n d ha ve   bee n  use d  b y  o ur  researc h tea m.  
Ti meli ne F oll o w- Bac k, i ncl usi ve of detaile d q ua ntificati o n of alc o h ol use, meas ure d i n sta n dar d dri n ks, 
will be c o n d ucte d at baseli ne t o c haracterize self-re p orte d alc o h ol a n d ot her s u bsta nce use. 5 3 T his a p pr oac h 
will  be  e n ha nce d  d uri n g  trial  partici pati o n  b y  t he  i m ple me ntati o n  of  m o bile  tec h n ol o g y- deli vere d  dail y 
alc o h ol a n d ot her s u bsta nce use re p orts, usi n g met h o ds esta blis he d b y o ur researc h tea m (see Preli mi nar y 
St u dies). 4 0  At  baseli ne  assess me nt  a n d  d uri n g  eac h  dail y  s ur ve y,  partici pa nts  are  s h o w n  vis uals  a n d 
pr o vi de d  t he  defi niti o n  of  a  sta n dar d  dri n k  t o  ai d  i n  re p orti n g.  T he  s ur ve y  e x pires  at  mi d ni g ht  s o  t hat 
partici pa nts ca nn ot  access  a n  ol d  s ur ve y.  A  tra diti o nal  Ti meli ne  F oll o w- Bac k  will  be  c o n d ucte d  d uri n g 
la b orat or y visits t o fill i n missi n g data. T hese alc o h ol use q ua ntificati o n strate gies will be use d i n calc ulati n g 
pri mar y efficac y o utc o me meas ures, i ncl u di n g t otal sta n dar d dri n ks, c o m pare d bet wee n t he 4 wee ks pri or 
t o i nta ke a n d t he last 4 wee ks of st u d y treat me nt.  T he trial is p o were d t o test t his pri mar y o utc o me (see 
St atistic al  Met h o ds ),  a n d  ot her  alc o h ol  use-relate d  o utc o mes  are  e x pl orat or y  at  t his  P hase  II  sta ge  of 
i n vesti gati o n. 
T he MI NI I nter nati o nal Ne ur o ps yc hiatric I nter vie w will be c o n d ucte d at t he i nitial assess me nt visit t o 
e val uate f or ps yc hiatric a n d s u bsta nce use dis or ders. 5 4, 5 5 T hr o u g h o ut t he st u d y, a variet y of self-re p ort a n d 
cli nicia n-a d mi nistere d meas ures (s u m marize d i n t he St u d y Ti met a ble ) will be c ollecte d.  I n ge neral, t hese 
meas ures will be use d t o assess a n d trac k me ntal healt h, s u bsta nce use-relate d pr o ble ms, q ualit y of life, a n d 
ot her f u ncti o nal o utc o mes o ver t he c o urse of st u d y partici pati o n as e x pl orat or y ai m s. A d verse e ve nts will 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 1 5 of 2 8  
 
be d oc u me nte d, rate d f or se verit y a n d relate d ness, c o de d i n Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A)  ter ms,  a n d  ma na ge d/re p orte d  a p pr o priatel y  via  esta blis he d  pr oce d ures  (see  H u ma n  S u bjects 
secti o n).  T o e val uate pe netrati o n of t he bli n d, partici pa nts a n d t he pri mar y st u d y pers o n nel w h o i nteract 
wit h t he partici pa nt will be as ke d at m ulti ple ti me p oi nts w het her t he y t hi n k t he partici pa nt is recei vi n g 
N A C or place b o. 
L a b or at ory Tests  
C o m bi ne d   use  of et ha n ol meta b olites  a n d tra diti o nal bi o mar kers  [i.e. alc o h ol breat hal yzer, uri ne et h yl  
gl uc ur o ni de ( Et G), bl o o d car b o h y drate deficie nt tra nsferri n ( C D T) , a n d bl o o d p h os p hati d ylet ha n ol ( P Et h)] 
will   be utilize d  t o m o nit or   dri n ki n g a n d c orr o b orate self-re p ort meas ures. 5 6 -5 9 Uri ne  dr u g  tests 
(c o m pre he nsi ve pa nel  testi n g  f or Et G,  c ocai ne,  c oti ni ne,  T H C , K 2, 
a m p heta mi nes,  o pi oi ds,  a n d 
be nz o diaze pi nes) will be use d t o m o nit or ot her s u bsta nce use. Uri ne pre g na nc y tests will be c o n d ucte d wit h 
partici pa nts assi g ne d fe male at birt h.  If a vaila ble w he n t he trial is c o n d ucte d, we will i nc or p orate weara ble 
alc o h ol bi ose ns ors (e. g., B A Ctrac k S k y n ™) as a n ot her p ote ntial bi o mar ker of use, t h o u g h at t his sta ge basic 
q uesti o ns  of  partici pa nt  acce pta bilit y  ( willi n g ness  t o  wear)  a n d  data  ma na ge me nt/i nter pretati o n  ( best 
met h o ds t o assess a n d c o m pare wit h self-re p ort a n d ot her bi o mar kers) are n ot yet a d dresse d; t his w o ul d be 
e x pl orat or y, t h o u g h p ote ntiall y hi g hl y val ua ble i n a pr o of- of-c o nce pt trial. 
C o g nitive T ask Perf or m a nce Assess me nts 
C N S Vital Si g ns, a c o m p uter-a d mi nistere d batter y of perf or ma nce tests, assessi n g s u btle c ha n ges i n 
me ntal  ac uit y,  lear ni n g  a n d  me m or y,  ps yc h o m ot or  s pee d,  c o m ple x  atte nti o n,  i m p ulsi vit y,  pla n ni n g  a n d 
se q ue nci n g,  a n d  ot her  as pects  of  perf or ma nce,  will  be  a d mi nistere d  at  baseli ne,  d uri n g  treat me nt,  at 
treat me nt  c o ncl usi o n,  a n d  at  p ost-treat me nt  f oll o w- u p.6 0  A  trai ni n g/ practice  sessi o n  will  be  c o n d ucte d 
d uri n g  scree ni n g.    T he  perf or ma nce  batter y,  vali date d  a m o n g  a d olesce nts,  re q uires  a p pr o xi matel y  4 5 
mi n utes t o c o m plete a n d i ncl u des t he f oll o wi n g c o m p o ne nts: Ver b al Me m ory Test ( P art 1), Vis u al Me m ory 
Test ( P art 1), Fi n ger T a p pi n g Test, Sy m b ol Di git C o di n g, Str o o p Test, S hifti n g Atte nti o n Test, C o nti n u o us 
Perf or m a nce Test, Perce pti o n of E m oti o ns Test, Re as o ni n g Test, F o ur P art C o nti n u o us Perf or m a nce Test, 
D u al T ask Test, Ver b al Me m ory Test ( P art 2), Vis u al Me m ory Test ( P art 2) .  We ha ve utilize d t his batter y 
i n o ur pri or w or k wit h N A C i n a d olesce nts wit h C U D, de m o nstrati n g e vi de nce of perf or ma nce c ha n ges i n 
s o me c o g niti ve d o mai ns wit h a bsti ne nce vers us c o nti n ue d use. 6 1 
 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 1 6 of 2 8  
 
St u d y Ti met a ble 
 
S C  
D o u ble -Bli n d Me dicati o n P hase (± 3 da y visit wi n d o w)  
F U ( ±5 da y visit 
wi n d o w)  
Wee k à        S C  
0 ø 
1  
2  
3  
4 &  
5  
6  
7  
8 # 
1 2  
2 6 / E T 
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
L ocat or F or m a n d U p dates  
X ꜝx  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
De m o gra p hics  w/ Mac Art h ur S ocial La d der  
X ꜝ x 
 
 
 
 
 
 
 
 
 
 
 
Tec h n ol o g y S ur ve y  
 
 
X  
 
 
 
 
 
 
 
 
 
Beliefs a b o ut Me dici nes & Me dicati o n A d here nce Vi de o 
Fee d bac k F or m  
 
 
 
 
 
 
 
 
 
X 
 
X >  
Me dic al Assess me nts  
 
 
 
 
 
 
 
 
 
 
 
Hist or y a n d P h ysical  
X % ꜝ 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht, Wei g ht, Bl o o d Press ure, a n d P ulse  
X % ꜝ 
 
 
 
 
X  
 
 
 
X  
 
X  
Cli nical I nstit ute Wit h dra wal Assess me nt of Alc o h ol -
Re vise d ( CI W A)  
X %  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A d verse E ve nts  
X %  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Pri or/ C o nc o mita nt Me ds  
X % ꜝ 
X $ 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Pe netrati o n of Bli n d Assess me nt  
 
 
 
 
 
X  
 
 
 
X  
 
X  
Cli nical Gl o bal I m pressi o n of Se verit y Scale ( C GI -S)  
X %  
 
 
 
 
X 
 
 
 
X 
 
X 
Alc o h ol Use Dis or der  O utc o mes  
X %  
 
 
 
 
X  
 
 
 
X  
 
X  
Ps yc h ol o gic al Assess me nts  
 
 
 
 
 
 
 
 
 
 
 
M I NI I nter nati o nal Ne ur o ps yc hiatric I nter vie w  
X % ꜝ x  
 
 
 
 
 
 
 
 
 
 
 
Barratt I m p ulsi ve ness Scale  
X ꜝ  
 
 
 
 
 
 
 
 
 
 
 
S h ort U P P S -Y  I m p ulsi vit y Scale 
X ꜝ x 
 
 
 
 
 
 
 
 
 
 
 
C urre nt Q ualit y of Life  
Xꜝ 
 
 
 
 
X 
 
 
 
X 
 
X 
S h ort F or m 3 6 Healt h S ur ve y ( S F 3 6)  
X  
 
 
 
 
X  
 
 
 
X  
 
X  
M o difie d Ris k Be ha vi or S ur ve y  
X  
 
 
 
 
X  
 
 
 
X  
 
X  
Bec k De pressi o n I n ve nt or y  
X ꜝ 
X  
 
 
 
X  
 
 
 
X  
 
X  
Bec k A n xiet y I n ve nt or y  
X ꜝ 
X  
 
 
 
X  
 
 
 
X  
 
X  
A D H D Rati n g Scale  
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Pitts b ur g h Slee p Q ualit y I n de x  
X ꜝ x 
 
 
 
 
X  
 
 
 
X  
 
X  
C ol u m bia S uici de Se verit y Rati n g Scale  
X ꜝ 
X $ 
 
 
 
X  
 
 
 
X  
 
X  
C o g niti ve Tas k Perf or ma nce Testi n g  
X # ꜝ 
X  
 
 
 
X  
 
 
 
X  
 
X  
Treat me nt Ser vices Re vie w  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
S u bst a nce Self -Re p ort  
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol a n d Ot her S u bsta nce Use Hist or y  
Xꜝ x 
 
 
 
 
 
 
 
 
 
 
 
S O C R A T E S  
X  x 
X  
 
 
 
X  
 
 
 
X  
 
X  
M o difie d M o nit ori n g t he F ut ure Q uesti o n naire  
X  
 
 
 
 
 
 
 
 
 
 
 
Dri n ki n g M oti ves Q uesti o n naire  
X  
 
 
 
 
 
 
 
 
 
 
 
R ut gers Alc o h ol Pr o ble m I n de x  
X  x 
 
 
 
 
X  
 
 
 
X  
 
X  
Alc o h ol a n d Ot her S u bsta nce Use Dail y Re p orts, 
C o nfir me d wit h T L F B  
X %ꜝ x  
X $ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
O bsessi ve C o m p ulsi ve Dri n ki n g Scale  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Alc o h ol P urc hase Tas k  
X  
X  
 
 
 
X  
 
 
 
X  
X  
X  
Marij ua na A d olesce nt Pr o ble m I n de x , c a n n a bis users o nly 
X ꜝ x 
 
 
 
 
X  
 
 
 
X  
 
X  
M o difie d Fa gerstr ö m T olera nce Q uesti o n naire ( m F T Q) , 
t o b acc o users o nly 
Xꜝ x 
 
 
 
 
X 
 
 
 
X 
 
X 
Pe n n State E -ci g De pe n de nce I n de x, e-ci g users o nly  
X ꜝ x 
 
 
 
 
X  
 
 
 
X  
 
X  
L a b S a m ples/ Testi n g  
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol Breat hal yzer  
X  x 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Uri ne Et h yl Gl uc ur o ni de ( Et G)  
X 
X 
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
Bl o o d Car b o h y drate Deficie nt Tra nsferri n ( % C D T)  
X  
 
 
 
 
X  
 
 
 
X  
 
X  
Bl o o d P h os p hati d ylet ha n ol ( P Et h)  
X  
 
 
 
 
X  
 
 
 
X  
 
X  
Uri ne Dr u g Test  
X ꜝ x 
X  
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
X Å  
Uri ne Pre g na nc y Test ‡ 
X ꜝ x 
X $ 
X * Å  X * Å  X * Å  
X Å  
X * Å  X * Å  X * Å  
X Å  
 
 
Ps yc h os oci al Pr oce d ures  
 
 
 
 
 
 
 
 
 
 
 
Me dicati o n A d here nce Assess me nt  
(Cli nic Visit Self -Re p ort, Pill C o u nt, Pills y  Ca p, Dail y 
Re p orts, a n d R E D Ca p Vi de o Re vie w)  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Brief Alc o h ol I nter ve nti o n  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
Me dicati o n Ma na ge me nt  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 1 7 of 2 8  
 
 
S C  
D o u ble -Bli n d Me dicati o n P hase (± 3 da y visit wi n d o w)  
F U ( ±5 da y visit 
wi n d o w)  
Wee k à        S C  
0 ø 
1  
2  
3  
4 &  
5  
6  
7  
8 # 
1 2  
2 6 / E T 
Me dicati o n Dis pe nsati o n  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Esti mate d Visit Le n gt h ( h o urs) à  
2 -3  
1. 5  . 7 5 . 7 5 . 7 5 1. 5  . 7 5 . 7 5 . 7 5 
1. 5  
1  
1. 5  
S C = Scree ni n g/ Assess m e nt, E O T = E n d of Treat m e nt, F U = F oll o w -U p , E T = Earl y Ter mi nati o n 
ø  t he W ee k 0 visit is t he Ra n d o mizati o n Visit ; ‡  i n di vi d uals assi g ne d fe male at birt h o nl y ; * as-nee de d  f or safet y/ preca uti o nar y meas ure; ^  uri ne dr u g test  s h o ul d be perf or me d at 
scree ni n g/ baseli ne  a n d  a gai n  bef ore  ra n d o mizati o n  t o  e ns ure  eli gi bilit y; $  s h o ul d  be  c o m plete d  pri or  t o  ra n d o mizati o n  t o  e ns ure  eli gi bilit y;  &   if t he  Wee k  4  visit  is  misse d, 
assess me nts t hat are o nl y c o m plete d at t hat visit s h o ul d be perf or me d at t he ne xt atte n de d visit, as l o n g as t he wi n d o w f or t he Wee k 8 visit  has n ot yet o pe ne d ; #  if t he W ee k 8 visit 
is misse d, assess me nts t hat are o nl y c o m plete d at t hat visit s h o ul d be perf or me d at t he ne xt atte n de d visit, as l o n g as t he wi n d o w f or t he W ee k 2 6 visit has n ot yet o pe ne d; %  these 
assess me nts ma y be perf or me d at t he ra n d o mizati o n visit, as l o n g as t he y occ ur pri or t o ra n d o mizati o n t o e ns ure eli gi bilit y ; #  trai ni n g/ practice c o g niti ve tas k perf or ma nce sessi o n; ꜝ 
data  s hari n g  of c o m plete d  pr ot oc ol  pr oce d ures  fr o m  P R O # 5 4 4 9 9  as  a  res ult  of  scree n  fail ure ;  >  if  E T  occ urs  d uri n g  treat me nt  p hase; x c o m plete d  as  part  of data  s hari n g  wit h 
P R O # 9 4 7 4 3 ; Å  f or visits occ urri n g e ntirel y re m otel y, will be c ollecte d a n d teste d re m otel y b y t he partici pa nt, wit h res ults verifie d b y vide o a n d p h ot o ca pt ure  
1 1. 0  S peci me n C ollecti o n a n d B a n ki n g  (if a p plic a ble) 
Uri ne s peci me ns will be c ollecte d f or la b orat or y testi n g, i ncl u di n g dr u g tests, pre g na nc y tests, a n d et h yl 
gl uc ur o ni de  (alc o h ol  use  bi o mar ker)  tests.    F or  visits  c o n d ucte d  e ntirel y  re m otel y,  t he  partici pa nt  will 
c ollect a n d test uri ne s peci me ns wit h C LI A wai ve d q ualitati ve et h yl gl uc ur o ni de ( Et G) tests, U D S, a n d 
pre g na nc y tests f or partici pa nts assi g ne d fe male at birt h, wit h res ults verifie d usi n g vi de o or p h ot o ca pt ure. 
Bl o o d  will  be  c ollecte d  f or  la b orat or y  testi n g,  i ncl u di n g  car b o h y drate  deficie nt  tra nsferri n  a n d 
p h os p hati d ylet ha n ol (alc o h ol use bi o mar ker) tests.  N o sa m ples will be ba n ke d after t he af ore me nti o ne d 
assa ys  are  c o m plete d.    All  la b orat or y  testi n g  will  occ ur  at  t he  Cli nical  Ne ur o bi ol o g y  La b orat or y  i n  t he 
I nstit ute  of  Ps yc hiatr y  o n  t he  M U S C  ca m p us.  F or  visits  c o n d ucte d  e ntirel y  re m otel y,  bl o o d  will  n ot  be 
c ollecte d f or la b orat or y testi n g. 
1 2. 0  D at a M a n a ge me nt   
St atistic al Met h o ds 
P o wer a n d S a m ple Size 
T his P hase II pr o of- of-c o nce pt trial is p o were d o n t he pri mar y h y p ot hesis t hat t here will be a cli nicall y 
si g nifica nt differe ntial i n t he decrease i n t otal sta n dar d alc o h ol dri n ks a n d dri n ks per dri n ki n g da y d uri n g 
t he fi nal f o ur wee ks of treat me nt ( wee ks 5- 8) i n t he N A C gr o u p c o m pare d t o t he place b o gr o u p.  I n t he 
pr o p ose d st u d y, t he t w o treat me nt ar ms, N A C a n d place b o, will be assesse d f or differe nces i n dri n ki n g 
be ha vi or usi n g ge neral li near m o dels.  I n a pri or pil ot trial assessi n g a d olesce nt dri n ki n g be ha vi or ( N = 1 1), 
o ur tea m n ote d a n a vera g e t otal of 4 9 ( S D = 2 6) dri n ks wit h 5. 5 ( 2. 0) dri n ks per dri n ki n g da y d uri n g t he 4 
wee ks pri or t o st u d y e nr oll me nt.  A d diti o nall y, alt h o u g h t he partici pa nts n ote d i n o ur pri or C U D trial were 
n ot re q uire d t o e x hi bit A U D n or was treat me nt tar gete d at dri n ki n g be ha vi or, t he hea vier dri n kers i n t he 
st u d y ( u p per q uartile of t otal dri n ks pri or t o baseli ne, ≥ 2 4 dri n ks/ 3 0 da ys) re p orte d a mea n of 5 8 ( S D = 3 0; 
me dia n = 5 4 dri n ks) dri n ks d uri n g t he 4 wee ks pri or t o st u d y e ntr y. 2 6  I n t his sa m ple of hea vier dri n kers, 
t h ose ra n d o mize d t o place b o ha d a me dia n 1 0. 7 % decrease i n t otal dri n ks at t he e n d of C U D treat me nt (last 
4 wee ks of st u d y treat me nt) as c o m pare d t o a me dia n 3 3. 0 % decrease i n t otal dri n ks i n t he N A C treate d 
gr o u p. Ass u mi n g a m ore r o b ust treat me nt effect w he n alc o h ol use is t he t hera pe utic tar get, a 5 0 % decrease 
i n t otal dri n ks d uri n g t he fi nal 4 wee ks of st u d y treat me nt i n t he acti ve treat me nt gr o u p, as c o m pare d t o 
baseli ne, w o ul d be a cli nicall y rele va nt treat me nt effect. We c o nser vati vel y esti mate a si milarl y m ore r o b ust 
2 0 % decrease i n t otal dri n ks i n t he place b o treate d gr o u p.  Ass u mi n g si milar baseli ne dri n ki n g be ha vi or t o 
t he a d olesce nt st u d y ( baseli ne mea n = 4 9 dri n ks/ 4 wee ks) a n d a si milar gr o u p le vel varia nce esti mate as i n 
t he baseli ne st u d y data ( S D = 2 5), we will ha ve 8 0 % p o wer wit h a 5 % t y pe I err or rate t o detect t he cli nicall y 
rele va nt differe nce bet wee n a 5 0 % decrease i n t he N A C treate d gr o u p a n d 2 0 % decrease i n t he place b o 
treate d gr o u p (e q ui vale nt t o 2 5 t otal dri n ks vers us 4 0 t otal dri n ks d uri n g t he fi nal 4 wee ks of treat me nt) 
wit h  4 5  partici pa nts  ra n d o mize d  t o  eac h  treat me nt  gr o u p  ( n = 9 0  t otal).    A d diti o nall y,  we  a ntici pate  t hat 
rete nti o n  ma y  be  a  c halle n ge  i n  t his  p o p ulati o n,  a n d  we  a ntici pate  a  2 5 %  dr o p- o ut  rate  d uri n g  st u d y 
treat me nt, i nflati n g t he necessar y ra n d o mize d sa m ple size t o n = 6 0 partici pa nts per treat me nt ar m ( N = 1 2 0 
t ot al  r a n d o mize d  p artici p a nts).    T he  n ote d  sa m ple  will  ha ve  greater  t ha n  9 0 %  p o wer  t o  fi n d  a 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 1 8 of 2 8  
 
c orres p o n di n g 5 0 % decrease i n dri n ks per dri n ki n g da y i n t he N A C treate d gr o u p as c o m pare d t o a 2 0 % 
decrease i n t he place b o treate d gr o u p [ 2. 8 ( S D = 2. 0) vs. 4. 4 ( 2. 0) dri n ks per dri n ki n g da y]. 
Pri m ary D at a A n alysis 
Baseli ne  cli nical  a n d  de m o gra p hic  c haracteristics  will  be  c ollecte d  a n d  c o ntrasts  of  baseli ne 
c haracteristics a n d cli nical pre dict ors of s u bsta nce use will be perf or me d bet wee n gr o u ps. C o nti n u o us a n d 
or di nal  c haracteristics  will  be  c o m pare d  usi n g  a  Wilc o x o n  Ra n k- S u m  test  statistic  w hile  cate g orical 
c haracteristics  will  be  c o m pare d  usi n g  a  Pears o n  C hi- S q uare  test  statistic.  If  a  baseli ne  c haracteristic  is 
si g nifica ntl y ass ociate d wit h t he o utc o mes of i nterest, t he c orres p o n di n g varia bles will be use d as i nit ial 
c o variates i n t he m o del a nal yses. Sec o n daril y, p ossi ble c o variates will be teste d f or c o nf o u n di n g effects o n 
t he m o dels s pecifie d a n d w he n prese nt, t he y will be i ncl u de d i n t he fi nal a dj uste d m o del.  S pecific Ai m 1:  
T he pri mar y meas ure of i nterest will be t he esti mate d re d ucti o n i n self-re p orte d sta n dar d alc o h ol dri n ks a n d 
t he ass ociate d varia nce ar o u n d t hese esti mates d uri n g t he fi nal f o ur wee ks of st u d y treat me nt ( wee ks 5- 8) 
i n t h ose ra n d o mize d t o N A C as c o m pare d t o t h ose ra n d o mize d t o place b o. T he mai n effect of N A C vers us 
place b o o n t he t otal n u m ber of sta n dar d dri n ks will be assesse d usi n g ge neralize d li near m o dels a n d m o del-
base d  mea ns  wit h  ass ociate d  sta n dar d  err ors  will  be  re p orte d.    A nal ytic  m o dels  will  be  c o m p ute d  b ot h 
u na dj uste d  a n d  a dj uste d  f or  si g nifica nt  c o variates  a n d  c o nf o u n ders  f o u n d  i n  t he  preli mi nar y  a nal ysis.  
S pecific Ai m 2:  Self -re p orte d dri n ki n g ( wee kl y T L F B a n d m o bile tec h n ol o g y- deli vere d dail y diar y) as well 
as bi o mar kers of rece nt alc o h ol use ( Et G, C D T, P Et h , a n d alc o h ol breat hal yzer) will be c ollecte d at st u d y 
visits.    A gree me nt  bet wee n  c ollecti o n  meas ures  will  be  meas ure d  as  perce nt  a gree me nt  a n d  ka p pa 
c oefficie nts.  A gree me nt will be assesse d wee kl y d uri n g t he e ntire ti me c o urse of t he treat me nt st u d y a n d 
de viati o ns bet wee n self-re p orte d m o derate/ hea v y use a n d bi o mar ker-i n dicate d m o derate/ hea v y use will be 
assesse d t o c haracterize t he re p orti n g ( u n der-re p orti n g) of self-re p orte d use a m o u nts.  Si milarl y, me dicati o n 
a d here nce  will  be  meas ure d  at  wee kl y  st u d y  visits  usi n g  self-re p ort  (s elf-re p ort  a n d  m o bile  tec h n ol o g y 
deli vere d vi de o) a n d M E M S.  C o nc or da nce perce nta ges a n d ka p pa c oefficie nts will be calc ulate d bet wee n 
t he a d here nce meas ure me nt met h o ds.  D ue t o hi g h pre vale nce of self-re p orte d a d here nce i n s u bsta nce use 
dis or der  st u dies,  ka p pa  c oefficie nts  will  be  calc ulate d  as  t he  pre vale nce  a dj uste d  bias  a dj uste d  ka p pa 
( P A B A K).6 2  Cl ustere d l o gistic re gressi o n m o del usi n g t he met h o ds of ge neralize d esti mati n g e q uati o ns 
will be a p plie d t o assess t he differe nces i n self-re p orte d dri n ki n g a n d me dicati o n a d here nce meas ure me nt 
met h o ds o n bi nar y a d here nce o utc o mes o ver ti me. 6 3 W or ki n g c orrelati o n str uct ures will be i n de pe n de ntl y 
c o m pare d a n d t he fi nal m o del str uct ures will be c h ose n usi n g t he q uasili keli h o o d u n der t he i n de pe n de nce 
m o del criteri o n statistic. 6 4 T he mai n effects of meas ure me nt met h o d a n d visit, as well as t he i nteracti o n 
bet wee n met h o d a n d visit, will e xa mi ne d f or si g nifica nce.  
All  ra n d o mize d  partici pa nts  will  be  i ncl u de d  i n  t he  pri mar y  a nal ysis  (i nte nt- t o-treat;  I T T)  a n d  all 
statistical m o dels will be i m ple me nte d usi n g S A S v. 9. 4. 
Sec o n d ary D at a A n alysis 
I n a d diti o n t o t he pri mar y use o utc o me, sec o n dar y m o dels will assess o verall alc o h ol a bsti ne nce, t he 
pr o p orti o n of dri n ki n g da ys a n d t he pr o p orti o n of hea v y dri n ki n g da ys n ote d d uri n g t he fi nal 4 wee ks of 
st u d y treat me nt.  T he te m p oral patter n i n wee kl y dri n ki n g be ha vi or o ver t he c o urse of t he e ntire st u d y is 
als o of i nterest.  Wee kl y dri n ki n g data i n t his p o p ulati o n is li kel y t o f oll o w a P oiss o n distri b uti o n a n d will 
be assesse d usi n g ra n d o m effects P oiss o n/ Ne gati ve Bi n o mial m o dels a n d i n t he case of a hi g h n u m ber of 
partici pa nts  ac hie vi n g  a bsti ne nce  fr o m  wee kl y  alc o h ol  use,  zer o  i nflate d  m o dels  will  be  e x pl ore d.  
Si milarl y, bi nar y wee kl y a bsti ne nce data will be assesse d usi n g mi xe d effects l o gistic re gressi o n m o dels t o 
assess t he l o g- o d ds of wee kl y a bsti ne nce i n t he N A C- vers us- place b o treate d partici pa nts. D ura bilit y of 
treat me nt effects will be assesse d t hr o u g h a nal ysis of p ost-treat me nt alc o h ol use data at t he Wee k 1 2 a n d 
Wee k 2 6 p ost-treat me nt visits, usi n g m o del de vel o p me nt pr ocesses si milar t o S pecific Ai m 1. 
T o assess t he ass ociati o n bet wee n alc o h ol use re d ucti o n a n d c ha n ges i n f u ncti o nal o utc o mes (alc o h ol-
relate d pr o ble ms; alc o h ol cra vi n g; c o g niti ve tas k perf or ma nce; a n xiet y, m o o d, a n d slee p q ualit y meas ures; 
q ualit y of life), ge neral li near re gressi o n m o dels will be de vel o pe d.  O utc o me s pecific distri b uti o ns will be 
use d  t o  m o del  f u ncti o nal  a n d  c o g niti ve  o utc o mes  (e. g.,  c o u nt,  bi nar y  a n d  Ga ussia n).    F or  Ga ussia n 


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Pa ge 1 9 of 2 8  
 
distri b uti o n ass u m pti o ns, resi d ual n or malit y will be assesse d usi n g Q Q pl ots, a n d w he n de viati o ns fr o m 
n or malit y occ ur a p pr o priate tra nsf or mati o ns will be ma de. 
Missi n g D at a a n d Attriti o n 
Missi n g  data  are  c o m m o n  i n  l o n git u di nal  alc o h ol  cli nical  trials  w here  use  rates  are  t he  pri mar y  e n d 
p oi nt.  T he pri mar y ca use attri b ute d t o s uc h missi n g data is partici pa nt attriti o n.  Attriti o n ca n i ntr o d uce 
bias i nt o t he para meter esti mate a n d re d uce st u d y p o wer, esti mate precisi o n a n d ge neraliza bilit y.  I n or der 
t o mi ni mize missi n g data a n d st u d y attriti o n, st u d y si m plificati o n a n d e n ha nce d c o m m u nicati o n bet wee n 
st u d y c o or di nat ors a n d partici pa nts will be e m p hasize d.  We will ma ke e ver y eff ort t o pre ve nt attriti o n, e. g., 
p h o ne/te xt/e mail  re mi n ders  pri or  t o  visits,  c o m pe nsati o n  f or  partici pati o n,  meeti n g  wit h  partici pa nts  i n 
c o m m u nit y if nee de d, a n d rei nf orci n g a d here nce at eac h visit.  H o we ver, t hese met h o ds d o n ot e ns ure t hat 
all data will be c ollecte d a n d a p pr o priate a nal ysis met h o ds will be e m pl o ye d t o acc o m m o date missi n g data.  
Si m pl y re placi n g missi n g data wit h t he last o bser vati o n carrie d f or war d or usi n g w orst case sce nari o a d ds 
s u bsta ntial bias t o b ot h para meter a n d varia nce esti mates. 6 5, 6 6 Ma xi m u m li keli h o o d met h o ds ( M L) yiel d 
vali d i nfere nces ass u mi n g i g n ora ble attriti o n (i.e., attriti o n is acc o u nte d f or b y c o variates or t he de pe n de nt 
varia ble meas ure d pri or t o dr o p o ut).  A d diti o nall y, F ull I nf or mati o n Ma xi m u m Li keli h o o d met h o ds ( FI M L) 
will be i m ple me nte d a n d c o m pare d t o t he res ults fr o m t he M L esti mati o n t o assess bias t hat ma y be prese nt 
d ue t o missi n g data. 6 7  I n a d diti o n, i n kee pi n g wit h t he I nte nt t o Treat Pri nci ple, we will ma ke e ver y eff ort 
t o c o nti n ue assess me nts f or t he e ntire c o urse of ra n d o mize d treat me nt, e ve n a m o n g t h ose w h o fail t o a d here 
t o ra n d o mize d assi g n me nt or st o p partici pati n g i n t he st u d y assi g ne d i nter ve nti o n. 
1 3. 0  Pr o visi o ns t o M o nit or t he D at a t o E ns ure t he S afet y of S u bjects 
Tri al M a n a ge me nt 
All  as pects  of  t he  st u d y  will  be  r u n  t hr o u g h  t he  M U S C  De part me nt  of  Ps yc hiatr y  a n d  Be ha vi oral 
Scie nces, w here t he M PI h ol d fac ult y a p p oi nt me nts.  T he ti meta ble is as f oll o ws: 
 
Ye ar 1 
( m o nt hs) 
Ye ar 2 
( m o nt hs) 
Ye ar 3 
( m o nt hs) 
Ye ar 4 
( m o nt hs) 
Ye ar 5 
( m o nt hs) 
Refi ne all pr oce d ures 
1- 3 
 
 
 
 
Pr oc ure s u p plies  
1 -3  
 
 
 
 
Refi ne recr uit me nt met h o ds  
1 -3  
 
 
 
 
Trai n Pers o n nel 
1- 3 
 
 
 
 
St u dy E nr oll me nt 
 
 
 
 
 
   C u m ulati ve N  t o e nr oll * 
( 2 2) 
( 3 0) 
( 3 0) 
( 3 0) 
( 8) 
   First Partici pa nt E nr olls  
 4  
 
 
 
 
   First Partici pa nt C o m pletes 
1 0 
 
 
 
 
   Last Partici pa nt E nr olls  
 
 
 
 
5 1  
   Last Partici pa nt C o m pletes  
 
 
 
 
5 7  
Data A nal ysis 
 
 
 
 
5 8- 6 0 
Ma n uscri pt Pre parati o n 
 
 
 
 
5 8- 6 0 
All n u m bers reflect m o nt hs wit hi n t otal st u d y d urati o n ( * wit h t he e xce pti o n of c u m ulati ve N ) 
D at a M a n a ge me nt a n d A n al ysis 
Data will be c ollecte d b y t he a p pr o priate i n di vi d ual (researc h assista nt, PI, C o-I) usi n g sta n dar dize d 
pa per f or ms a n d will o nl y be i de ntifie d wit h t he st u d y’s I D of t he partici pa nt. T he c o des li n ki n g t he na me 
of t he partici pa nt t o t he st u d y I D will be ke pt c o nfi de ntial i n a sec ure d ca bi net b y t he PI.  C ollecte d f or ms 
will be sec urel y tra ns p orte d t o t he PI’s data e ntr y ce nter.  Researc h assista nts will e nter data i n R E D Ca p 
( Researc h Electr o nic Data Ca pt ure), a sec ure, we b- base d a p plicati o n desi g ne d e xcl usi vel y t o s u p p ort data 
ca pt ure f or researc h st u dies. R E D Ca p pr o vi des: 1) a n i nt uiti ve i nterface f or data e ntr y ( wit h data vali dati o n); 


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Pa ge 2 0 of 2 8  
 
2) a u dit trails f or trac ki n g data ma ni p ulati o n a n d e x p ort pr oce d ures; 3) a ut o mate d e x p ort pr oce d ures f or 
sea mless  data  d o w nl oa ds  t o  c o m m o n  statistical  pac ka ges  ( S P S S,  S A S,  Stata,  R);  4)  pr oce d ures  f or 
i m p orti n g  data  fr o m  e xter nal  s o urces;  a n d  5)  a d va nce d  feat ures,  s uc h  as  bra nc hi n g  l o gic  a n d  calc ulate d 
fiel ds. T hese pr oce d ures are effecti ve i n mi ni mizi n g data e ntr y err ors (e. g., missi n g or erra nt data). W he n 
p ossi ble, partici pa nt direct e ntr y i nt o R E D Ca p (rat her t ha n pa per f or ms) will be utilize d. 
 
 
Q u alit y Ass ur a nce 
Acc urac y  a n d  c o m plete ness  of  t he  data  c ollecte d  will  be  e ns ure d  b y  wee kl y  re vie w.  T he  R E D Ca p 
s yste m d oes n ot acce pt o utliers, ill o gical res p o nse patter ns, etc. T he M PI a n d pr o gra m c o or di nat or will ha ve 
wee kl y  meeti n gs  wit h  t he  researc h  assista nts  t o  disc uss  q ualitati ve  c o m me nts  recei ve d  d uri n g  data 
c ollecti o n  a n d  a n y  pr o ble ms  i n  data  c ollecti o n  or  e ntr y.  T he  statisticia n  will  peri o dicall y  e xa mi ne  t he 
data base f or p ote ntial irre g ularities. I nitial data a nal yses will e xa mi ne distri b uti o ns of varia ble sc ores a n d 
c o m para bilit y of baseli ne c haracteristics acr oss c o n diti o ns i n case a nal yses nee d t o be a dj uste d f or t hese. 
C o nfi de ntialit y pr otecti o ns are o utli ne d a b o ve. 
Re g ul at or y Iss ues 
Pri or  t o  t he  start  of  t he  st u d y,  t he  pr ot oc ol  will  be  re gistere d  o n  t he  cli nical  trials  re gistr y 
(cli nicaltrials. g o v). All seri o us a d verse e ve nts will be re p orte d t o t he M U S C I nstit uti o nal Re vie w B oar d 
(I R B) wit hi n 2 4 hrs. F oll o w- u p of all seri o us a d verse e ve nts will be re p orte d as well. All a d verse e ve nts are 
re vie we d wee kl y b y t he M PI a n d yearl y b y b ot h t he D S M B a n d t he I R B. A n y si g nifica nt acti o ns ta ke n b y 
t he l ocal I R B, i ncl u di n g si g nifica nt pr ot oc ol c ha n ges, will be rela ye d t o NI A A A. We a ntici pate t he seri o us 
a d verse e ve nt rate t o be e xtre mel y l o w. If m o nit ori n g i n dicates ot her wise, we will c o n ve ne a s pecial meeti n g 
of t he Data a n d Safet y M o nit ori n g B oar d ( D S M B).  
Tri al S afet y 
T he  p ote ntial  ris ks  a n d  be nefits  a n d  met h o ds  t o  mi ni mize  t hese  ris ks  are  o utli ne d  i n 1 5. 0  Ris ks  t o 
S u bjects .   G ui deli nes ha ve bee n de vel o pe d f or ma na gi n g a n d re p orti n g of a d verse e ve nts ( A Es), i ncl u di n g 
seri o us  a d verse  e ve nts  ( S A E;  defi ne d  as  a n y  u nt o war d  me dical  occ urre nce  t hat  res ults  i n  deat h,  is  life-
t hreate ni n g,  re q uires  or  pr ol o n gs  h os pitalizati o n,  ca uses  persiste nt  or  si g nifica nt  disa bilit y/i nca pacit y, 
res ults  i n  c o n ge nital  a n o malies/ birt h  defects,  or  i n  t he  o pi ni o n  of  t he  i n vesti gat ors  re prese nts  ot her 
si g nifica nt hazar ds or p ote ntiall y seri o us har m t o researc h s u bjects or ot hers).  PI Dr. Gra y will ser ve as t he 
Pr o gra m Ma na ger f or A Es.  T he A d verse E ve nt L o g will be use d t o d oc u me nt all A Es.  If a n A E is n o n-
seri o us (self-li mite d wit h n o i nter ve nti o n nee de d), n o f urt her acti o n will be necessar y.  H o we ver, i n t he case 
of a seri o us, u nres ol ve d e ve nt, a n A E f oll o w- u p l o g will be c o m plete d. T he cli nicia n will t he n call Dr. Gra y 
wit h i nitial re p orts wit hi n 2 4 h o urs of t he start of t he S A E.  T he cli nicia n will rec or d t he i nf or mati o n o n 
S A E N otificati o n F or m.  T he cli nicia n will f or war d har d c o pies of t he c o m plete re p ort ( S A E N otificati o n 
F or m, C o nc o mita nt Me dicati o n L o g, a n d A E L o g) t o Dr. Gra y, w h o will, i n t ur n n otif y t he I R B, D S M B, 
a n d NI H a b o ut t he S A E.  A d diti o nall y, Dr. Gra y will c o m m u nicate s u m mar y re p orts of D S M B disc ussi o n 
of t he S A E, or a n y deli berati o ns of I R B re gar di n g t he re vie w of t he S A E or t he trial itself, t o NI H.  If t he 
e ve nt is “ Seri o us, U ne x pecte d a n d Ass ociate d” (a n S A E is c o nsi dere d u ne x pecte d if it is n ot descri be d i n 
t he Pac ka ge I nsert), Dr. Gra y will c o m plete F o o d a n d Dr u g A d mi nistrati o n ( F D A) F or m 3 5 0 0 A a n d will 
f or war d it t o t he F D A.  Dr. Gra y als o will i nf or m t he I R B a n d t he st u d y partici pa nts (a n d pare nts/ g uar dia ns, 
as  a p pr o priate)  a b o ut  t he  S A E.  I n  all  of  t hese  re vie ws  a n d  re p orts,  strict  patie nt  c o nfi de ntialit y  will  be 
mai ntai ne d. 
A Es will be c o de d o n a wee kl y basis usi n g Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
r ules a n d e ntere d i nt o a data base. F or eac h wee kl y st u d y meeti n g, t he researc h assista nts will pre pare a 
s u m mar y of all A Es, i ncl u di n g t heir se verit y a n d pres u me d relati o n t o st u d y me dicati o n. T he PI will re vie w 
t his at t he wee kl y st u d y meeti n g ( or bef ore if m ore ur ge nt). 


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Pa ge 2 1 of 2 8  
 
St u d y pr oce d ures will f oll o w as m uc h as p ossi ble t he F D A’s G o o d Cli nical Practice G ui deli nes.  We 
will e nc o ura ge partici pa nts (a n d pare nts/ g uar dia ns as a p pr o priate) t o n otif y t heir p h ysicia ns t hat a) t he y are 
i n a ra n d o mize d c o ntr olle d researc h st u d y e val uati n g N -acet ylc ystei ne f or a d olesce nt alc o h ol use dis or der, 
a n d b) t he p h ysicia n s h o ul d c o ntact t he PI directl y if t he p h ysicia n has a n y q uesti o ns. 
T he researc h assista nts will be i nstr ucte d n ot t o re veal w het her a pers o n is a partici pa nt i n t he st u d y a n d 
will  re p ort  t o  t he  PI  a n y  o utsi de  re q uests  f or  i nf or mati o n  a b o ut  a  partici pa nt  or  a n y  breac hes  i n 
c o nfi de ntialit y. All re q uests b y partici pa nts’ p h ysicia ns a n d ot her me dical pr o vi ders will be referre d directl y 
t o t he PI.  
Tri al Effic ac y 
T he Data a n d Safet y M o nit ori n g B oar d ma y re q uest a bli n de d i nteri m efficac y re p ort ( bli n de d t o t he PI 
a n d researc h tea m) f or re vie w w hile t he trial is o n g oi n g.  Fi nal (f ull y u n bli n de d) efficac y a nal ysis will occ ur 
after all partici pa nts ha ve c o m plete d all visits. 
D at a a n d S afet y M o nit ori n g Pl a n A d mi nistr ati o n 
T he PI will be res p o nsi ble f or m o nit ori n g t he trial. T he statisticia n will e xa mi ne t he o utc o mes data base 
q uarterl y f or missi n g data, u ne x pecte d distri b uti o ns or res p o nses, a n d o utliers. T he PI will wee kl y c hec k 
t he a d verse e ve nt data base pre pare d b y t he researc h assista nts i m me diatel y pri or t o t he la b meeti n g t o a) 
see  if  a n y  partic ular  Me d D R A  cate g ories  are  bei n g  e n d orse d  m ore  fre q ue ntl y  t ha n  a ntici pate d,  a n d  b) 
deter mi ne if a n y a d verse e ve nt s y m pt o m c hec klist sc ores are hi g her t ha n e x pecte d. A D S M re p ort will be 
file d wit h t he I R B a n d NI D A o n a yearl y basis, u nless greater t ha n e x pecte d pr o ble ms occ ur. T he re p ort 
will  i ncl u de  partici pa nt  c haracteristics,  rete nti o n  a n d  dis p ositi o n  of  st u d y  partici pa nts,  q ualit y  ass ura nce 
iss ues a n d re p orts of a d verse e ve nts, si g nifica nt/ u ne x pecte d a d verse e ve nts a n d seri o us a d verse e ve nts. We 
will re p ort efficac y at t he e n d of t he trial. 
D at a a n d S afet y M o nit ori n g B o ar d 
We  will  create  a  Data  a n d  Safet y  M o nit ori n g  B oar d,  c o m prise d  of  m ulti disci pli nar y  fac ult y  wit h 
e x pertise  i n  p har mac ot hera p y  a n d  be ha vi oral  treat me nt  trials  (a d olesce nt  a n d/ or  a d dicti o n-relate d).  T he 
D S M B will meet a n n uall y ( m ore fre q ue ntl y as nee de d f or e mer ge nt sit uati o ns) t o re vie w a n y A Es relate d 
t o t he st u d y, as well as re vie w a n y data ma na ge me nt relate d err ors. T he b oar d ma y be calle d at a n y p oi nt if 
nee de d f or seri o us a d verse e ve nts, etc. M o dificati o n will be ma de i n t he pr oce d ures a n d/ or t he pr ot oc ol if 
necessar y base d o n t he fi n di n gs of t he b oar d. 
1 4. 0  Wit h dr a w al of S u bjects  (if a p plic a ble) 
Disc o nti n u ati o n/ St o p pi n g R ules 
E ver y  eff ort  will  be  ma de  t o  retai n  partici pa nts  i n  t he  trial.    If  a  partici pa nt  e x perie nces  i nt olera ble 
a d verse effects wit h st u d y me dicati o n t hat are n ot re me die d b y a d ose re d ucti o n, t he me dicati o n ma y be 
disc o nti n ue d w hile t he partici pa nt c o nti n ues t o partici pate i n all n o n- me dicati o n st u d y i nter ve nti o ns a n d 
pr oce d ures. 
Cli nic al Deteri or ati o n “ Resc ue ” Pl a n 
A cli nical deteri orati o n “resc ue” pla n will be i n place f or partici pa nts t hat e x perie nce ps yc hiatric or 
s u bsta nce use deteri orati o n d uri n g t he st u d y.  S y m pt o ms will be m o nit ore d cl osel y t hr o u g h o ut t he trial t o 
assess  f or  deteri orati o n  a n d  a p pr o priate  i nter ve nti o n  will  be  arra n ge d  f or  a n y  partici pa nt  de m o nstrati n g 
gr oss  cli nical  deteri orati o n.    T he  resc ue  meas ures  will  i ncl u de  i m me diate  assess me nt  b y  t he  me dical 
cli nicia n  f or  a  c o m pre he nsi ve  ps yc hiatric  a n d  s u bsta nce  a b use  e val uati o n  a n d  referral  f or  a p pr o pr iate 
cli nical i nter ve nti o n.  M PI Gra y has f ull me dical a n d ps yc hiatric a d mitti n g pri vile ges at t he M U S C Me dical 
Ce nter. 
Referr al f or P artici p a nts Nee di n g C o nti n ui n g Tre at me nt  
At t he e n d of st u d y partici pati o n, if a partici pa nt re q uires or re q uests c o nti n ui n g treat me nt f or A U D , a n 
a p pr o priate treat me nt referral will be ma de. 


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Pa ge 2 2 of 2 8  
 
1 5. 0  Ris ks t o S u bjects  
P ote nti al Ris ks 
Q uesti o n naires  a n d  i nter vie ws  are  all  n o n-i n vasi ve  a n d,  as  s uc h,  i n v ol ve  mi ni mal  p h ysical  ris k  t o 
partici pa nts.  P ote ntial ris ks i nc urre d b y partici pa nts i ncl u de: 
1.  A d verse e ve nts relate d t o st u d y me dicati o n 
2.  L oss of c o nfi de ntialit y 
3.  Ve ni p u nct ure-ass ociate d ris ks 
A d verse e ve nts relate d t o st u d y me dicati o n 
N -acet ylc ystei ne has a ge nerall y be ni g n a d verse effect pr ofile.  A meta-a nal ysis of st u dies e val uati n g 
l o n g-ter m  oral  treat me nt  wit h N -acet ylc ystei ne  f or  pre ve nti o n  of  c hr o nic  br o nc hitis  f o u n d  t hat N -
acet ylc ystei ne was well t olerate d, wit h ge nerall y mil d, m ost c o m m o nl y gastr oi ntesti nal, a d verse effects t hat 
di d n ot re q uire treat me nt i nterr u pti o n. 1 7  O ur e x perie nce t o date wit h N -acet ylc ystei ne at t he sa me d ose 
pr o p ose d  i n  t his  trial  i n  b ot h  a d olesce nts  a n d  a d ults  wit h  s u bsta nce  use  dis or ders,  ma n y  of  w h o m  use d 
alc o h ol fre q ue ntl y, s u g gests a be ni g n a d verse e ve nt pr ofile. 1 9 -2 6 
S o me  patie nts  w h o  ha ve  ta ke n  i ntra ve n o us N -acet ylc ystei ne  f or  t he  treat me nt  of  aceta mi n o p he n 
o ver d ose ha ve ha d m ore seri o us reacti o ns.  Aller gic reacti o ns ha ve occ urre d i n a b o ut 5 % of patie nts ta ki n g 
i ntra ve n o us N -acet ylc ystei ne.6 8  T hese reacti o ns ma y be mil d, c o nsisti n g of fl us hi n g, ras h, a n d itc hi n g.  Less 
c o m m o n si de effects i ncl u de tr o u ble breat hi n g, l o w or hi g h bl o o d press ure, fe ver, a n d hi ves.  If u ntreate d, 
s uc h a reacti o n c o ul d lea d t o deat h.  E ve n m ore rare seri o us si de effects of i ntra ve n o us N -acet ylc ystei ne are 
irrita bilit y, c o nf usi o n, a n d seiz ures.  T hese reacti o ns (se vere aller gic reacti o n or seiz ures) ha ve ne ver bee n 
re p orte d w he n N -acet ylc ystei ne is ta ke n orall y, as it will be i n t his st u d y. 
L oss of c o nfi de ntialit y 
A n y c o m m u nicati o n of pers o nal i nf or mati o n carries t he p ote ntial ris k of breac h of c o nfi de ntialit y. 
Ve ni p u nct ure-ass ociate d ris ks 
T he ris ks of dra wi n g bl o o d i ncl u de te m p orar y disc o mf ort fr o m t he nee dle stic k a n d br uisi n g. T his ris k 
is n ot rele va nt t o re m ote- o nl y partici pa nts. 
A de q u acy of Pr otecti o n A g ai nst Ris ks  
Recr uit me nt a n d I nf or me d C o nse nt  
Recr uit me nt of t he partici pa nts will be fr o m t he l ocal c o m m u nit y. T he Me dical U ni versit y of S o ut h 
Car oli na ( M U S C) I nstit uti o nal Re vie w B oar d (I R B) a p pr o ve d I nf or me d C o nse nt (I C) will be o btai ne d pri or 
t o t he start of a n y st u d y pr oce d ures as part of t he i nitial assess me nt.  T he c o nse nt will be e x plai ne d orall y 
a n d  i n  t he  writte n  f or m,  a n d  will  be  d oc u me nte d  b y  t he  si g nat ure  of  t he  partici pa nt  o n  t he  I C.    F or 
partici pa nts u n der 1 8 years ol d, a pare nt/le gal g uar dia n will pr o vi de c o nse nt a n d t he partici pa nt wil l pr o vi de 
asse nt.    T he  c o nse nt  d oc u me nt  will  c o ntai n  a  t h or o u g h  re vie w  of  p ote ntial  ris ks  ass ociate d  wit h  trial 
partici pati o n, i ncl u di n g p ote ntial me dicati o n-relate d ris ks. 
A bse nce of C oerci o n: Partici pati o n i n t he st u d y is v ol u ntar y. C o m pe nsati o n f or st u d y partici pati o n is 
c o nsiste nt  wit h  t he  le vel  of  b ur de n  i n v ol ve d  i n  c o m pleti n g  st u d y  pr oce d ures,  a n d  is  c o nsiste nt  wit h  t he 
c o m pe nsati o n sc he d ule i n si milar pri or st u dies.   T he i nf or me d c o nse nt a gree me nt t hat will be rea d t o eac h 
v ol u nteer (a n d pare nt/ g uar dia n as a p plica ble) pri or t o e nr oll me nt i n t he st u d y e x plai ns t he f oll o wi n g: 
a) C o m pe nsati o n is s u p plie d at eac h st u d y visit. 
b)  Partici pa nts ma y disc o nti n ue partici pati o n i n t he st u d y at a n y p oi nt. 
c) Wit h dra wi n g fr o m t he st u d y will n ot res ult i n a n y a d verse c o nse q ue nces t o t he partici pa nts. 
Pr otecti o n A g ai nst Ris k  
A d verse e ve nts relate d t o st u d y me dicati o n 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 2 3 of 2 8  
 
T he i nf or me d c o nse nt pr ocess will be use d t o t h or o u g hl y e d ucate partici pa nts a n d pare nts/ g uar dia ns 
a b o ut p ote ntial me dicati o n-relate d ris ks, i ncl u di n g a d verse e ve nts.  T his disc ussi o n will i ncl u de t h or o u g h 
re vie w of a d verse e ve nts ass ociate d wit h oral N -acet ylc ystei ne treat me nt.  Ri g or o us scree ni n g pr oce d ures 
a n d strict e xcl usi o n criteria are desi g ne d t o e xcl u de p ote ntial partici pa nts at ele vate d ris k f or a d verse e ve nts.  
T he  st u d y  me dical  cli nicia n  will  c o n d uct  serial  a d verse  e ve nts  m o nit ori n g  as  part  of  me dicati o n 
ma na ge me nt.  Partici pa nts a n d pare nts/ g uar dia ns will ha ve access t o t he st u d y me dical cli nicia n 2 4 h o urs, 
7  da ys  a  wee k  f or  e mer ge ncies.      Partici pa nts  e x perie nci n g  i nt olera ble  a d verse  e ve nts  will  ha ve  t he 
o p p ort u nit y t o re d uce d ose or disc o nti n ue me dicati o n alt o get her, w hile re mai ni n g i n t he st u d y f or o n g oi n g 
m o nit ori n g.    M PI  Gra y  has  f ull  h os pital  a d mitti n g  pri vile ges  i n  t he  e ve nt  of  a n  a d verse  e ve nt  re q uiri n g 
h os pitalizati o n.    Uri ne  pre g na nc y  tests  will  be  c o n d ucte d  at  baseli ne  a n d  seriall y  d uri n g  treat me nt  f or  
partici pa nts assi g ne d fe male at birt h. 
L oss of c o nfi de ntialit y 
T he researc h tea m has esta blis he d pr oce d ures i n place t o mi ni mize t he ris k of a n y c o nfi de ntialit y breac h.  
Partici pa nt  rec or ds  are  st ore d  i n  l oc ke d  files  wit hi n  l oc ke d  offices  t hat  are  l oc ke d  d uri n g  h oli da ys, 
wee ke n ds, a n d n o n- w or ki n g h o urs.  I nf or mati o n c o ntai ne d i n c o m p uter data bases is pass w or d pr otecte d, 
mai ntai ne d b y partici pa nt n u m ber o nl y, a n d de v oi d of s pecific i de ntifiers.  N o s pecific or ge neral partici pa nt 
i nf or mati o n  will  be  left  i n  p u blic  access  areas,  a n d  n o  oral  c o m m u nicati o n  re gar di n g  partici pa nts  wit h 
i de ntifiers will be ma de i n a n y p u blic areas.  Researc h staff me m bers ha ve ha d e xte nsi ve trai ni n g i n HI P A A 
re g ulati o ns a n d i n mai ntai ni n g c o nfi de ntialit y. 
Ve ni p u nct ure-ass ociate d ris ks 
T he bl o o d dra ws f or alc o h ol use bi o mar ker testi n g will be c o n d ucte d b y a n e x perie nce d p hle b ot o mist 
wit h  all  re q uire d  trai ni n g  a n d  certificati o n.  A n y  c o ncer ns  or  iss ues  relate d  t o  t he  bl o o d  dra w  will  be 
a d dresse d as nee de d. 
1 6. 0  P ote nti al Be nefits t o S u bjects  or Ot hers  
Partici pa nts i n t his st u d y, re gar dless of ra n d o mizati o n t o acti ve or place b o me dicati o n, ma y be nefit b y 
recei vi n g a) c o m pre he nsi ve me dical a n d ps yc hiatric e val uati o n, a n d b) brief alc o h ol i nter ve nti o n t hr o u g h o ut 
acti ve treat me nt.   
T he p ote ntial be nefits of t he k n o wle d ge t o be gai ne d fr o m t he pr o p ose d st u d y are c o nsi dera ble. T he 
pr o p ose d st u d y will a ns wer i m p orta nt q uesti o ns re gar di n g t he p ote ntial of N A C as a p har mac ot hera p y f or 
a d olesce nt  A U D,  w hile  als o  e val uati n g  de vel o p me ntall y-i nf or me d  met h o ds  t o  g ui de  f ut ure 
p har mac ot hera p y trials f or a d olesce nt A U D. T he pla ns f or m o nit ori n g ris k as descri be d a b o ve warra nt t he 
c o n d uct of t his st u d y f or t he k n o wle d ge t hat ma y reas o na bl y be e x pecte d t o res ult. 
1 7. 0  S h ari n g of Res ults wit h S u bjects  
At t he c o ncl usi o n of st u d y partici pa nt pr oce d ures (after t he last data p oi nt is e ntere d f or t he last 
partici pa nt), t he ra n d o mizati o n assi g n me nts will be u n bli n de d.  Partici pa nts ma y c o ntact t he 
researc h tea m at t hat p oi nt t o lear n t heir treat me nt assi g n me nts (i.e., N A C or place b o).  T he 
researc h tea m will als o welc o me i n q uiries fr o m partici pa nts o n t he o verall res ults of t he trial, 
w hic h will als o be pr o vi de d via scie ntific p u blicati o n a n d p osti n g t o cli nicaltrials. g o v. 
1 8. 0  Dr u gs or De vices  
N A C a n d place b o ca ps ules will be c o m p o u n de d a n d dis pe nse d b y t he M U S C I n vesti gati o nal Dr u g 
Ser vice, usi n g esta blis he d met h o ds acr oss m ulti ple ot her N A C trials. 
T he Pri nci pal I n vesti gat or ( Dr. Gra y) h ol ds a n I N D f or N A C, a n d has s u b mitte d a n I N D a me n d me nt 
re q uest t o a d d t his pr ot oc ol. 
Refere nces  


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 2 4 of 2 8  
 
1. S we n dse n, J., B urstei n, M., Case, B., C o n wa y, K. P., Dier ker, L., He, J., & Meri ka n gas, K. R. ( 2 0 1 2). 
Use a n d a b use of alc o h ol a n d illicit dr u gs i n U S a d olesce nts: Res ults of t he Nati o nal C o m or bi dit y 
S ur ve y- A d olesce nt S u p ple me nt. Arc hives of Ge ner al Psyc hi atry, 6 9 ( 4), 3 9 0- 3 9 8. 
2. Deas, D., & T h o mas, S. ( 2 0 0 2). C o m or bi d ps yc hiatric fact ors c o ntri b uti n g t o a d olesce nt alc o h ol a n d 
ot her dr u g use. Alc o h ol Rese arc h & He alt h, 2 6 ( 2), 1 1 6- 1 2 1. 
3. R o we, C. L., Li d dle, H. A., Gree n ba u m, P. E., & He n ders o n, C. E. ( 2 0 0 4). I m pact of ps yc hiatric 
c o m or bi dit y o n treat me nt of a d olesce nt dr u g a b users. J o ur n al of S u bst a nce A b use Tre at me nt, 2 6 ( 2), 
1 2 9- 1 4 0. 
4. Kristja nss o n, A. L., Si gf us d ottir, I. D., & Alle gra nte, J. P. ( 2 0 1 3). A d olesce nt s u bsta nce use a n d peer 
use: A m ultile vel a nal ysis of cr oss-secti o nal p o p ulati o n data. S u bst a nce A b use Tre at me nt, Preve nti o n, 
a n d P olicy, 8 ( 2 7). 
5. S q ue glia, L. M., & Gra y, K. M. ( 2 0 1 6). Alc o h ol a n d dr u g use a n d t he de vel o pi n g brai n. C urre nt 
Psyc hi atry Re p orts, 1 8 , 4 6. P M CI D: P M C 4 8 8 3 0 1 4 
6. S q ue glia, L. M., Jac o b us, J., & Ta pert, S. F. ( 2 0 1 4). T he effect of alc o h ol use o n h u ma n a d olesce nt 
brai n str uct ures a n d s yste ms. H a n d b o ok of Cli nic al Ne ur ol o gy, 1 2 5 , 5 0 1- 5 1 0. P M CI D: P M C 4 3 2 1 7 1 5 
7. S q ue glia, L. M., Ta pert, S. F., S ulli va n, E. V., Jac o b us, J., Mel o y, M. J., R o hlfi n g, T., & Pfeffer ba u m, 
A. ( 2 0 1 5). Brai n de vel o p me nt i n hea v y- dri n ki n g a d olesce nts. A meric a n J o ur n al of Psyc hi atry, 1 7 2 ( 6), 
5 3 1- 5 4 2. P M CI D: P M C 4 4 5 1 3 8 5 
8. De ge n har dt, L., O' L o u g hli n, C., S wift, W., R o ma ni u k, H., Carli n, J., C offe y, C., Hall, W., & Patt o n, G. 
( 2 0 1 3). T he persiste nce of a d olesce nt bi n ge dri n ki n g i nt o a d ult h o o d: Fi n di n gs fr o m a 1 5- year 
pr os pecti ve c o h ort st u d y. B MJ O pe n, 3 ( 8), e 0 0 3 0 1 5 
9. Hi n gs o n, R. W., Heere n, T., & Wi nter, M. R. ( 2 0 0 6). A ge at dri n ki n g o nset a n d alc o h ol de pe n de nce: 
A ge at o nset, d urati o n, a n d se verit y. Arc hives of Pe di atrics a n d A d olesce nt Me dici ne, 1 6 0 ( 7), 7 3 9-
7 4 6. 
1 0. Hi n gs o n, R. W., Heere n, T., & Wi nter, M. R. ( 2 0 0 6). A ge of alc o h ol- de pe n de nce o nset: Ass ociati o ns 
wit h se verit y of de pe n de nce a n d see ki n g treat me nt. Pe di atrics, 1 1 8 ( 3), e 7 5 5- 7 6 3. 
1 1. Je nse n, C. D., C us hi n g, C. C., A yl war d, B. S., Crai g, J. T., S orell, D. M., & Steele, R. G. ( 2 0 1 1). 
Effecti ve ness of m oti vati o nal i nter vie wi n g i nter ve nti o ns f or a d olesce nt s u bsta nce use be ha vi or 
c ha n ge:  A meta-a nal ytic re vie w. J o ur n al of C o ns ulti n g a n d Cli nic al Psyc h ol o gy, 7 9 ( 4), 4 3 3- 4 4 0. 
1 2. Tri p o di, S. J., Be n der, K., Litsc h ge, C., & Va u g h n, M. G. ( 2 0 1 0). I nter ve nti o ns f or re d uci n g 
a d olesce nt alc o h ol a b use: A meta-a nal ytic re vie w. Arc hives of Pe di atrics a n d A d olesce nt Me dici ne, 
1 6 4 ( 1), 8 5- 9 1. 
1 3. Br o w n, S. A., Gle g h or n, A., Sc h uc kit, M. A., M yers, M. G., & M ott, M. A. ( 1 9 9 6). C o n d uct dis or der 
a m o n g a d olesce nt alc o h ol a n d dr u g a b users. J o ur n al of St u dies o n Alc o h ol, 5 7 , 3 1 4- 3 2 4. 
1 4. Wi nters, K. C., Sti nc hfiel d, R. D., O pla n d, E., Weller, C., & Lati mer, W. W. ( 2 0 0 0). T he effecti ve ness 
of t he Mi n nes ota M o del a p pr oac h i n t he treat me nt of a d olesce nt dr u g a b users. A d dicti o n, 9 5 , 6 0 1 –
6 1 2. 
1 5. Mira n da, R., Ra y, L., Bla nc har d, A., Re y n ol ds, E. K., M o nti, P. M., C h u n, T., J ust us, A., S wift, R. M., 
Ti de y, J., G walt ne y, C. J., & Ra mirez, J. ( 2 0 1 4). Effects of naltre x o ne o n a d olesce nt alc o h ol c ue 
reacti vit y a n d se nsiti vit y: A n i nitial ra n d o mize d trial. A d dicti o n Bi ol o gy, 1 9 ( 5), 9 4 1- 9 5 4. 
1 6. Bri d ge, J. A., I ye n gar, S., Salar y, C. B., Bar be, R. P., Bir ma her, B., Pi nc us, H. A., Re n, L., & Bre nt, 
D. A. ( 2 0 0 7). Cli nical res p o nse a n d ris k f or re p orte d s uici dal i deati o n a n d s uici de atte m pts i n pe diatric 
a nti de pressa nt treat me nt: A meta-a nal ysis of ra n d o mize d c o ntr olle d trials. J o ur n al of t he A meric a n 
Me dic al Ass oci ati o n, 2 9 7 ( 1 5), 1 6 8 3- 1 6 9 6. 


Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 2 5 of 2 8  
 
1 7. Gra n djea n, E. M., Bert het, P., R uff ma n, R., & Le ue n ber ger, P. ( 2 0 0 0).  Efficac y of oral l o n g-ter m 
N -acet ylc ystei ne i n c hr o nic br o nc h o p ul m o nar y disease: A meta-a nal ysis of p u blis he d, d o u ble- bli n d, 
place b o-c o ntr olle d cli nical trials.  Cli nic al T her a pe utics, 2 2 , 2 0 9- 2 2 1. 
1 8. Baile y, B., & Mc G ui ga n, M. A. ( 1 9 9 8). Ma na ge me nt of a na p h ylact oi d reacti o ns t o i ntra ve n o us N-
acet ylc ystei ne. A n n als of E mer ge ncy Me dici ne, 3 1 ( 6), 7 1 0- 7 1 5. 
1 9. Bac k, S. E., Mc Ca ule y, J. L., K orte, K. J., Gr os, D. F., Lea vitt, V., Gra y, K. M., Ha m ner, M. B., 
De Sa ntis, S. M., Malc ol m, R., Bra d y, K. T., & Kali vas, P. W. ( 2 0 1 6). A d o u ble- bli n d ra n d o mize d 
c o ntr olle d pil ot trial of N-acet ylc ystei ne i n Vetera ns wit h P T S D a n d s u bsta nce use dis or ders. J o ur n al 
of Cli nic al Psyc hi atry, 7 7 , e 1 4 3 9-e 1 4 4 6. P M CI D: P M C 5 2 2 6 8 7 3 
2 0. Fr oeli ger, B., Mc C o n nell, P. A., Sta n ke vici ute, N., Mc Cl ure, E. A., Kali vas, P. W., & Gra y, K. M. 
( 2 0 1 5). T he effects of N -acet ylc ystei ne o n fr o nt ostriatal resti n g-state f u ncti o nal c o n necti vit y, 
wit h dra wal s y m pt o ms a n d s m o ki n g a bsti ne nce: A d o u ble- bli n d, place b o-c o ntr olle d f M RI st u d y. Dr u g 
a n d Alc o h ol De pe n de nce, 1 5 6 , 2 3 4- 2 4 2. P M CI D: P M C 4 6 3 3 3 2 0 
2 1. Gra y, K. M., Car pe nter, M. J., Ba ker, N. L., De Sa ntis, S. M., Kr y wa y, E., Hart well, K. J., Mc Rae-
Clar k, A. L., & Bra d y, K. T. ( 2 0 1 2). A d o u ble- bli n d ra n d o mize d c o ntr olle d trial of N -acet ylc ystei ne i n 
ca n na bis- de pe n de nt a d olesce nts. A meric a n J o ur n al of Psyc hi atry, 1 6 9 , 8 0 5- 8 1 2. P M CI D: 
P M C 3 4 1 0 9 6 1 
2 2. Gra y, K. M., S o n ne, S. C., Mc Cl ure, E. A., G hitza, U. E., Matt he ws, A. G., Mc Rae- Clar k, A. L., 
Carr oll, K. M., P otter, J. S., Wiest, K., M o o ne y, L. J., Hass o n, A., Wals h, S. L., L of wall, M. R., 
Ba bal o nis, S., Li n d bla d, R. W., S pare n b or g, S., Wa hle, A., Ki n g, J. S., Ba ker, N. L., T o m k o, R. L., 
Ha y nes, L. F., Va n dre y, R. G., & Le vi n, F. R. ( 2 0 1 7). A ra n d o mize d place b o-c o ntr olle d trial of N -
acet ylc ystei ne f or ca n na bis use dis or der i n a d ults. Dr u g a n d Alc o h ol De pe n de nce, 1 7 7 , 2 4 9- 2 5 7. 
P M CI D: P M C 5 5 3 5 8 1 3 
2 3. La R o we, S. D., Kali vas, P. W., Nic h olas, J. S., Ra n dall, P. K., Mar di kia n, P. N., & Malc ol m, R. J. 
( 2 0 1 3). A d o u ble- bli n d place b o-c o ntr olle d trial of N-acet ylc ystei ne i n t he treat me nt of c ocai ne 
de pe n de nce. T he A meric a n J o ur n al o n A d dicti o ns, 2 2 ( 5), 4 4 3- 4 5 2. P M CI D: P M C 4 3 4 8 5 7 5 
2 4. Mc Cl ure, E. A., Ba ker, N. L., Gi ps o n, C. D., Car pe nter, M. J., R o per, A. P., Fr oeli ger, B. E., & Gra y, 
K. M. ( 2 0 1 5). A n o pe n-la bel pil ot trial of N-acet ylc ystei ne a n d vare nicli ne i n a d ult ci garette s m o kers. 
T he A meric a n J o ur n al of Dr u g a n d Alc o h ol A b use, 4 1 , 5 2- 5 6. P M CI D: P M C 4 2 6 2 7 4 0 
2 5. S q ue glia, L. M., Ba ker, N. L., Mc Cl ure, E. A., T o m k o, R. L., A diseti y o, V. & Gra y, K. M. ( 2 0 1 6). 
Alc o h ol use d uri n g a trial of N-acet ylc ystei ne f or a d olesce nt marij ua na cessati o n. A d dictive 
Be h avi ors, 6 3 , 1 7 2- 1 7 7. P M CI D: P M C 4 9 9 3 6 5 5 
2 6. S q ue glia, L. M., T o m k o, R. L., Ba ker, N. L., Mc Cl ure, E. A., B o o k, G. A., & Gra y, K. M. ( 2 0 1 8). T he 
effect of N-acet ylc ystei ne o n alc o h ol use d uri n g a ca n na bis cessati o n trial. Dr u g a n d Alc o h ol 
De pe n de nce, 1 8 5 , 1 7- 2 2. ( P M CI D J o ur nal – I n Pr ocess) 
2 7. Kali vas, P. W., & V ol k o w, N. D. ( 2 0 1 1). Ne w me dicati o ns f or dr u g a d dicti o n hi di n g i n gl uta mater gic 
ne ur o plasticit y. M olec ul ar Psyc hi atry, 1 6 ( 1 0), 9 7 4- 9 8 6. 
2 8. La L u miere, R. T., & Kali vas, P. W. ( 2 0 0 8). Gl uta mate release i n t he n ucle us acc u m be ns c ore is 
necessar y f or her oi n see ki n g. J o ur n al of Ne ur oscie nce, 2 8 ( 1 2), 3 1 7 0- 3 1 7 7. 
2 9. Mc Farla n d, K., La pis h, C. C., & Kali vas, P. W. ( 2 0 0 3). Prefr o ntal gl uta mate release i nt o t he c ore of 
t he n ucle us acc u m be ns me diates c ocai ne-i n d uce d rei nstate me nt of dr u g-see ki n g be ha vi or. J o ur n al of 
Ne ur oscie nce, 2 3 ( 8), 3 5 3 1- 3 5 3 7. 
3 0. Mc Cl ure, E. A., Gi ps o n, C. D., Malc ol m, R. J., Kali vas, P. W., & Gra y, K. M. ( 2 0 1 4). P ote ntial r ole 
of N -acet ylc ystei ne i n t he ma na ge me nt of s u bsta nce use dis or ders. C N S Dr u gs, 2 8 , 9 5- 1 0 6. P M CI D: 
P M C 4 0 0 9 3 4 2 
3 1. R o berts- W olfe, D. J., & Kali vas, P. W. ( 2 0 1 5). Gl uta mate tra ns p orter G L T- 1 as a t hera pe utic tar get 
f or s u bsta nce use dis or ders. C N S & Ne ur ol o gic al Dis or ders – Dr u g T ar gets, 1 4 ( 6), 7 4 5- 7 5 6. 


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3 2. D uaili bi, M. S., C or deir o, Q., Brietz ke, E., Ri beir o, M., La R o we, S., Ber k, M., & Tre viz ol, A. P. 
( 2 0 1 7). N-acet ylc ystei ne i n t he treat me nt of cra vi n g i n s u bsta nce use dis or ders: S yste matic re vie w a n d 
meta -a nal ysis. A meric a n J o ur n al o n A d dicti o ns, 2 6 ( 7), 6 6 0- 6 6 6. 
3 3. Q ui nta nilla, M. E., Ri vera- Meza, M., Berrí os- Cárca m o, P., Sali nas- L u y paert, C., Herrera- Marsc hitz, 
M., & Israel, Y. ( 2 0 1 6). Be y o n d t he “first hit”: Mar ke d i n hi biti o n b y N-acet yl c ystei ne of c hr o nic 
et ha n ol i nta ke b ut n ot of earl y et ha n ol i nta ke. Parallel effects o n et ha n ol-i n d uce d sacc hari n 
m oti vati o n. Alc o h olis m: Cli nic al a n d Ex peri me nt al Rese arc h, 4 0 ( 5), 1 0 4 4- 1 0 5 1. 
3 4. Le b o ur ge ois, S., G o nzález- Marí n, M. C., Jea n bla nc, J., Naassila, M., & Vil p o u x, C. ( 2 0 1 8). Effect of 
N-acet ylc ystei ne o n m oti vati o n, see ki n g a n d rela pse t o et ha n ol self-a d mi nistrati o n. A d dicti o n Bi ol o gy, 
2 3 ( 2), 6 4 3- 6 5 2. 
3 5. Sc h nei der, R. Jr, Ba n diera, S., S o uza, D. G., Bella ver, B., Caletti, G., Q ui nc ozes- Sa nt os, A., 
Elisa bets k y, E., & G o mez, R. ( 2 0 1 7). N-acet ylc ystei ne pre ve nts alc o h ol relate d ne ur oi nfla m mati o n i n 
rats. Ne ur oc he mic al Rese arc h, 4 2 ( 8), 2 1 3 5- 2 1 4 1. 
3 6. M oceli n, R., Marc o n, M., D’a m br os, S., Herr ma n n, A. P., da R osa Ara uj o, A. S., & Piat o, A. ( 2 0 1 8). 
Be ha vi oral a n d bi oc he mical effects of N-acet ylc ystei ne i n ze brafis h ac utel y e x p ose d t o et ha n ol. 
Ne ur oc he mic al Rese arc h, 4 3 ( 2), 4 5 8- 4 6 4. 
3 7. Car ne y, M. A., Te n ne n, H., Afflec k, G., Del B oca, F. K., & Kra nzler, H. R. ( 1 9 9 8). Le vels a n d 
patter ns of alc o h ol c o ns u m pti o n usi n g ti meli ne f oll o w- bac k, dail y diaries a n d real-ti me "electr o nic 
i nter vie ws". J o ur n al of St u dies o n Alc o h ol, 5 9 , 4 4 7- 4 5 4.  
3 8. Searles, J. S., Helzer, J. E., R ose, G. L., & Ba d ger, G. J. ( 2 0 0 2). C o nc urre nt a n d retr os pecti ve re p orts 
of alc o h ol c o ns u m pti o n acr oss 3 0, 9 0 a n d 3 6 6 da ys: i nteracti ve v oice res p o nse c o m pare d wit h t he 
ti meli ne f oll o w bac k. J o ur n al of St u dies o n Alc o h ol , 6 3 ( 3), 3 5 2- 3 6 2.  
3 9. Harris, P. A., Ta yl or, R., T hiel ke, R., Pa y ne, J., G o nzalez, N., & C o n de, J. G. ( 2 0 0 9). Researc h 
electr o nic data ca pt ure ( R E D Ca p) — A meta data- dri ve n met h o d ol o g y a n d w or kfl o w pr ocess f or 
pr o vi di n g tra nslati o nal researc h i nf or matics s u p p ort. J o ur n al of Bi o me dic al I nf or m atics, 4 2 , 3 7 7- 3 8 1. 
4 0. T o m k o, R. L., Gra y, K. M., O p pe n hei mer, S. R., Wa hl q uist, A. E., & Mc Cl ure, E. A. (i n press). Usi n g 
R E D Ca p f or a m b ulat or y assess me nt: I m ple me ntati o n i n a cli nical trial f or s m o ki n g cessati o n t o 
a u g me nt i n- pers o n data c ollecti o n. A meric a n J o ur n al of Dr u g a n d Alc o h ol A b use.  
4 1. Mc Ca n n, D. J., Petr y, N. M., Bresell, A., Isacss o n, E., Wils o n, E., & Ale xa n der, R. C. ( 2 0 1 5). 
Me dicati o n n o na d here nce, “ pr ofessi o nal s u bjects,” a n d a p pare nt place b o res p o n ders: o verla p pi n g 
c halle n ges f or me dicati o ns de vel o p me nt. J o ur n al of Cli nic al Psyc h o p h ar m ac ol o gy, 3 5 , 5 6 6- 5 7 3.  
4 2. Mc Rae- Clar k, A. L., Ba ker, N. L., S o n ne, S. C., De Va ne, C. L., Wa g ner, A., & N ort o n, J. ( 2 0 1 5). 
C o nc or da nce of direct a n d i n direct meas ures of me dicati o n a d here nce i n a treat me nt trial f or ca n na bis 
de pe n de nce. J o ur n al of S u bst a nce A b use Tre at me nt, 5 7 , 7 0- 7 4. 
4 3. A n ders o n, A. L., Li, S. H., Mar k o va, D., H ol mes, T. H., C hia n g, N., Ka h n, R., … El kas hef, A. M. 
( 2 0 1 5). B u pr o pi o n f or t he treat me nt of met ha m p heta mi ne de pe n de nce i n n o n- dail y users: A 
ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d trial. Dr u g a n d Alc o h ol De pe n de nce, 1 5 0 , 1 7 0- 1 7 4. 
4 4. Carr oll, K. M., & R o u nsa ville, B. J. ( 2 0 0 7). A perfect platf or m: C o m bi ni n g c o nti n ge nc y ma na ge me nt 
wit h me dicati o ns f or dr u g a b use. A meric a n J o ur n al of Dr u g a n d Alc o h ol A b use, 3 3 ( 3), 3 4 3- 3 6 5. 
4 5. Le d ger w o o d, D. M., Alessi, S. M., Ha ns o n, T., G o dle y, M. D., & Petr y, N. M. ( 2 0 0 8). C o nti n ge nc y 
ma na ge me nt f or atte n da nce t o gr o u p s u bsta nce a b use treat me nt a d mi nistere d b y cli nicia ns i n 
c o m m u nit y cli nics. J o ur n al of A p plie d Be h avi or A n alysis, 4 1 ( 4), 5 1 7- 5 2 6. 
4 6. Si n ha, R., East o n, C., Re nee- A u bi n, L., & Carr oll, K. M. ( 2 0 0 3). E n ga gi n g y o u n g pr o bati o n-referre d 
marij ua na-a b usi n g i n di vi d uals i n treat me nt: A pil ot trial. T he A meric a n J o ur n al o n A d dicti o ns, 1 2 ( 4), 
3 1 4- 3 2 3. 


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4 7. Festi n ger, D. S., Marl o we, D. B., D u g os h, K. L., Cr oft, J. R., & Ara bia, P. L. ( 2 0 0 8). Hi g her 
ma g nit u de cas h pa y me nts i m pr o ve researc h f oll o w- u p rates wit h o ut i ncreasi n g dr u g use or percei ve d 
c oerci o n. Dr u g a n d Alc o h ol De pe n de nce, 9 6 ( 1- 2), 1 2 8- 1 3 5. 
4 8. Ca vall o, D. A., Nic h, C., Sc he pis, T. S., S mit h, A. E., Liss, T. B., Mc Fetri d ge, A. K., & Kris h na n-
Sari n, S. ( 2 0 1 0). Preli mi nar y e xa mi nati o n of a d olesce nt s pe n di n g i n a c o nti n ge nc y ma na ge me nt base d 
s m o ki n g cessati o n pr o gra m. J o ur n al of C hil d a n d A d olesce nt S u bst a nce A b use, 1 9 ( 4), 3 3 5- 3 4 2. 
4 9. S q ue glia, L. M., Ball, T. M., Jac o b us, J., Br u m bac k, T., Mc Ke n na, B. S., N g u ye n- L o uie, T. T., S or g, 
S. F., Pa ul us, M. P., & Ta pert, S. F. ( 2 0 1 7). Ne ural pre dict ors of i nitiati n g alc o h ol use d uri n g 
a d olesce nce. T he A meric a n J o ur n al of Psyc hi atry, 1 7 4 ( 2), 1 7 2- 1 8 5. P M CI D: P M C 5 2 8 8 1 3 1 
5 0. S ulli va n, J. T., S y k ora, K., Sc h nei der ma n, J., Nara nj o, C. A., & Sellers, E. M. ( 1 9 8 9). Assess me nt of 
alc o h ol wit h dra wal: T he re vise d cli nical i nstit ute wit h dra wal assess me nt f or alc o h ol scale ( CI W A- Ar). 
Britis h J o ur n al of A d dicti o n, 8 4 ( 1 1), 1 3 5 3- 1 3 5 7. 
5 1. Hser, Y. I., Grella, C. E., H u b bar d, R. L., Hsie h, S. C., Fletc her, B. W., Br o w n, B. S., & A n gli n, M. D. 
( 2 0 0 1). A n e val uati o n of dr u g treat me nts f or a d olesce nts i n 4 U S cities. Arc hives of Ge ner al 
Psyc hi atry, 5 8 ( 7), 6 8 9- 6 9 5. 
5 2. Nati o nal I nstit ute o n Alc o h ol A b use a n d Alc o h olis m. ( 2 0 1 5). Alc o h ol Scree ni n g a n d Brief 
I nter ve nti o n f or Y o ut h: A Practiti o ner's G ui de. 
5 3. S o bell, L. C., & S o bell, M. B. ( 1 9 9 2). Ti mli ne f oll o w- bac k: A tec h ni q ue f or assessi n g self-re p orte d 
alc o h ol c o ns u m pti o n. Me as uri n g Alc o h ol C o ns u m pti o n: Psyc h os oci al a n d Bi oc he mic al Met h o ds , 4 1-
7 2. 
5 4. S hee ha n, D. V., Lecr u bier, Y., Har nett- S hee ha n, K., A m ori m, P., Ja na vs, J., Weiller, E., Her g ueta, T., 
Ba ker,  R.,  &  D u n bar,  G.  ( 1 9 9 8).  T he  Mi ni-I nter nati o nal  Ne ur o ps yc hiatric  I nter vie w  ( M.I. N.I.):  t he 
de vel o p me nt a n d vali dati o n of a str uct ure d dia g n ostic ps yc hiatric i nter vie w f or D S M-I V a n d I C D- 1 0. 
J o ur n al of Cli nic al Psyc hi atry, 5 9 , S 2 2- S 3 3. 
5 5. S hee ha n, D. V., S hee ha n, K. H., S h ytle, R. D., Ja na vs, J., Ba n n o n, Y., R o gers, J. E., Mil o, K. M., 
St oc k, S. L., & Wil ki ns o n, B. ( 2 0 1 0). Relia bilit y a n d vali dit y of t he Mi ni I nter nati o nal 
Ne ur o ps yc hiatric I nter vie w f or C hil dre n a n d A d olesce nts ( MI NI- KI D). J o ur n al of Cli nic al 
Psyc hi atry, 7 1 , 3 1 3- 3 2 6. 
5 6. A nt o n, R. F., Lie ber, C., Ta ba k off, B., & Gr o u p, C. D. S. ( 2 0 0 2). Car b o h y drate- deficie nt tra nsferri n 
a n d ga m ma- gl uta m yltra nsferase f or t he detecti o n a n d m o nit ori n g of alc o h ol use: Res ults fr o m a 
m ultisite st u d y. Alc o h olis m: Cli nic al a n d Ex peri me nt al Rese arc h, 2 6 ( 8), 1 2 1 5- 1 2 2 2. 
5 7. Litte n, R. Z., & Alle n, J. P. ( 1 9 9 5). P har mac ot hera p y f or alc o h olics wit h c ollateral de pressi o n or 
a n xiet y: A n u p date of researc h fi n di n gs. Ex peri me nt al a n d Cli nic al Psyc h o p h ar m ac ol o gy, 3 ( 1), 8 7- 9 3. 
5 8. Litte n, R. Z., Bra dle y, A. M., & M oss, H. B. ( 2 0 1 0). Alc o h ol bi o mar kers i n a p plie d setti n gs: Rece nt 
a d va nces a n d f ut ure researc h o p p ort u nities. Alc o h olis m: Cli nic al a n d Ex peri me nt al Rese arc h, 3 4 ( 6), 
9 5 5- 9 6 7.  
5 9. L o we, J. M., Mc D o nell, M. G., Leic kl y, E., A n gel o, F. A., Vilar da ga, R., Mc P hers o n, S., . . . Ries, R. 
K. ( 2 0 1 5). Deter mi ni n g et h yl gl uc ur o ni de c ut offs w he n detecti n g self-re p orte d alc o h ol use i n 
a d dicti o n treat me nt patie nts. Alc o h olis m: Cli nic al a n d Ex peri me nt al Rese arc h, 3 9 ( 5), 9 0 5- 9 1 0. 
6 0. G ualtieri, C. T., & J o h ns o n, L. G. ( 2 0 0 6). Relia bilit y a n d vali dit y of a c o m p uterize d ne ur oc o g niti ve 
test batter y, C N S Vital Si g ns. Arc hives of Cli nic al Ne ur o psyc h ol o gy, 2 1 ( 7), 6 2 3- 6 4 3. 
6 1. R ote n, A., Ba ker, N. L., & Gra y, K. M. ( 2 0 1 5). C o g niti ve perf or ma nce i n a place b o-c o ntr olle d 
p har mac ot hera p y trial f or y o ut h wit h marij ua na de pe n de nce. A d dicti o n Be h avi or, 4 5 , 1 1 9- 1 2 3. 
P M CI D: P M C 4 3 7 3 9 6 3 
6 2. B yrt, T., Bis h o p, J. & Carli n, J. B. ( 1 9 9 3). Bias, pre vale nce a n d ka p pa. J o ur n al of Cli nic al 
E pi de mi ol o gy, 4 6 , 4 2 3- 4 2 9. 


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6 3. Ze ger, S. L., & Lia n g, K. Y., ( 1 9 8 6). L o n git u di nal data a nal ysis f or discrete a n d c o nti n u o us o utc o mes. 
Bi o metrics, 4 2 , 1 2 1- 1 3 0. 
6 4. Pa n, W. ( 2 0 0 1). A kai ke’s i nf or mati o n criteri o n i n ge neralize d esti mati n g e q uati o ns. Bi o metrics, 5 7 , 
1 2 0- 1 2 5. 
6 5. Hall gre n, K. A., & Wit kie witz, K. ( 2 0 1 3). Missi n g data i n alc o h ol cli nical trials: A c o m paris o n of 
met h o ds. Alc o h olis m: Cli nic al a n d Ex peri me nt al Rese arc h, 3 7 , 2 1 5 2- 2 1 6 0. 
6 6. Wit kie witz, K., Fal k, D. E., Kra nzler, H. R., Litte n, R. Z., Hall gre n, K. A., O’ Malle y, S. S., & A nt o n, 
R. F. ( 2 0 1 4). Met h o ds t o a nal yze treat me nt effects i n t he prese nce of missi n g data f or a c o nti n u o us 
hea v y dri n ki n g o utc o me meas ure w he n partici pa nts dr o p o ut fr o m treat me nt i n alc o h ol cli nical trials. 
Alc o h olis m: Cli nic al a n d Ex peri me nt al Rese arc h, 3 8 , 2 8 2 6- 2 8 3 4. 
6 7. Bar nes, S. A., Larse n, M. D., Sc hr oe der, D., Ha ns o n, A., & Dec ker, P. A. ( 2 0 1 0). Missi n g data 
ass u m pti o ns a n d met h o ds i n a s m o ki n g cessati o n st u d y. A d dicti o n, 1 0 5 , 4 3 1- 4 3 7. 
6 8. Baile y, B., & Mc G ui ga n, M. A. ( 1 9 9 8).  Ma na ge me nt of a na p h ylact oi d reacti o ns t o i ntra ve n o us N -
acet ylc ystei ne.  A n n als of E mer ge ncy Me dici ne, 3 1 , 7 1 0- 7 1 5. 
6 9. Aria n M, Ha q ue M, J o hal L, Mat h ur P, Nel W, Rais A, Sa n d h u R, & S har ma S ( 2 0 1 3). Mat urati o n of 
t he a d olesce nt brai n. Ne ur o psyc hi atr Dis Tre at, 9 , 4 4 9- 4 6 1. P M CI D: P M C 3 6 2 1 6 4 8