A Proof-of-Concept Trial of N-Acetylcysteine for Adolescent Alcohol Use Disorder
Phase: PHASE2
Conditions: Alcohol Use Disorder
Sponsor: Medical University of South Carolina

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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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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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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 

Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
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. 

Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
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 

Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
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). 

Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
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. 

Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
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. 

Versi o n : 1 6; Versi o n Date: 1 1J U L Y 2 0 2 3 
 
Pa ge 2 6 of 2 8  
 
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 
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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