Neuroimaging, Omega-3 and Reward in Adults With ADHD (NORAA) Trial

Objective:

Both attention deficit hyperactivity disorder (ADHD) and addictive behaviors have been
persistently related to impaired reward-related processes in the ventral striatum as
evidenced by functional magnetic resonance imaging studies (fMRI). These impairments
characterized by decreased BOLD activation are thought to be linked to dopamine pathways
including decreased D2 receptor function. Omega-3 highly unsaturated fatty acids (HUFAs) are
critical for cell-signaling among other complex functions throughout the central nervous
system. Animal models have demonstrated that depriving animals of the omega-3 DHA in utero
significantly decreases the density of ventral striatal D2- like receptors and furthermore
depletes dopamine in the nucleus acumens by 40-60%. The behavioral profile of animals
subjected to dietary induced deficiencies of omega-3 reflect decreased goal-directed behavior
and increased goal-irrelevant activity, hyperactivity, increased anxiety and reduced behavior
flexibility. Abnormally low levels of omega-3 HUFAs have been persistently reported in the
erythrocytes of both children and adults with ADHD while supplementation with omega-3 HUFAs
was found in a meta-analysis of 10 clinical trials to improve symptoms of ADHD. However, to
date no one has tested the potential mediating effects of omega-3 supplementation in
reward-related processes in adults with ADHD using neuroimaging techniques. There is hence a
need to research the potential treatment effects of omega-3 on assessments of brain function.
Therefore, the primary objective of this study is to test the effects of omega-3 intervention
(compared to a placebo) in increasing ventral striatal activation during the monetary
incentive delay (MID) task. Secondary objectives include collecting neuroimaging data and
standardized questionnaires measuring, mood, quality of life and symptoms of ADHD.

Study Population:

150 adults, other-wise healthy, aged 18-55 with ADHD.

Design:

The active group will be stratified according to age and sex to either an active intervention
group receiving (1) 3000 mg of omega-3 HUFA smoothie or a placebo group (2) 3000 mg of
smoothie macadamia nut oil for 16 weeks. After enrollment and baseline testing, active
participants will be randomized to either the treatment or placebo group and instructed to
begin consumption of assigned emulsions. Randomized participants will be assessed at
baseline, 1 month, 8 weeks, and 16 weeks.

Outcome Measures:

The primary outcome assessments will measure ventral-striatum activation during the MID task.
Secondary objectives include: structural MRI, symptoms of ADHD using the Conner s Adult ADHD
Rating Scales; negative affective symptoms; endocannabinoid levels and weight change.

- INCLUSION CRITERIA:

Participants will be 18 or over and up to 55 years old.

- In general good health.

- Body Mass Index (BMI) between 18 and 35.

- Able to come to the NIH clinical center for each of their scheduled appointments for
the duration of the study and have a working phone number.

- Able to understand the consent form and provide written informed consent.

- Have an IQ of 70 or greater as assessed by the WASI for fast IQ testing (a score of
less than this is considered to have global intellectual disability - classified in
DSM-IV as mental retardation). There are often issues around the ability to give
informed consent in adults with global intellectual disability.

- Meet DSM diagnostic criteria for ADHD as assessed by the CAADID Conners Adult ADHD
Diagnostic Interview for DSM-IV.

- Have significant symptoms of ADHD despite concurrent pharmacological and psychological
therapies as assessed by the Connors Adult ADHD rating scale (CAARS) (as assessed at
telephone screen).

- Be willing to have a 48hour wash-out of stimulant medication prior to both baseline
and follow-up scans.

- Willing to stop all nutritional supplements including omega-3 fats.

- Willing to stop eating seafood for the study duration of 16 weeks.

- Be willing to have 2 MRI scanning sessions.

- People who are willing to take the smoothie emulsion every day for 16 weeks.

EXCLUSION CRITERIA:

- Any medical illness or treatment that in the view of the investigators would
compromise participation in research or participant safety, as determined by medical
history, physical examination, laboratory tests (see details under Screening measures
below), including, but not limited to:

- Unstable medical conditions requiring immediate intervention.

- Unstable or rapidly progressive neurological diseases.

- History hemorrhagic or ischemic stroke within the last 3 months.

- Known heart disease.

- Hypertension.

- Asthma

- If the participant is related to the study investigator or their superior,
subordinate, or immediate family member.

- HIV positive.

- Significant dietary limitations:

Allergy, hypersensitivity, or intolerance to fish oils or omega-3 fats which are found in
fish..

- Allergy, hypersensitivity, or intolerance to Macadamia nuts or any nuts such as
almonds, walnuts, pecans, peanuts, etc.

- Pregnancy or breastfeeding (by urine pregnancy test; self-report).

- Reported consumption of fish and seafood three or more times per week within the last
three months.

- Regular consumption of omega-3 supplements (e.g., cod liver oil, borage oil, fish oil
or evening primrose oil) , defined as an average of 250 mg/day of omega-3 HUFAs over
the previous 3 months.

- Severe alcohol or substance use disorder according to the AUDIT.

- Acute intoxication or withdrawal from alcohol or other CNS active substances to the
extent that they may impair capacity to provide informed consent or participate in
research.

- Some neuropsychiatric disorders are either so rare or associated with such profound
alterations of brains structure and function that they will be excluded. This includes
a diagnosis of severe Bipolar disorders or Axis 1 psychotic disorder assessed by SCID,
including schizophrenia, psychosis NOS, autism, substance dependence; dementia, eating
disorder.

- Cognitive impairment severe enough to preclude informed consent or valid responses on
self-report questionnaires.

- Behavioral instability significant enough to impair ability for consent and
participation.

- Participation in other research studies that in the opinion of the investigators would
interfere with study outcomes or study compliance.

- On any of the following medications: Atomoxetine (Strattera), bupropion (Wellbutrin),
tricyclic antidepressants (imipramine), alpha adrenergic agonists (clonidine,
guanfacine) or modafinil (Provigil) depending whether dose interferes with scan and
whether or not patient can stay on same dose throughout study.

- Use of non-steroidal anti-inflammatory drugs (NSAIDs), dalteparin, dipyrdamole,
enoxaparin, ticlopedine, more than once per week within the last three months.

- Living situation unsuitable for the storage or use of intervention materials.

MRI Exclusion Criteria:

- Have ferromagnetic objects in their bodies, which might be adversely affected by MRI
(e.g., surgical clips, metal fragments in or near brain, eye or blood vessels, cardiac
or neurological pacemaker, cochlear or eye implant). Any doubt about presence of these
objects will result in exclusion from this study.

- Extreme claustrophobia.

- Left-handed individuals.