A Randomized, Double-blind, Placebo-controlled Trial of D-cycloserine Augmentation of Behavior Therapy for Body Dysmorphic Disorder
Phase: EARLY_PHASE1
Conditions: Body Dysmorphic Disorder
Sponsor: Massachusetts General Hospital

March 15, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
An investigation of D-cycloserine as a memory enhancer 
NCT00842309 
March 15, 2019 
Sabine Wilhelm, Ph.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
May 23, 2016
May 23, 2016

May 23, 2016 
 
 
2
1. Background and Significance 
BDD is defined as a preoccupation with an imagined defect in 
appearance; if a slight physical anomaly is present, the concern is markedly 
excessive (American Psychiatric Association [APA], 1994).  Preoccupations 
may focus on any body area but commonly involve the face or head, most 
often the skin, hair, or nose (Phillips et al., 1993). These preoccupations 
have an obsessional quality, in that they occur frequently and are usually 
difficult to resist or control (Phillips et al., 1998).  Additionally, more than 
90% of BDD patients perform repetitive, compulsive behaviors (Phillips et 
al., 1998), such as frequent mirror checking (Alliez & Robin, 1969), 
excessive grooming (Vallat et al., 1971), and skin picking (Phillips & Taub, 
1995).   
Accordingly, a core component of Cognitive-Behavioral treatment for 
BDD is exposure and response prevention (ERP).  Exposure and response 
prevention involves asking patients to gradually expose themselves to 
situations that make them anxious (e.g. talking to a stranger, going to a 
party) while refraining from engaging in any rituals (e.g. excessive grooming 
or camouflaging) or safety behaviors (e.g. avoiding eye contact).  Rituals 
and safety behaviors are thought to maintain the fear response because they 
prevent the sufferer from staying in contact with the stimulus long enough 
for his or her anxiety to extinguish.  By exposing the patient to the feared 
situation while preventing the rituals and safety behaviors, the patient’s 
anxiety is allowed to naturally extinguish and he is able to acquire a sense of 
safety in the presence of the feared stimulus.   
 
We know from basic research that such fear extinction does not reflect 
unlearning of the original association but rather the formation of new 
associations that compete with the previously learned conditioned response 
(e.g., Rescorla, 2001), i.e., extinction is new learning.  Fear extinction has 
been shown to be blocked by N-Methyl-D-Aspartate (NMDA) receptor 
antagonists (e.g., Cox & Westbrook, 1994; Lee & Kim, 1998). Thus, it has 
been proposed that NMDA receptor agonists could facilitate fear extinction 
(e.g., Walker, Ressler, Lu, & Davis, 2002).  D-cycloserine (DCS) is an NMDA 
partial agonist and therefore has recently come under study for this purpose.   
Initial work examining the effect of DCS focused primarily on learning 
and memory, in general.  For example, DCS has been shown in pre-clinical 
studies to enhance performance on visual recognition tasks in primates 
(Matsuoka & Aigner, 1996), avoidance learning in rats and mice (e.g., Land & 
Riccio, 1999), eyeblink conditioning in rabbits (Thompson, Moskal, & 
Disterhoftt, 1992), and maze learning in rats and mice (e.g., Monahan et al., 
1989; Pitkanen et al., 1995; Pussinen et al., 1997).  In clinical studies, DCS 
has been found to improve cognitive abilities and disorder-related symptoms 
in populations including individuals with Alzheimer’s Disease, schizophrenia, 
and posttraumatic stress disorder (PTSD; Heresco-Levy et al., 2002; Javitt et 
al., 1994; Schwartz et al., 1996; Goff et al., 1999; Tsai et al., 1999).   

May 23, 2016 
 
 
3
More recently, however, research on DCS has shown that it may 
specifically promote the extinction of conditioned fear.   This is of particular 
clinical relevance because a reduced ability to extinguish fear associations is 
a significant problem in a variety of anxiety disorders, such as height 
phobias, panic disorder, PTSD, and OCD (e.g., Morgan et al., 1995; Fyer, 
1998; Gorman et al., 2000).  The treatment of anxiety disorders commonly 
involves the extinction of maladaptive fear associations (e.g., Zarate & 
Agras, 1994; Foa, 2000). Thus, it seems reasonable that pharmacological 
enhancement of fear extinction by DCS could be of great clinical relevance 
(Davis, 2002).  Indeed, recent clinical studies suggest that DCS can facilitate 
extinction-based behavioral treatments.  In the first study demonstrating 
this effect, Ressler and colleagues randomized patients with height phobia to 
received DCS (500mg/d or 50mg/d) or placebo prior to 2 sessions of 
exposure therapy (Ressler, Rothbaum, Tannenbaum, Anderson, Graap, 
Zimand, Hodges, & Davis, 2004).  Those patients who received DCS prior to 
the therapy improved significantly more than the placebo comparison group. 
There were no differences between the group who received 50mg/d and the 
group who received 500mg/d, although there may have been a slight trend 
in favor of the latter (Ressler et al., 2004). 
Since this initial trial, DCS has been found to augment behavior 
therapy in the treatment of Social Anxiety Disorder (Hofmann et al., 2006), 
Obsessive Compulsive Disorder (Wilhelm et al., 2008; Kushner et al., 2007) 
and Panic Disorder (Otto et al., submitted).    
Side effects of DCS in human beings have been minimal.  DCS has 
been widely used in the treatment of tuberculosis (500mg per day or higher), 
without causing neurotoxicity (e.g., Rivas Salazar, 1970).  Goff et al. (1999) 
reported that only one patient dropped out of a schizophrenia study because 
of vague somatic discomfort. van Berckel et al. (1997) tested DCS in healthy 
participants and found that it was well tolerated and did not induce any side 
effects.  In our recent trial examining the efficacy of DCS augmentation of 
behavior therapy for Obsessive Compulsive Disorder, no subjects reported 
any side effects as a result of the medication.  DCS readily crosses the blood-
brain barrier (Hanngren, Hansson, & Ullberg, 1961).  Its half-life in serum is 
approximately 7 to 15 hours (Nair, Epstein, Baron, & Mulinos, 1956). 
Altogether, when added to exposure therapy, DCS seems to be a 
promising treatment for patients suffering from anxiety. In the current study, 
we are planning to investigate DCS augmentation of exposure therapy for 
BDD. Consistent with our previous trial of DCS in OCD, we intend to 
administer 100mg of DCS one hour before each treatment session.  The dose 
was chosen on the basis of a literature review and personal communication 
with Dr. Goff and Dr. Ressler (the lead-author of the above mentioned DCS 
height phobia trial). The timing of the dose relative to the therapy session 
was chosen on the basis of feedback from Dr. Ressler.   As noted above, 
Ressler et al. (2004) found a significant reduction of height phobia severity 

May 23, 2016 
 
 
4
with 500mg/d of DCS, and they did not report any side effects at this 
dosage. In order to test whether DCS specifically works through augmenting 
fear extinction within ERP, DCS will only be administered one hour before 
each treatment session, and not on a daily basis. This will be in contrast to 
Goff et al. (1995), who administered DCS daily to improve negative 
symptoms in schizophrenia, but in accord with Ressler et al., (2004) who 
only gave DCS prior to each behavior treatment session for height phobia.  
This trial also presents a unique opportunity to examine genetic and 
biological mediators of treatment response to extinction-based interventions.  
Accordingly, we have added an optional genetics component to this study for 
willing participants.  Although genetic association studies have been plagued 
by concerns that reported associations may be spurious and difficult to 
replicate, a key strategy for minimizing the risk of Type I error is selecting 
candidate loci with the highest prior probability of association.  Fortunately, 
compelling candidate loci with strong probability of involvement in NMDA-
receptor mediated fear extinction are readily available due to the growing 
body of work on the molecular basis of this phenomenon. Specifically we will 
focus our analyses on genes that meet one or more of the following criteria: 
(a) encodes a subunit of NMDA receptors involved in fear 
conditioning/extinction, (b) involved in the action of DCS or d-serine co-
activation of NMDA receptors, or (c) gene product shown to mediate fear 
extinction in preclinical models. Based on review of the literature, we 
selected loci that meet these criteria and have the strongest supportive 
evidence.   
Studies of the molecular mechanism of fear memory acquisition on the 
one hand and extinction on the other have demonstrated that the receptors, 
ligands, and signaling cascades involved overlap but are not identical (Lin et 
al. 2003).  We will therefore focus on genes involved specifically in extinction 
pathways. These include genes encoding NR1 and NR2 subunits that make 
up NMDA receptors subunits involved in fear extinction (Stoppel et al., 
2006).  In particular, GRIN1 encodes the NR1 subunit that contains the 
glycine/serine binding site.  NMDA receptor activation requires binding of 
glycine or serine as a co-activator and DCS binds to this site.  The NMDA 
receptor NR2A subunit (encoded by GRIN2A) and the NR2B subunit 
(GRIN2B) are also integral to NMDA receptors involved in fear extinction 
learning.  It is now known that NR1-NR2A heterodimers constitute the 
functional unit of NMDA receptor ion channel opening (Furukawa et al., 
2005). Transgenic overexpression of GRIN2B is associated with enhance fear 
extinction (Tang et al., 1999; Tang et al. 2001).  The activity of d-serine at 
NMDA receptors is attentuated by its degradation by d-amino acid oxidase 
(encoded by DAAO) (Mothet, 2000). Recently, genetic studies of 
schizophrenia led to the discovery of an activator of DAAO, now known as d-
amino acid oxidase activator (DAOA, formerly G72 

May 23, 2016 
 
 
5
In addition to these genes involved in NMDA receptor and d-serine 
activity, several additional proteins and genes have been strongly implicated 
in fear extinction. These include brain derived neurotrophic factor (BDNF). 
Chhatwal et al. (2006) and Rattiner et al. (2004) have demonstrated that 
amygdala BDNF signaling via the TrkB receptor (encoded by NTRK2) is 
essential for consolidation of extinction memories. BDNF and TrkB signaling 
activate the intracellular MAPK and PI-3 kinase pathways that have been 
shown to be central to the facilitation of fear extinction by DCS (Yang et al., 
2005; Ou et al., 2006). Of note, serum BDNF levels have been reported to 
differentiate good vs. poor responders to CBT for anxiety (specifically, panic 
disorder; Kobayashi et al., 2005), and variation at the BDNF Val66Met 
polymorphism has been associated with impaired memory function in 
humans (Egan et al., 2003; Hariri et al., 2003).  The endogenous 
cannabinoid system also appears to play an important role in fear extinction 
(Wotjak, 2005).  Cannabinoid receptor 1 (CB1) knockout mice show 
profound deficits in short-term and long-term extinction (though not 
acquisition) of conditioned fear (Kamprath et al., 2006; Marsicano et al., 
2002), and these effects appear to be mediated by alterating signaling 
cascades and GABA-ergic neurotransmission (Kamprath et al., 2006; 
Marsicano et al., 2002). Injection of CB1 receptor antagonists mimics the 
impaired extinction phenotype of null-mutant mice (Marsicano et al., 2002); 
interestingly, this effect appears to be specific to fear extinction rather than 
extinction of an appetitive operant task (Holter et al., 2005). CB1 is 
expressed in the amygdala, a central structure for fear learning and 
extinction (Barad et al., 2006). The gene encoding human cannabinoid 
receptor 1 (CNR1) has been previously associated with substance 
dependence and schizophrenia in several studies (Ballon et al., 2006; 
Herman et al., 2006; Hofer et al., 2006; Martinez-Gras et al., 2006; Zhang 
et al., 2004). 
 
In addition to those reviewed above, a larger number of proteins have 
been implicated in fear conditioning and extinction, including components of 
the MAPK and PI-3 kinase intracellular signaling cascades (Lin et al., 2003), 
the dopamine D1 receptor (Pickel et al., 2006), calcineurin (Lin et al., 2003), 
gephyrin (Chhatwal et al., 2005), AMPA glutamatergic receptors (Barad, 
2005), and GABA(A) receptors (Davis & Myers, 2002).  However, for this 
initial study of genetic influences on extinction learning and DCS 
augmentation, we believe it is prudent to limit multiple testing and Type I 
error by pursuing a focused analyses of a core set of extinction-related 
genes. Thus, we will examine key NMDA receptor-related genes (GRIN1, 
GRIN2A, GRIN2B, DAAO, DAOA) and extinction-related neuropeptides 
(BDNF, NTRK2, CNR1).  Future studies in larger samples may permit 
analysis of a wider net of potentially relevant genes.   
 
 

May 23, 2016 
 
 
6
2. Specific Aims 
 
Primary Aim: 
The purpose of the proposed study is to conduct a double-blind, 
placebo-controlled trial of DCS augmentation of ERP in patients with BDD.  
Specifically, we intend to treat 50 BDD patients who will receive either DCS 
(100mg, n=25) or placebo (n=25) one hour before 8 of 10 behavior therapy 
sessions.  We anticipate that some participants who sign consent for the 
study will be deemed ineligible after the initial screening visit.  Consequently, 
our enrollment goal is 80 in order to reach our goal of 50 individuals who 
begin treatment.   
 
We hypothesize that patients receiving DCS will show significantly more 
improvement in BDD symptoms, compared to patients receiving placebo.  We 
intend to conduct the proposed study to collect sufficient pilot data to apply 
for an externally funded larger-scale research project.  
 
Secondary Aim: 
 
This treatment study also provides us with the opportunity to 
further explore the molecular genetics of BDD, as well as the genetic 
predictors of response to an extinction-based treatment.  We will take a 
hypothesis-driven approach by focusing on genes and systems previously 
shown to mediate fear acquisition and NMDA-dependent extinction learning 
including NMDA-related glutamatergic loci (GRIN1, GRIN2A, GRIN2B, DAAO, 
DAOA) and three other genes strongly implicated in fear extinction (BDNF, 
NTRK2, CNR1).  Other loci of interest in the molecular genetics of BDD 
include:  the serotonin transporter gene, dopamine, GABA-A, and 
cytochrome P450 genes  
 
 
We hypothesize that genes implicated in fear extinction will provide 
general prediction of the success of exposure treatment, and that the degree 
of additional benefit associated with DCS will be influenced by NMDA-related 
glutamatergic loci.  
 
3. Subject Selection  
Inclusion criteria are a diagnosis of BDD by DSM-IV standards and a 
BDD Yale-Brown Obsessive Compulsive Scale score greater than or equal to 
24 in people 18 years of age or older.  Subjects must be able to give 
informed consent, and females of childbearing potential must have a 
negative urinary beta-HCG test.  Pregnant or breastfeeding women, people 
taking medications that may interfere with DCS, and people with a history of 
seizure disorder or other serious medical illnesses such as cardiovascular, 
hepatic, renal, respiratory, endocrine, neurological or hematological disease 
are excluded from this study.  Other criteria for exclusion are comorbid 

May 23, 2016 
 
 
7
psychiatric diagnoses (alcohol dependence, bipolar disorder, psychosis, 
borderline personality disorder, organic mental disorder, or developmental 
disorder).  Also excluded are patients taking medications that may lower the 
seizure threshold, including clozapine, pethidine, and the following 
antibiotics in high dosages: penicillins, cephalosporins, amphotericin, and 
imipenem. Those deemed to pose a serious suicidal or homicidal threat will 
be excluded. If patients have any other comorbid disorder, the BDD 
symptoms must be the primary concern.  Furthermore, current 
psychotherapy and failure to benefit from ten or more sessions of previous 
CBT treatment are a rule-out.  Moreover, if a patient is taking a psychotropic 
medication, he or she must be at a stable dose prior to enrolling in the 
study.   
Participants will be withdrawn from the study if their clinical condition 
deteriorates substantially, as defined by a rating of 6 (much worse) or 7 
(very much worse) on the Clinical Global Impressions-Improvement (CGI-I) 
scale.  Participants may also be withdrawn if, in the judgment of the PI or 
therapist, remaining in the study poses a substantial risk to the participant, 
or if a higher level of care is needed. 
There will be no exclusion based upon gender or minority status. 
Based upon the composition of the patient population at the BDD Clinic at 
MGH, we anticipate that at least 50% of the participants will be women. The 
percentage of minority participants is expected to be at least 5%. We will 
make vigorous attempts to increase this number by posting advertisement 
flyers in minority communities.  
Subjects will initially be recruited through the General Recruitment 
Protocol (protocol # 2009P-002227), which includes general BDD 
advertisements.  Every effort will be made to recruit subjects for whom 
English is a 2nd language. While some of our questionnaires have been 
translated and validated in a few languages, several have not. Therefore, for 
scientific validity purposes, we have to restrict our participants to those 
individuals with English as a 2nd language that have sufficient fluency to 
understand the questionnaires as well as our therapist during behavior 
therapy treatment. 
Potential participants may be informed about the study by clinicians in 
the BDD Clinic at Massachusetts General Hospital (MGH) and by fliers posted 
at MGH, coffee shops, restaurants, Laundromats, barber shops, churches, 
daycares, libraries, newspapers, and on the internet.   
Individuals who are interested in treatment or in learning more about 
the ongoing research in the BDD clinic usually call the BDD clinic’s main 
number. As part of the usual intake process, the intake coordinator discusses 
with patients the reason for their call and their current symptoms.  She also 
asks a number of screening questions to form a preliminary impression 
regarding whether the caller suffers from BDD, OCD, an OCD spectrum 
disorder such as trichotillomania, depression, or substance abuse. She notes 

May 23, 2016 
 
 
8
the patients’ name, age, sex, address and phone number. The intake 
coordinator then informs all callers about evaluation and treatment options 
and asks whether he/she would potentially be interested in learning more 
about or participating in ongoing research projects. If so, the intake 
coordinator presents pertinent patient information in the BDD clinic’s weekly 
staff meeting where the clinical staff (including the PI) determines which 
research project(s) are appropriate for interested potential participants. The 
intake coordinator is very experienced with screening potential patients and 
has been working at the BDD Clinic since 1999.   Once interested participants 
are referred to this study, a research assistant will contact them and provide 
more detailed information about the study.  
We never identify potential participants through medical records, and 
we never contact potential participants without their permission to be 
contacted.  If a medical colleague identifies one of his or her patients as 
potentially appropriate for this study, we request that the colleague 
encourage the patient to contact a member of the study staff directly.  
Alternatively, the colleague may ask the patient to give permission to be 
contacted over the phone by a member of the study staff.   
 
4. Subject Enrollment  
Individuals who express an interest in participating will be screened by 
a research assistant over the phone.  We only ask for the patient’s name and 
contact information at the end of the phone screen if the patient is eligible 
and interested in participating (see attached phone screen). Before coming 
for their first visit, patients will be given information about the study via 
phone and allowed as much time for consideration and questioning as they 
need before the initial appointment is made.  At that time, patients will be 
further informed about the study’s purpose and procedures and advised 
regarding alternative treatment options in our clinic or elsewhere.  Because 
the primary intervention in this study is a psychological treatment, consent 
will be obtained by the study therapist.  However, the study physician will be 
available to answer any questions about the medication should they arise.  
Additionally, all eligible subjects will meet with the study physician at the first 
visit for the medical evaluation.   
 
Eligible participants will be randomized to receive either the D-
cycloserine (100 mg) or placebo.  The MGH research pharmacy will create 
and maintain the coded randomization schedule for this double-blind design 
and prepare and dispense the study medication (DCS or placebo) to study 
staff.  None of the investigators will be privy to the code, except for the 
study physician in case of an emergency. 
 
 
 

May 23, 2016 
 
 
9
 
5. Study Procedures 
 
Overview 
At the initial visit, we will first obtain informed consent from the 
participant.  We will also have participants sign their initials and date if they 
consent to sharing their de-identified data with other researchers in our 
group or across studies for research purposes only.  This procedure will save 
subjects time if they participate in more than one study at our clinic because 
it will eliminate repeating assessments shared between studies.  The 
participant will then undergo a structured clinical interview and fill out 
several questionnaires assessing BDD symptoms, anxiety, and depression. If 
the participant is eligible for participation based on this evaluation, the study 
physician will then meet with him or her to conduct the medical evaluation 
(more detail below).  If the participant remains eligible for the study after 
the medical evaluation then he or she will be randomized to receive either 
the D-cycloserine or placebo.  The MGH research pharmacy will create and 
maintain the coded randomization schedule for this double-blind design and 
prepare and dispense the study medication (DCS or placebo) to study staff.  
None of the investigators will be privy to the code, except for the study 
physician in case of an emergency.  Participants who choose to participate in 
the optional genetics component of the study will also have their blood 
drawn at this visit.  In all, the initial visit will last approximately 3-4 hours.  
After randomization, the participant will come to the clinic for a 
psychoeducation/treatment planning session approximately one week later 
(see below for more detail).  If we are unable to schedule the treatment 
planning session within 21 days of the screening visit, participants will be 
asked to complete a modified screening session directly prior to the 
treatment planning session.  This visit will take approximately 30 minutes.  
This visit will last approximately 1.5 to 2 hours.  The participant will not take 
the study medication/placebo prior to this visit.  After this treatment 
planning session the participant will be scheduled for 10 once weekly 
behavior therapy sessions over a 10 week period.  The first two therapy 
sessions will involve primarily cognitive interventions and so the study 
medication will not be administered prior to these sessions.  The participant 
will be asked to come to the clinic one hour before sessions 3-10 to take the 
study medication/placebo in the presence of the therapist.  Study 
medication will be kept at the clinic for the duration of the study.  In 
addition to the therapy visits, comprehensive assessments of BDD 
symptoms, mood state and cognitions to assess the outcome of therapy will 
be given at midtreatment (after session #5), post treatment and at 1- and 
6- month follow-ups.  These assessments will take approximately 1 hour.  
BDD symptoms, CGI-I score, and depressive symptoms will be assessed via 
self-report questionnaires at every treatment session.  These questionnaires 

May 23, 2016 
 
 
10 
will take approximately 5 minutes to complete.  A detailed assessment 
schedule is submitted for review. 
 
Psychological Assessments 
Comprehensive assessments of BDD symptoms, mood state and 
cognitions to assess the outcome of therapy will be given at pretreatment, 
midtreatment, post treatment and at 1- and 6- month follow-up.  BDD 
symptoms, CGI-I score, and depressive symptoms will be assessed every 
treatment session. 
 
The following instruments will be used and are submitted for review: 
(1) Demographic information sheet.  This sheet assesses general information 
such as age, years of education, etc.   
(2) Structured Clinical Interview for DSM-IV (SCID; First, Spitzer, Gibbon et 
al., 1995).  This instrument will be used to determine the Axis I psychiatric 
diagnosis(es).  
(3) Structured Clinical Interview for DSM-IV Axis II Personality Disorders 
(SCID-II; First et al., 1997).  Patients will complete the SCID-II self-report 
questionnaire; for any personality disorder for which the patient’s report 
approaches criterion (number of criteria required minus 1), the rater will 
administer all interview questions for that personality disorder.   
(4) Yale Brown Obsessive Compulsive Scale modified for BDD (BDD-YBOCS).  
This reliable and valid 12-item semi-structured clinician-administered scale, 
which was adapted from the Y-BOCS (Goodman et al., 1989), rates current 
severity of BDD symptoms (Phillips et al., 1997). It will be the study's 
primary outcome measure.   The BDD-YBOCS has excellent interrater and 
test-retest reliability (ICC for total score=.99 and .88, respectively), internal 
consistency (Cronbach’s alpha=.80), convergent validity (r=.55 with the 
CGI), and sensitivity to change with treatment (Phillips et al., 1997).  
(5) BDD-Symptom Scale (BDD-SS) The PI developed the BDD-SS to rate the 
severity of specific BDD symptoms.  
(6) Clinical Global Impression Scale (CGI) This global rating scale, which 
ranges from 1 (very much improved) to 7 (very much worse) on levels of 
improvement (CGI-I) and from 1 (normal, not at all ill) to 7 (extremely ill) 
on severity (CGI-S), is commonly used in pharmacotherapy trials (Guy, 
1976). The CGI will be a secondary outcome measure and will also be used 
to determine clinical deterioration of BDD.  
(7) Brown Assessment of Beliefs Scale (BABS)  This reliable and valid 7-item 
semi-structured clinician-administered interview, assesses current delusional 
thinking categorically and dimensionally (Eisen et al., 1998). Excellent 
interrater and test-retest reliability (ICC for total score=.96 and .95), 
internal consistency (Cronbach’s alpha=.87), convergent validity (r’s=.56-
.85 with measures of delusionality), and divergent validity (r=.20 with the 

May 23, 2016 
 
 
11 
BDD-YBOCS [158]) have been demonstrated (Eisen et al., 1998). The 
cutpoint for the presence of delusional thinking in BDD had a sensitivity of 
100% and a specificity of 86%, and it correctly identified 90% of 20 
participants as delusional or nondelusional (Eisen et al., 1998). It is also 
sensitive to change (Phillips et al., 1998). 
(8) Multidimensional Body-Self Relations Questionnaire (MBSRQ) While the 
BDD measures include some assessment of body image, we will also use a 
standard body image scale that is not specific to BDD and which assesses 
body image more broadly. The MBSRQ is a widely used 69-item self-report 
scale that assesses 3 domains of attitudes towards one’s body, including 
appearance (Cash, 1994). Test-retest reliability (r=.91) and internal 
consistency (D=.88) are good; concurrent validity (r=.66) is acceptable.  
(9) Beck Depression Inventory II (BDI II; Beck, Steer & Brown, 1996). The 
BDI II is a 21-item self-report inventory that measures the severity of 
depression.  
(10) Young Schema Questionnaire (YSQ)  This 75-item self-report scale 
(Young & Brown, 1990) assesses the following areas of maladaptive 
schemas: emotional deprivation, abandonment, mistrust/abuse, social 
isolation, defectiveness/shame, failure to achieve, functional 
dependence/incompetence, vulnerability to harm and illness, enmeshment, 
subjugation, self-sacrifice, emotional inhibition, unrelenting standards, 
entitlement, and insufficient self-control/self-discipline. It has high internal 
consistency and discriminant validity (Waller et al., 2001). This scale will 
assess core beliefs and schemas as potential mechanisms underlying 
change, as several of these (e.g., defectiveness/shame) appear particularly 
relevant to BDD.  
(11)  Multidimensional Perfectionism Scale (MPS) The MPS is a self-report 
45-item scale that assesses perfectionism from several perspectives: self-
oriented (e.g., “When I am working on something, I cannot relax until it is 
perfect”), other-oriented (e.g., “I have high expectations for the people who 
are important to me”), and socially prescribed (e.g., “I feel people are too 
demanding of me”) (Hewitt et al., 1991). It has good internal consistency 
(D=.74 to .88) and convergent validity (r’s=.62-.69 with other measures of 
perfectionism) (Hewitt et al., 1991).  
(12) Disability Inventory This 4-item self-report scale assesses work, social, 
and family disability on 10-point scales and overall disability on a 5-point 
scale (Leon et al., 1992). It has been used in pharmacologic studies and had 
acceptable reliability (internal consistency, factor structure) and satisfactory 
construct and criterion-related validity in a study of patients with panic 
disorder. 
(13) LIFE-RIFT To assess psychosocial functioning in multiple domains, these 
5- to 7-point rater-completed scales provide information about work, 
employment, household duties, student work, interpersonal relations with 
family and friends, recreation, overall life satisfaction, and global social 

May 23, 2016 
 
 
12 
adjustment (Leon et al., 1999). The concurrent validity is moderate (R2 = 
0.56) and the internal consistency is good (D=.82).  
(14)  Expectancy Questionnaire This 4-item self-report questionnaire 
assesses patients’ judgments about the credibility of the treatment rationale, 
expectancy of change, and treatment acceptability (Borkovec & Nau, 1972). 
It has good reliability (D=.81-.86), and validity is evident in its ability to 
differentiate between treatment rationales (Devilly & Borkovec, 2000). It will 
be given after the second visit when patients are familiar with the treatment 
protocol.  
(15) The Client Satisfaction Questionnaire (CSQ) is a 8 item self-report 
questionnaire which assesses the satisfaction with clinical services received 
on a Likert scale.  It has excellent internal consistency (D = .93; Larsen, 
Attkission, Hargeaves, & Nguyen, 1979).   
 (16) University of Rhode Island Change Assessment Questionnaire (URICA)  
This 32-item self-report questionnaire measures motivation to change 
(Greenstein et al., 1999). Its 4 scales (precontemplation, contemplation, 
action, and maintenance) have adequate internal consistency (D=.77-.89; 
Carey et al., 1999).  
(17)  Appearance Schemas Inventory-Revised (ASI-R)  This 20-item 
measure consists of two subscales assessing one’s cognitive-behavioral 
investment in one’s own appearance—Self-Evaluative Salience (12 items) 
and Motivational Salience (8 items). Self-Evaluative Salience reflects the 
extent to which individuals define or measure themselves and their self-
worth by their physical appearance.  Motivational Salience pertains to the 
extent to which persons attend to their appearance and engage in 
appearance-management behaviors. 
(18) The Brief Assessment of Appearance-related Beliefs (BAAB) This 2-item 
self-report measures the level of insight about the BDD symptoms the 
subject has. This measure was specially developed in our clinic in order to 
assess insight related specifically to BDD beliefs.   
(19)  Body Part Satisfaction Questionnaire (BPSQ) This 10-item self-report 
measure assesses the subject’s satisfaction with various body parts 
(Wilhelm, 2006. Feeling Good about the Way You Look).  
(10) The Brief Assessment of Motivation (BAM) This 3-item self-report 
measure assesses the motivation of the subject. This measure was specially 
developed in our clinic to assess the motivation of patients with BDD.  
(21) Cognitive and Behavioral Change Measures (CBCM) These measures 
assess how much cognitive and behavioral change may have occurred within 
the session and between sessions. 
(22) Parental Bonding Inventory (PBI) The PBI is a 25-item self-report that 
measures parental bonding styles and is completed for both mothers and 
fathers. The PBI consists of 12 items that measure parental “caring” and 13 
questions that measure parental “overprotection.” 

May 23, 2016 
 
 
13 
(23) Multidimensional Perfectionism Scale-35 (MPS-35) This 35 item self-
report measures perfectionistic tendencies on six subscores: personal 
standards, concern over mistakes, parental expectations, parental criticism, 
doubting of activities, and order and organization.  Participants rate their 
agreement with 25 statements using Likert scales ranging from 1 (strongly 
disagree) to 4 strongly agree. 
(24) Short Grit Scale (Grit-S) This 8 item self-report measures trait-level 
perseverance and passion for long-term goals.  Participants rate their 
agreement with 8 statements using a Likert scale ranging from “very much 
like me” to “not like me at all.”   
(25) Difficulties in Emotion Regulation Scale (DERS) This 36-item 
multidimensional self-report measures individuals’ characteristic patterns of 
emotion regulation.   
 
 
Data Collection and Storage 
 
Self-report measures will be collected using RedCapTM, a platform for 
electronic data capture that streamlines data collection and management, 
and ensures data integrity, resulting in improved data quality.  RedCap 
allows researchers to design and implement study surveys for collecting, 
storing, retrieving, and manipulating data electronically.  Participants and/or 
research staff enter survey responses into electronic assessment forms. This 
electronic data capture obviates the need for subsequent data entry by staff, 
thus minimizing human error. 
 
These surveys are completed securely via the internet by using any device 
with standard web access and browsers. For this study, participants and 
staff will complete the electronic assessments on computer terminals at the 
research site under the supervision of study staff.  All users will have defined 
roles and privileges pre-determined by the system administrator. Thus, the 
PI can determine the level of access for each study staff such that only a 
limited number of people have access to sensitive study data.  
 
 
Medical Assessment 
At the initial study visit, one of the study physicians will evaluate the 
participant with regard to the medical and psychiatric exclusion criteria to be 
sure that none are met.  Participants will be monitored in an ongoing 
manner for side effects or any adverse reactions to the study medication, 
and further evaluations will occur at any other times as necessary.  
Participants may contact the study physicians at any time to discuss their 
medication, side effects, or adverse reactions.  
Also at this time a urine pregnancy test will be performed for women 
of child-bearing potential. If the test is positive, the participant will be 

May 23, 2016 
 
 
14 
excluded.  Additionally, women of child-bearing potential must agree to use 
a reliable form of contraception for the duration of the study. Males and 
Females will be asked to provide a urine specimen in order to drug screen 
for use of the following drugs: opiates, phencyclidine, barbiturates, 
benzodiazepines, cocaine, amphetamine, methamphetamine, and marijuana. 
The test will be done in the medical evaluation room and labeled with 
participant code number. If participant screens positive for drugs of abuse, 
the study doctor will discuss sharing of this information and ask if the 
participant would like a referral for substance abuse treatment. Results of 
drug screen will be confidential, will not be shared without explicit consent 
and will not become part of the medical record. Testing positive for drugs of 
abuse, for which the participant does not have a valid prescription will make 
them ineligible to participate in this research study.  
 
Modified Screen 
 
This appointment will only be for participants who can not schedule the 
treatment planning session within 21 days of the initial study visit.  It would 
be completed directly prior to the treatment planning session.  It would 
consist of assessment measures completed at the screening visit to ensure 
the information is accurate and up to date.     
 
Treatment Planning Session 
The second appointment will take 1.5-2 hours and will include 
psychoeducation about the theory of BDD and how it relates to the patient’s 
specific symptoms.  A detailed hierarchy of exposure exercises will be 
developed that is specific to the areas that are most relevant for each 
patient. 
 
Behavior Therapy 
Dr. Ragan, Hannah Reese, Kiara Timpano and Jedidiah Siev will 
administer the ERP treatment to the BDD patients.   Dr. Ragan is a licensed 
clinical psychologist and has been working at MGH since 2004.   She will 
meet weekly with Dr. Wilhelm for clinical research supervision.  Hannah 
Reese has her masters degree in Clinical Psychology and is currently a 
doctoral student in Clinical Psychology at Harvard University.  Kiara Timpano 
and Jedidiah Siev are clinical psychology interns in the final year of their 
doctoral programs.  They will meet weekly with either Dr. Ragan or Dr. 
Wilhelm for clinical research supervision.  Fifty patients will be treated with 
ERP.   Treatment will follow the exposure principles outlined in “Feeling 
Good About the Way You Look,” a self-help book for individuals with BDD 
written by the PI (Wilhelm, 2007).    The treatment will consist of ten 
weekly sessions. Thus, the entire ERP treatment will take ten weeks.  The 
first two sessions will include primarily cognitive interventions in order to lay 
the groundwork for effective exposure exercises in the remaining 8 sessions.  

May 23, 2016 
 
 
15 
During the exposure sessions, the patient will be confronted with 
moderately anxiety-provoking situations or stimuli and will be asked not to 
engage in any rituals until the anxiety comes down.  In this manner, the 
patient will learn that he or she does not have to perform the ritual to lower 
the anxiety.  The last treatment session (#10) will also include relapse 
prevention. That is, the study therapist will provide the patient with 
information about how to schedule “self-therapy sessions” in which the 
patient will (1) review what he or she has learned during the course of 
therapy and (2) engage in exposure and response prevention. Furthermore, 
the study therapist will also discuss with the patient that the BDD symptoms 
may worsen during times of stress but that overall the BDD symptoms may 
be expected to improve if the patient keeps doing the exposure techniques 
learned during the course of the treatment.   
 
Optional Genetics Component 
 
Participants who agree to participate in the optional genetics 
component of the protocol will have their blood drawn at the first visit by a 
member of the study staff who has received formal training in phlebotomy.   
 
 
DNA Collection and Extraction.  DNA will be extracted from blood samples 
collected by a member of the study staff who is also a certified phlebotomist, 
labeled by coded identifiers, and sent to Dr. Smoller’s laboratory at MGH for 
genotyping.  If a patient is interested in providing a genetics sample but is 
unwilling to have their blood drawn, they will have the option to provide a 
saliva sample.  Laboratory personnel will not have access to personal 
identifiers.  Dr. Smoller’s laboratory has extensive experience with the 
collection, extraction and genotyping of DNA. The process of DNA collection 
through blood and saliva samples is highly acceptable to participants and, in 
our hands, each sample provides approximately 60 ug of genomic DNA.  
Given that each genotyping assay requires only 2.5 – 5 ng of DNA, this yield 
will be more than adequate. After DNA extraction, sample yield is 
determined by picogreen analysis. 
 
 
Genotyping Methods: Genotyping will be performed in Dr. Smoller’s lab at 
the MGH Center for Human Genetic Research. Single nucleotide 
polymorphism (SNP) genotyping will be performed using the Sequenom 
MassArray system (Tang et al., 1999; Smoller et al., 2003). Genotyping will 
be performed in multiplex reactions in 384-well plates. For each assay, four 
duplicate samples and 4 blank samples will be included. SNPs will be used 
for association analyses only if they meet the following quality control 
criteria: 1) >90% of attempted genotypes for any SNP are successful, 2) 
alleles are in Hardy Weinberg equilibrium, and 3) agreement between all 

May 23, 2016 
 
 
16 
duplicates and no more than 1 of 4 blanks with genotypes. Genotyping of 
the functional promoter variant in the GRIN2A gene (Itokawa et al., 2003) 
will be performed using the Applied Biosystems 3730 DNA Analyzer and 
standard protocols. GeneMapper v3.5 is used to analyze the raw results from 
the ABI3730, however, a genotype is not considered final until two 
laboratory personnel have independently checked (and corrected) the 
GeneMapper results and both individuals are in agreement. 
 
Given the small number of genetic samples, we will add BDD DNA samples 
collected by the PI for a separate BDD treatment study of Lexapro 
discontinuation as well as BDD DNA samples collected by project collaborator 
Dr. Katharine Phillips at Brown University as part of a longitudinal BDD 
study. Both studies obtained consent for participants to collect DNA, to store 
this DNA at MGH, and to conduct genetic association studies for BDD.  Only 
subjects who specifically consented for the genetic portion of the study had 
blood drawn and DNA extracted; therefore, only subjects who consented for 
the optional genetic study will be used for the current genotyping study. 
All DNA tubes/samples are fully de-identified.  For the samples collected at 
Brown, no MGH investigators have any access to subject identifiers. 
 
In order to conduct a BDD case-control genetic association study, we have 
obtained ancestry and gender-matched control DNAs from the Genome 
Superstruct Project (GSP), (Massachusetts General Hospital, Boston; PI: J. 
Smoller, R. Buckner, J. Roffman).   All of these control samples were 
consented for genotyping in targeted and whole-genome association studies 
as well as for data sharing.  No control subjects who did not consent to 
future sharing will be used in this study. Of note, we need to conduct direct 
genotyping of the BDD candidate genes to control for likely experimental 
confounds if the BDD case DNAs were genotyped and compared to control 
data generated on a different platform at a different site.  The DNAs all exist 
in the MGH PNGU Core Lab, and are fully de-identified; thus, BDD study 
investigators have no way of knowing to whom the samples belong.  
 
 
Privacy and Confidentiality 
All information gathered will be kept strictly confidential.  Participants 
will be assigned a code number, and the participants’ names will not appear 
on any questionnaires or therapy protocols.  Moreover, the data will be 
stored in locked file cabinets located in locked offices.  Only the study 
personnel will have access to the data.  
 
Participants may also choose to provide consent for the use of their samples 
in related research.  We have included in the consent form a description of 
what information will be shared with any outside investigators.   

May 23, 2016 
 
 
17 
 
6. Biostatistical Analysis 
Please note: The blind may be broken after every ten subjects to conduct 
preliminary analyses to assess for the efficacy of D-cycloserine. 
Primary analyses: Our primary hypothesis is that ERP in combination 
with DCS is more effective than ERP in combination with a placebo.  To 
measure this, the BDD-YBOCS will be the primary outcome measure. The 
main analyses will compare the two patient groups at mid-treatment and 
post-treatment using analysis of variance (ANOVA) and analysis of 
covariance (ANCOVA, controlling for BDD-YBOCS-pretreatment scores).   To 
further determine the clinical significance of these findings, we will use the 
Jacobson and Truax (1991) formula to calculate the percentage of patients 
who fulfill the criteria for reliable and clinically significant change in each 
treatment condition at mid-treatment and post-treatment. Fisher’s exact 
test for differences in frequencies of responders between the two patient 
groups will be performed. We will further compare the two groups at the 1- 
and 6-month follow-up assessments.   
Power analysis: A power analysis with a sample size of 25 per group 
and p < .05 reveals that this study will convey 80% power to detect a group 
difference in post-treatment BDD-YBOCS scores of d = 0.78, which is a 
large effect size.  Moreover, we will estimate between-group effect sizes of 
this pilot study to be used in designing future studies.  
Secondary analyses: We hypothesize that patients who receive DCS 
augmentation will have greater improvement on the CGI-I, BDI, BDD-SS, 
and Disability Inventory at mid-treatment, post-treatment and 1- and 6-
month follow-up assessments than patients who receive the placebo. 
ANCOVAs (controlling for pretreatment scores) and multivariate ANCOVAs 
(MANCOVAs) will be used for these analyses as described above, and effect 
sizes will be computed.  Furthermore, the Cognitive and Behavioral Change 
Measures will be used to identify in more detail within which session, or 
between which sessions, any changes occurred.  
Predictors of outcome: We also wish to evaluate whether ERP in 
combination with DCS is particularly effective or ineffective for different 
symptoms (as measured by the BDD Symptom Scale), attitudes (i.e., 
patient’s judgments about the credibility of the treatment, as measured by 
the Expectancy Rating), or comorbid problems (e.g., depression). These 
factors will be included in regression analyses. We also intend to explore the 
relationship between minority status and treatment outcome; however, 
power will be limited given the small sample size. 
Mechanisms of improvement: We are also interested in potential 
mechanisms of change during treatment. These can be tested with multiple 
regression procedures via hierarchical regression models. Treatment group 
(DCS vs. placebo) will be the independent variable, changes in BDD 
symptom severity (BDD-YBOCS) the dependent variable, and, for example, 

May 23, 2016 
 
 
18 
changes in beliefs as measured by the Schema Questionnaire will be the 
mediator. We will follow the procedures for establishing statistical mediation 
outlined by Baron and Kenney (1986), using residual gain scores as the 
measure of change in both the dependent variable and the mediator 
(Cohen, 1983). These residual scores will give a reliable estimate of changes 
in symptom severity and beliefs independent of differences in baseline 
severity. We will interpret our results with caution because the absence of 
statistical significance may reflect the somewhat limited power with only 50 
patients. 
 
 Genetic Analyses:  We will use quantitative trait association analytic 
methods to examine whether alleles and/or haplotypes of the loci selected 
for analyses are associated with outcome of ERP with or without DCS.  
Analyses will be conducted in two stages.  The initial analyses will examine 
whether any of the genetic variants are associated with ERP outcome 
indexed by change in BDD-YBOCS score from baseline (at end of treatment 
and at 1-month and 6 month follow-up). The analyses will include a main 
effect analysis of each genetic variant as well as a gene x treatment 
interaction analysis, to examine whether allelic effects on outcome differ by 
treatment condition (DCS vs. placebo).  If evidence of interaction is 
detected, we will also examine allelic effects within treatment group.  For 
example, we expect that genes involved in NMDA receptor function (e.g. the 
GRIN1 gene whose product includes the glycine (DCS) binding domain) may 
mediate response to DCS.  
 
 In the second stage, genetic predictors demonstrating univariate 
association will be entered into a multivariable linear regression model along 
with other predictors of treatment response in an effort to build a model that 
parsimoniously explains the greatest proportion of variance in response to 
ERP (with and without DCS). For genes in which more than one 
polymorphism shows evidence of association, we will select the SNP with the 
minimum p value to enter into the multivariable model.  
Univariate single marker and haplotype-based analyses will be 
conducted using WHAP (Curran et al., 2005; 
http://www.broad.mit.edu/~shaun/whap/).  Using an approach similar to 
those of Schaid et al. (2002) and Zaykin et al. (2002), WHAP is based on a 
two-stage method. The primary test is a regression-based analysis of 
association between marker (or haplotype) and trait, with one regression 
coefficient per marker (or haplotype). The independent secondary test 
analyses the relationship between marker (or haplotype) similarity and 
regression coefficient similarity. Evidence from the primary and secondary 
stages can be combined to provide a more powerful test of association, by 
combining log-transformed P values. The method is based on a mixture of 
regression models which accounts for the potential ambiguity in individuals’ 
statistically-inferred haplotypes. For H haplotypes, a single omnibus test is 
performed to test jointly for any difference in haplotype effect, which is an H 

May 23, 2016 
 
 
19 
– 1 single-degree-of-freedom test. The independent secondary test assesses 
whether pairs of more similar haplotypes show more similar effects. A 
multivariate weighted least squares regression of haplotype effect similarity 
on haplotype genetic similarity is used and empirical significance levels are 
determined by permutation testing. We will define haplotype blocks using 
the conservative definition of Gabriel et al. (2002) as implemented in 
Haploview (Barrett et al., 2004). 
Evaluation of Population Structure.  It has been well recognized that 
ethnic admixture or population stratification may confound case-control 
genetic association studies, although the importance of this phenomenon 
has been debated (Freedman et al., 2004; Wacholder et al., 2002). 
Nevertheless, we will evaluate the possibility of confounding due to 
population stratification, by typing a panel of 100 informative unlinked (null) 
SNPs. The main approach used will be that described by Purcell and Sham 
(2004), which implements a method very similar to that of Pritchard et al. 
(2001) and Satten et al. (2001). All these approaches look for Hardy-
Weinberg disequilibrium and LD between unlinked markers, and 
probabilistically break down the sample to a number of subgroups, within 
which Hardy-Weinberg equilibrium and linkage equilibrium hold (as one 
would expect in a homogeneous population). We will evaluate population 
structure by performing analyses using the L-POP program (Purcell et al., 
2004). Because the sample is expected to be primarily Caucasian, if more 
than one subgroup is detected, we expect that only one subgroup will have 
sufficient power for analysis. Thus our analyses would focus on the largest 
subgroup.   
 
7. Risks and Discomforts 
 
Patients may feel uncomfortable due to the sensitive nature of the 
questions they may be asked.   
 
Side effects.  The potential side effects associated with the administration of 
DCS include drowsiness, headache, prolonged or momentary dizziness, 
seizures, confusion, hallucinations, weakness, coma, rash, vitamin B12 
deficiency and/or folate deficiency (both of which may cause weakness and 
anemia (low blood counts)), liver enzymes increases (which could cause 
weakness or bleeding), and shaking. However, these side effects are most 
commonly related with doses greater than 500mg/day, which is five times 
what is administered in this study. The use of DCS at doses of 100 mg (as in 
this study) does not appear to be associated with significant emergent 
adverse effects.  Indeed, in our recent trial examining the efficacy of DCS 
augmentation of behavior therapy for individuals with OCD no subjects 
reported any side effects as a result of the study medication.   
 

May 23, 2016 
 
 
20 
 
Interactions.  
(1) Intake of alcohol at the same day may increase the possibility and 
risk of epileptic episodes. Thus, we will exclude patients with current alcohol 
dependence. Furthermore, we will instruct the patients not to consume any 
alcohol 12 hours prior to and 24 hours after receiving the study medication.  
To ensure that patients have not consumed alcohol prior to taking the study 
medication we will administer a saliva test to measure BAC levels 
immediately before dispensing the medication.    
(2) Intake of Isoniazid at the same day may result in increased CNS 
side effects. Thus, we will exclude patients who currently take Isoniazid. 
 
Optional Genetics Component 
There is a risk associated with the sensitivity of the genetic 
information. The results of genetic analyses will be kept confidential and will 
not be returned to participants in this study. Consequently, the potential 
risks of subjects learning sensitive genetic information or of discrimination 
related to participation in a genetic study should be avoided. There is a 
theoretical risk of discrimination by employers or insurers should subjects’ 
enrollment into or the results of the study unintentionally become known 
despite procedures in place to maintain confidentiality. The following steps 
will be taken to protect the confidentiality and privacy of the genetic data: 
a. No genetic research data will be entered into the medical record.  
b. The results of the genetic analyses will not be shared with 
participants or their family members.  
c. Only coded identifiers, rather than personal identifiers, will be used 
in any analytic datasets. The genetic laboratory will not have access 
to personal identifiers.  
 
 
To protect confidentiality, information about subjects will be stored in 
research files identified only by code. The code key connecting IDs to 
identifying information will be kept in a separate secure location at the 
research site at which a participant is enrolled. Data in databases is similarly 
identified only by coded ID number and is password-protected.  
 
  
Minimizing of Risks and Safety Reporting. Subjects will be monitored in an 
ongoing manner for side effects or any adverse reactions to the study 
medication. The study physicians, Drs. Dougherty and Jenike, will review all 
reports of adverse events and forward them to the IRB.  Patients may also 
contact them at any time to discuss their medication, side effects, or 
adverse reactions. 
 

May 23, 2016 
 
 
21 
Adverse event reporting: In case of an adverse event and in accordance with 
Partners Human Research Committee Adverse Event Reporting Guidelines, 
we will complete the appropriate adverse event form and forward it to the 
IRB within the required time frame for reporting. 
 
8. Potential Benefits 
Patients may benefit by experiencing some relief from their BDD 
symptoms.  Our research will help us better understand what treatments are 
beneficial in this disorder. 
 
9. Monitoring and Quality Assurance 
Dr. Ragan and Hannah Reese will be responsible for ensuring that all 
study procedures are conducted according to the IRB-approved protocol and 
reviewing the accuracy and completeness of source documents.  Dr. Ragan 
and Hannah Reese will meet with Dr. Wilhelm regularly to discuss the study 
procedures and progress.  Drs. Wilhelm and Ragan will be responsible for 
ensuring that the study treatment is delivered appropriately. 
 
Subjects will be monitored in an ongoing manner for side effects or 
any adverse reactions to the study medication. The study physicians will 
review all reports of adverse events and forward them to the IRB according 
to Partners guidelines.  Participants may also contact the study physicians at 
any time to discuss their medication, side effects, or adverse reactions.  The 
PI, in collaboration with the study physicians will ultimately be responsible 
for determining whether the research should be altered or stopped.   
 
Participants will be withdrawn from the study if their clinical condition 
deteriorates substantially.  Deterioration will be defined by a rating of 6 
(much worse) or 7 (very much worse) on the CGI-I.  Participants may also 
be withdrawn if in the judgment of the PI or therapist remaining in the study 
poses a substantial risk to the participant or a higher level of care is needed. 
 
In case of an adverse event and in accordance with Partners Human 
Research Committee Adverse Event Reporting Guidelines, we will complete 
the appropriate adverse event form and forward it to the IRB within the 
required time frame for reporting. 
 
10.  References 
 
Alliez, J., & Robin, M.  (1969). Aspects psycho-pathologiques de la 
defiguration leur relation avec dysmorphophobie [Psychopathologic 
aspects of disfiguration; their relation to dysmorphophobia]. Ann Med 
Psychol,  2, 479-94. 

May 23, 2016 
 
 
22 
American Psychiatric Association (1994). Diagnostic and statistical manual of 
mental disorders, 4th edition. Washington, DC, American Psychiatric 
Association Press. 
Ballon, N., Leroy, S., Roy, C., Bourdel, M. C., Charles-Nicolas, A., Krebs, M. 
O., et al. (2006). (AAT)n repeat in the cannabinoid receptor gene 
(CNR1): association with cocaine addiction in an African-Caribbean 
population. Pharmacogenomics J, 6(2), 126-130. 
Barad, M. (2005). Fear extinction in rodents: basic insight to clinical 
promise. Curr Opin Neurobiol, 15(6), 710-715. 
Barad, M., Gean, P. W., & Lutz, B. (2006). The role of the amygdala in the 
extinction of conditioned fear. Biological Psychiatry, 60(4), 322-328. 
Barrett, J. C., Fry, B., Maller, J., & Daly, M. J. (2004). Haploview: analysis 
and visualization of LD and haplotype maps. Bioinformatics. 
Beck, A.T., Steer, R.A. & Brown, G.K. (1996). Beck Depression Inventory – 
Second Edition: Manual. San Antonio, TX: The Psychological 
Corporation.  
Borkovec, T. D., & Nau, S. D.  (1972). Credibility for analogue therapy 
rationales. J Behav Ther Exp Psychiatry, 3, 257-260. 
Carey, K. B., Purnin, D. M., Maisto, S. A., & Carey, M. P.  (1999).  Assessing 
readiness to change substance abuse: a critical review of instruments. 
Clin Psychol Sci Prac, 6, 245-266. 
Cash, T. F.  (1994). The User's Manual for the Multidimensional Body-Self 
Relations Questionnaire. Available from the author, Old Dominion 
University, Norfolk, VA. 
Chhatwal, J. P., Myers, K. M., Ressler, K. J., & Davis, M. (2005). Regulation 
of gephyrin and GABAA receptor binding within the amygdala after fear 
acquisition and extinction. J Neurosci, 25(2), 502-506. 
Chhatwal, J. P., Stanek-Rattiner, L., Davis, M., & Ressler, K. J. (2006). 
Amygdala BDNF signaling is required for consolidation but not 
encoding of extinction. Nat Neurosci, 9(7), 870-872. 
acquisition and extinction of conditioned hypoalgesia responses in the rat. 
Quarterly Journal of Experimental Psychology B, 47B, 187-210. 
Curran, S., Purcell, S., Craig, I., Asherson, P., & Sham, P. (2005). The 
serotonin transporter gene as a QTL for ADHD. Am J Med Genet B 
Neuropsychiatr Genet. 
Davis, M. (2000). Role of NMDA receptors and MAP kinase in the amygdale 
in extinction of fear: clinical implications for exposure therapy. 
European Journal of Neuroscience, 16, 395-398. 
Davis, M., & Myers, K. M. (2002). The role of glutamate and gamma-
aminobutyric acid in fear extinction: clinical implications for exposure 
therapy. Biol Psychiatry, 52(10), 998-1007. 
Devilly, G. J., & Borkovec, T. D.  (2000).  Psychometric properties of the 
credibility/expectancy questionnaire. J Behav Ther Exp Psychiatry, 31, 
47-55. 

May 23, 2016 
 
 
23 
Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., 
Bertolino, A., et al. (2003). The BDNF val66met polymorphism affects 
activity-dependent secretion of BDNF and human memory and 
hippocampal function. Cell, 112(2), 257-269. 
Eisen, J.L., Phillips, K.A., Baer, L., Beer, D.A., Atala, K.D., & Rasmussen, 
S.A. (1998). The Brown Assessment of Beliefs Scale: Reliability and 
Validity. American Journal of Psychiatry, 155, 102-108. 
First, M.B., Spitzer, R.L., Gibbon, M., & Williams, J.B.W. (1995). Structured 
Clinical Interview for DSM-IV (SCID). Washington, DC: American 
Press. 
First, M.B., Gibbon, M., Spitzer, R.L., Williams, J.B.W., & Benjamin, L.S. 
(1997). Structured Clinical Interview for DSM-IV Axis II Personality 
Disorders (SCID-II). Washington, DC: American Press. 
Foa, E.B. (2000). Psychosocial treatment of posttraumatic stress disorder. 
Journal of Clinical Psychiatry, 61, 43-48. 
Freedman, M. L., Reich, D., Penney, K. L., McDonald, G. J., Mignault, A. A., 
Patterson, N., et al. (2004). Assessing the impact of population 
stratification on genetic association studies. Nat Genet, 36(4), 388-
393. 
Furukawa, H., Singh, S. K., Mancusso, R., & Gouaux, E. (2005). Subunit 
arrangement and function in NMDA receptors. Nature, 438(7065), 
185-192. 
Fyer, A. (1998). Current approaches to etiology and pathophysiology of 
specific phobia. Biological Psychiatry, 44, 1295-1304. 
Gabriel, S. B., Schaffner, S. F., Nguyen, H., Moore, J. M., Roy, J., 
Blumenstiel, B., et al. (2002). The structure of haplotype blocks in the 
human genome. Science, 296(5576), 2225-2229. 
Goff, D.C., Guochuan, T., Levitt, J., Amico, E., Manoach, D., Schoenfeld, D., 
et al. (1999). A Placebo-Controlled Trial of DCS Added to Conventional 
Neuroleptics in Patients with Schizophrenia. Archives of General 
Psychiatry, 56, 21-27. 
Goff, D.C., Tsai, G., Manoach, D.S., Coyle, J.T. (1995). Dose-finding trial of 
D-Cycloserine added to neuroleptics for negative symptoms in 
schizophrenia. American Journal of Psychiatry, 152, 1213-1215. 
Goodman, W. K., Price, L. H., Rasmussen, S. A., Mazure, C., Fleischman, R. 
L., Hill, C. L., Heninger, G. R. & Charney, D. S. (1989). The Yale-
Brown Obsessive-Compulsive Scale: development, use, and reliability. 
Archives of General Psychiatry, 46, 1006-1011. 
Gorman, J., Kent, J., Sullivan, G., & Coplan, J. (2000). Neuroanatomical 
hypothesis of panic disorder, revised. American Journal of Psychiatry, 
157, 493-505. 
Greenstein, D. K., Franklin, M. E., & McGuffin, P.  (1999).  Measuring 
motivation to change: an examination of the University of Rhode 

May 23, 2016 
 
 
24 
Island Change Assessment Questionnaire (URICA) in an adolescent 
sample. Psychotherapy, 36, 47-55. 
Guy, W.  (1976).  ECDEU Assessment Manual for Psychopharmacology. 
Washington, DC, US Department of HEW Publications. 
Hanngren, H., Hansson, E., & Ullberg, S. (1961). Antibiotics. Chemotherapy, 
12, 45-54. 
Hariri, A. R., Goldberg, T. E., Mattay, V. S., Kolachana, B. S., Callicott, J. H., 
Egan, M. F., et al. (2003). Brain-derived neurotrophic factor val66met 
polymorphism affects human memory-related hippocampal activity 
and predicts memory performance. J Neurosci, 23(17), 6690-6694. 
Heresco-Levy, U., Kremer, I., Javitt, D.C., Goichman, R., Reshef, A., 
Blanaru, M., & Cohen, T. (2002).  Pilot-controlled trial of DCS for the 
treatment of post-traumatic stress disorder. The International Journal 
of Neuropsychopharmacology, 5, 301-307. 
Herman, A. I., Kranzler, H. R., Cubells, J. F., Gelernter, J., & Covault, J. 
(2006). Association study of the CNR1 gene exon 3 alternative 
promoter region polymorphisms and substance dependence. Am J Med 
Genet B Neuropsychiatr Genet, 141(5), 499-503. 
Hewitt, P. L., Flett, G. L., Turnbull-Donovan, W., & Mikail, S.  (1991). The 
Multidimensional Perfectionism Scale:  Reliability, validity, and 
psychometric properties in psychiatric samples. Psychol Assessment, 
3, 464-468. 
Hofmann, S. G., Meuret, A. E., Smits, J. A., Simon, N. M., Pollack, M. H., 
Eisenmenger, K., Shiekh, M., & Otto, M. W.  (2006).  Augmentation of 
exposure therapy with D-cycloserine for social anxiety disorder.  Arch 
Gen Psychiatry, 63, 298-304.  
Holter, S. M., Kallnik, M., Wurst, W., Marsicano, G., Lutz, B., & Wotjak, C. T. 
(2005). Cannabinoid CB1 receptor is dispensable for memory 
extinction in an appetitively-motivated learning task. Eur J Pharmacol, 
510(1-2), 69-74. 
Hopfer, C. J., Young, S. E., Purcell, S., Crowley, T. J., Stallings, M. C., 
Corley, R. P., et al. (2006). Cannabis receptor haplotype associated 
with fewer cannabis dependence symptoms in adolescents. Am J Med 
Genet B Neuropsychiatr Genet. 
Itokawa, M., Yamada, K., Iwayama-Shigeno, Y., Ishitsuka, Y., Detera-
Wadleigh, S., & Yoshikawa, T. (2003). Genetic analysis of a functional 
GRIN2A promoter (GT)n repeat in bipolar disorder pedigrees in 
humans. Neurosci Lett, 345(1), 53-56. 
Javitt, D., Zylberman, I., Zukin, S., Heresco-Levy, U., Lindenmayer, J. 
(1994). Amelioration of negative symptoms in schizophrenia by 
glycine. American Journal of Psychiatry, 151, 1234-1236. 

May 23, 2016 
 
 
25 
Kamprath, K., Marsicano, G., Tang, J., Monory, K., Bisogno, T., Di Marzo, V., 
et al. (2006). Cannabinoid CB1 receptor mediates fear extinction via 
habituation-like processes. J Neurosci, 26(25), 6677-6686. 
Kobayashi, K., Shimizu, E., Hashimoto, K., Mitsumori, M., Koike, K., 
Okamura, N., et al. (2005). Serum brain-derived neurotrophic factor 
(BDNF) levels in patients with panic disorder: as a biological predictor 
of response to group cognitive behavioral therapy. Prog 
Neuropsychopharmacol Biol Psychiatry, 29(5), 658-663. 
Kubany, E. S., Haynes, S. N., Leisen, M. B., Owens, J. A., Kaplan, A. S., 
Watson, S. B., & Burns, K. (2000). Development and preliminary 
validation of a brief broad-spectrum measure of trauma exposure: the 
Traumatic Life Events Questionnaire.  Psychological  Assessment 12, 
210-24. 
Kushner, M.G., Kim, S.W., Donahue, C., Thuras, P., Adson, D., Kotlyar, M., 
McCabe, J., Peterson, J., & Foa, E. B.  (2007).  D-cycloserine 
augmented exposure therapy for obsessive-compulsive disorder.  Biol 
Psychiatry, 62, 835-8.  
Land, C., & Riccio, D. (1999). D-Cycloserine: effects on long-term retention 
of a conditioned response and on memory for contextual attributes. 
Neurobiology of Learning and Memory, 72, 158-168. 
Lee, H., & Kim, J. (1998). Amygdala NMDA receptors are critical for new fear 
learning in previously fear-conditioned rates. Journal of Neuroscience, 
18, 8444-8454. 
Leon, A.C., Shear, M.K., Portera, L., Klerman, G.L. (1992).  Assessing 
impairment in patients with panic disorder: The Sheehan Disability 
Scale. Social Psychiatry and Psychiatric Epidemiology, 27, 78-82. 
Leon, A. C., Solomon, D. A., Mueller, T. I., Turvey, C. L., Endicott, J., Keller, 
M. B.  (1999). The Range of Impaired Functioning Tool (LIFE-RIFT): a 
brief measure of functional impairment. Psychol Med, 29, 869-78. 
Lin, C. H., Yeh, S. H., Leu, T. H., Chang, W. C., Wang, S. T., & Gean, P. W. 
(2003). Identification of calcineurin as a key signal in the extinction of 
fear memory. J Neurosci, 23(5), 1574-1579. 
Lin, C. H., Yeh, S. H., Lu, H. Y., & Gean, P. W. (2003). The similarities and 
diversities of signal pathways leading to consolidation of conditioning 
and consolidation of extinction of fear memory. J Neurosci, 23(23), 
8310-8317. 
Marsicano, G., Wotjak, C. T., Azad, S. C., Bisogno, T., Rammes, G., Cascio, 
M. G., et al. (2002). The endogenous cannabinoid system controls 
extinction of aversive memories. Nature, 418(6897), 530-534. 
Martinez-Gras, I., Hoenicka, J., Ponce, G., Rodriguez-Jimenez, R., Jimenez-
Arriero, M. A., Perez-Hernandez, E., et al. (2006). (AAT)n repeat in the 
cannabinoid receptor gene, CNR1: association with schizophrenia in a 
Spanish population. Eur Arch Psychiatry Clin Neurosci. 

May 23, 2016 
 
 
26 
Matsuoka, N., & Aigner, T. (1996). D-Cycloserine, a partial agonist at the 
glycine site coupled to N-methyl-D-aspartate receptors, improves 
visual recognition memory in rhesus monkeys. Journal of 
Pharmacology and Experimental Therapeutics, 278, 891-897. 
Mattick, R. P., Clarke, J.C.  (1998). Development and validation of measures 
of social phobia scrutiny fear and social interaction anxiety. Behav Res 
Ther, 36, 455-70. 
McMurtry, S. L. & Hudson, W. W. (2000). The Client Satisfaction Inventory: 
Results of an initial validation study. Research on Social Work Practice, 
10, 644-663. 
Monahan, J.B., Handelman, G.E., Hood, W.F., & Cordi, A.A. (1989). D-
Cycloserine, a positive modulator of the N-methyl-D-aspartate 
receptor, enhances performance of learning tasks in rats. 
Pharmacology, Biochemistry, and Behavior, 34, 649-653. 
Morgan, C.A., Grillon, C., Southwick, S.M., Davis, M., & Charney, D.S. 
(1995). Fear-potentiated startle in posttraumatic stress disorder. 
Biological Psychiatry, 38, 378-385. 
Mothet, J. P., Parent, A. T., Wolosker, H., Brady, R. O., Jr., Linden, D. J., 
Ferris, C. D., et al. (2000). D-serine is an endogenous ligand for the 
glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U 
S A, 97(9), 4926-4931. 
Nair, K.G.S., Epstein, I.G., Baron, H., & Mulinos, M.G. (1956). Absorption, 
distribution, and excretion of cycloserine in man. Antibiot Ann, 136-
140.  
Ou, L. C., & Gean, P. W. (2006). Regulation of amygdala-dependent learning 
by brain-derived neurotrophic factor is mediated by extracellular 
signal-regulated kinase and phosphatidylinositol-3-kinase. 
Neuropsychopharmacology, 31(2), 287-296. 
Phillips, K. A., McElroy, S. L., Keck, P. E., Jr., Pope, H. G., Jr., & Hudson, J.I. 
(1993).  Body dysmorphic disorder: 30 cases of imagined ugliness. Am 
J Psychiatry, 150, 302-8. 
Phillips, K. A., & Taub, S. L.  (1995).  Skin picking as a symptom of body 
dysmorphic disorder. Psychopharmacol Bull, 31, 279-88. 
Phillips, K. A., Hollander, E., Rasmussen, S. A., Aronowitz, B. R., DeCaria, 
C., & Goodman, W. K.  (1997). A severity rating scale for body 
dysmorphic disorder: development, reliability, and validity of a 
modified version of the Yale-Brown Obsessive Compulsive Scale. 
Psychopharmacol Bull 1997; 33, 17-22. 
Pickel, V. M., Colago, E. E., Mania, I., Molosh, A. I., & Rainnie, D. G. (2006). 
Dopamine D1 receptors co-distribute with N-methyl-d-aspartic acid 
type-1 subunits and modulate synaptically-evoked N-methyl-d-aspartic 
acid currents in rat basolateral amygdala. Neuroscience. 
Pitkanen, M., Sirvio, J., MacDonald, E., Niemi, S., Ekonsolo, T., & Riekkinen, 
P. (1995). The effects of D-Cycloserine and MK-801 on the 

May 23, 2016 
 
 
27 
performance of rats in two spatial learning and memory tasks. 
European Neuropsychopharmacology, 5, 391-393. 
Pritchard, J. K., & Donnelly, P. (2001). Case-control studies of association in 
structured or admixed populations. Theor Popul Biol, 60(3), 227-237. 
Purcell, S., & Sham, P. (2004). Properties of structured association 
approaches to detecting population stratification. Hum Hered, 58(2), 
93-107. 
Pussinen, R., Niememinen, S., Koivisto, E., Haapalinna, A., Riekkinen, S., & 
Sirvio, J. (1997). Enhancement of intermediate-term memory by an 
alpha1 agonist or a partial agonist at the glycine site of the NMDA 
receptor. Neurobiology of Learning and Memory, 67, 69-74. 
Rattiner, L. M., Davis, M., French, C. T., & Ressler, K. J. (2004). Brain-
derived neurotrophic factor and tyrosine kinase receptor B involvement 
in amygdala-dependent fear conditioning. J Neurosci, 24(20), 4796-
4806. 
 
Rescorla, R.A. (2001). Experimental extinction. In: Handbook of 
contemporary learning theories (Mowrer, R.R., Klein, S., eds.), 
pp.119-154. Mahwah, NJ: Erlbaum. 
Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., 
Zimand, E., Hodges, L., & Davis M.  (2004).  Cognitive enhancers as 
adjuncts to psychotherapy: use of D-cycloserine in phobic individuals 
to facilitate extinction of fear.  Arch Gen Psychiatry, 61, 1136-44. 
Rivas Salazar, J.L. (1970). On cycloserine in the treatment of pulmonary 
tuberculosis and its use for postoperative protection. Scandinavian 
Journal of Respiratory Diseases, 71, 314-324. 
Schaid, D. J., Rowland, C. M., Tines, D. E., Jacobson, R. M., & Poland, G. A. 
(2002). Score tests for association between traits and haplotypes 
when linkage phase is ambiguous. Am J Hum Genet, 70(2), 425-434. 
Satten, G. A., Flanders, W. D., & Yang, Q. (2001). Accounting for 
unmeasured population substructure in case-control studies of genetic 
association using a novel latent-class model. Am J Hum Genet, 68(2), 
466-477. 
Schwartz, B., Hashtroudi, S., Herting, R., Schwartz, P., Deutsch, S. (1996). 
D-Cycloserine enhances implicit memory in Alzheimer patients. 
Neurology, 46, 420-424. 
Smoller, J., Rosenbaum, J., Biederman, J., Kennedy, J., Dai, D., Racette, S., 
et al. (2003). Association of a genetic marker at the corticotropin 
releasing hormone locus with behavioral inhibition. Biol Psychiatry, 54, 
1376-1381. 
Stoppel, C., Albrecht, A., Pape, H. C., & Stork, O. (2006). Genes and 
neurons: molecular insights to fear and anxiety. Genes Brain Behav, 5 
Suppl 2, 34-47. 

May 23, 2016 
 
 
28 
Tang, K., Fu, D. J., Julien, D., Braun, A., Cantor, C. R., & Koster, H. (1999). 
Chip-based genotyping by mass spectrometry. Proc Natl Acad Sci U S 
A, 96(18), 10016-10020. 
Tang, Y. P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, 
M., et al. (1999). Genetic enhancement of learning and memory in 
mice. Nature, 401(6748), 63-69. 
Tang, Y. P., Wang, H., Feng, R., Kyin, M., & Tsien, J. Z. (2001). Differential 
effects of enrichment on learning and memory function in NR2B 
transgenic mice. Neuropharmacology, 41(6), 779-790. 
Thompson, L.T., Moskal, J.R., Disterhoftt, J.F. (1992). Hippocampus-
dependent learning facilitated by a monoclonal antibody or D-
Cycloserine. Nature, 359, 638-641. 
Tsai, G., Falk, W., Gunther, J., & Coyle, J. (1999). Improved cognition in 
Alzheimer’s disease with short term D-Cycloserine treatment. 
American Journal of Psychiatry, 156, 467-469. 
Vallat JN, Leger JM, Destruhaut J, Garoux R: [Dysmorphophobias, syndrome 
or symptom?]. Ann Med Psychol (Paris) 1971; 2(1):45-65 
van Berckel, B. N., Lipsch, C., Timp, S., Gispen-de Wied, C., Wynne, H., van 
Ree, J.M., & Kahn RS.  (1997).  Behavioral and neuroendocrine effects 
of the partial NMDA agonist D-cycloserine in healthy subjects.  
Neuropsychopharmacology, 16, 317-24.  
Wacholder, S., Rothman, N., & Caporaso, N. (2002). Counterpoint: bias from 
population stratification is not a major threat to the validity of 
conclusions from epidemiological studies of common polymorphisms 
and cancer. Cancer Epidemiol Biomarkers Prev, 11(6), 513-520. 
Walker, D.L., Ressler, K.J., Lu, K.-T., Davis, M. (2002).  Facilitation of 
Conditioned Fear Extinction by Systemic Administration or Intra-
Amygdala Infusions of DCS as Assessed with Fear-Potentiated Startle 
in Rats. Journal of Neuroscience, 22, 2343-2351. 
Waller, G., Meyer, C., & Ohanian, V.  (2001).  Psychometric properties of the 
long and short versions of the Young Schema Questionnaire: Core 
beliefs among bulimic and comparison women. Cog Ther Res, 25, 137-
147.  
Weissman, A.  (1979). The Dysfunctional Attitude Scale: A validation study. 
Dissertation Abstracts International, 40, 1389-1390. 
Wilhelm, S., Buhlmann, U., Tolin, D.F., Meunier, S.A., Pearlson, G.D., Reese, 
H.E., Cannistraro, P., Jenike, M.A., & Rauch, S.L. (2008). 
Augmentation of behavior therapy with d-cycloserine for obsessive-
compulsive disorder. American Journal of Psychiatry, 165, 335-341. 
Wotjak, C. T. (2005). Role of endogenous cannabinoids in cognition and 
emotionality. Mini Rev Med Chem, 5(7), 659-670. 
 
Yang, Y. L., & Lu, K. T. (2005). Facilitation of conditioned fear extinction by 
d-cycloserine is mediated by mitogen-activated protein kinase and 

May 23, 2016 
 
 
29 
phosphatidylinositol 3-kinase cascades and requires de novo protein 
synthesis in basolateral nucleus of amygdala. Neuroscience, 134(1), 
247-260. 
Young, J. E., & Brown, G.  (1990). Schema Questionnaire. Available from: 
Cognitive Therapy Center of New York, 3  East 80th Street - 
Penthouse, New York, NY 10021. 
Zarate, R., & Agras, W. (1994). Psychosocial treatment of phobia and panic 
disorders. Psychiatry, 57, 133-141. 
Zaykin, D. V., Westfall, P. H., Young, S. S., Karnoub, M. A., Wagner, M. J., & 
Ehm, M. G. (2002). Testing association of statistically inferred 
haplotypes with discrete and continuous traits in samples of unrelated 
individuals. Hum Hered, 53(2), 79-91. 
Zhang, P. W., Ishiguro, H., Ohtsuki, T., Hess, J., Carillo, F., Walther, D., et 
al. (2004). Human cannabinoid receptor 1: 5' exons, candidate 
regulatory regions, polymorphisms, haplotypes and association with 
polysubstance abuse. Mol Psychiatry, 9(10), 916-931.