Combined CBT and Lisdexamfetamine Doubles Binge-Eating Remission: The Trial That Should Change Treatment Guidelines
- Three-arm RCT (N=141) comparing CBT alone, lisdexamfetamine (LDX) alone, and CBT+LDX combined for binge-eating disorder with comorbid obesity over 12 weeks
- Binge-eating remission rates: CBT+LDX 70.2% vs. CBT alone 44.7% vs. LDX alone 40.4% (p=0.008) — combination therapy significantly outperformed both monotherapies
- Weight loss: LDX and CBT+LDX produced significant weight loss; CBT alone produced none. LDX had the highest rate of clinically meaningful weight loss (>=5%): 53.2% vs. CBT+LDX 40.4% vs. CBT 6.4%
- First major RCT demonstrating synergy between psychotherapy and pharmacotherapy for BED — neither alone matches the combined effect on binge-eating cessation
Binge-eating disorder is the most prevalent eating disorder in the United States. It is also the least treated. When treatment does occur, it typically follows a monotherapy logic: either psychotherapy or medication, depending on which specialist the patient reaches first. Grilo and colleagues have produced the trial that challenges this either/or framework — a three-arm RCT that directly compares CBT, lisdexamfetamine, and their combination. The results are unambiguous. Combination wins.
The design
One hundred forty-one adults with BED and comorbid obesity (83.7% women, mean age 43.6, mean BMI 38.6 kg/m2) were randomized to 12 weeks of CBT alone (N=47), lisdexamfetamine alone (N=47), or CBT plus lisdexamfetamine (N=47). The trial ran from March 2019 to September 2023 at a single academic site. Retention was strong: 87.2% completed post-treatment assessments. The primary outcome was binge-eating frequency; key secondary outcomes included binge-eating remission and percent weight loss.
What makes this design powerful is the three-arm structure. Most combination trials compare combination versus one monotherapy, leaving clinicians guessing whether the other component alone might have performed equally well. Grilo's team eliminated that ambiguity. Every comparison is head-to-head.
The binge-eating results
All three treatments reduced binge-eating frequency. That is expected — both CBT and lisdexamfetamine have established efficacy for BED as monotherapies. What matters is the separation. CBT+LDX produced the largest reduction and significantly outperformed both CBT alone (t(371)=3.24, p=0.001) and LDX alone (t(371)=2.05, p=0.04) at post-treatment.
The remission data are more striking. Remission — defined as zero binge-eating episodes in the preceding 28 days — reached 70.2% in the combination group. CBT alone: 44.7%. LDX alone: 40.4%. The difference was statistically significant (Chi-sq=9.77, p=0.008). In clinical terms: seven out of ten patients who received combined treatment stopped binge eating entirely by week 12. For either monotherapy, that number was closer to four out of ten.
The 25-percentage-point gap between combination and monotherapy is not a marginal effect. It is the difference between a treatment that helps some patients and a treatment that helps most.
The weight question
Here the story diverges. LDX and CBT+LDX both produced significant weight loss throughout treatment. CBT alone did not — weight remained unchanged. At post-treatment, LDX had the highest rate of achieving clinically meaningful weight loss (>=5% body weight): 53.2%, compared with 40.4% for CBT+LDX and 6.4% for CBT. The difference between LDX and CBT for weight loss was large: LDX outperformed CBT significantly starting at month one and through post-treatment (p<0.0001).
This creates a clinical tension. For binge-eating cessation, combination is clearly superior. For weight loss, LDX carries most of the effect, and adding CBT does not amplify it. Patients and clinicians who prioritize weight loss as the primary outcome might question whether the additional resource investment in combined treatment is justified.
But this framing misses the point. BED is an eating disorder, not an obesity treatment. The primary clinical target is binge-eating cessation and the restoration of controlled eating behavior. Weight loss, when it occurs, is a welcome secondary outcome — but it should not drive treatment selection for a psychiatric condition. The combination achieves what matters most: stopping the binges.
Why combination works
The synergy is mechanistically plausible. CBT addresses the cognitive and behavioral maintenance factors of BED: dietary restraint patterns, negative body image, emotional triggers for binge episodes, and the permission-giving thoughts that precede loss of control. Lisdexamfetamine, a prodrug stimulant, acts on dopaminergic and noradrenergic circuits involved in impulse control and reward processing. It reduces the urge to binge at a neurochemical level.
These are complementary mechanisms. CBT restructures the cognitive architecture around eating. LDX dampens the impulse signal. Together, the patient has both fewer triggers and less biological drive to act on the triggers that remain. The 70% remission rate reflects this convergence — neither mechanism alone achieves what both achieve together.
What this means for practice
BED affects approximately 2-3% of the general population. Among individuals with obesity seeking treatment, prevalence reaches 20-30%. Despite this, most patients with BED receive either psychotherapy or pharmacotherapy, rarely both. The barriers are systemic: prescribers and therapists often operate in separate systems, insurance frameworks may not cover combined modalities, and clinical guidelines have historically treated the two as alternatives rather than complements.
This trial argues for a paradigm shift. If you treat BED, advocate for multimodal treatment. If you are a therapist, collaborate with a prescriber. If you are a prescriber, refer for concurrent CBT. The 25-percentage-point difference in remission rates is not a nuance that can be ignored for convenience. It is an ethical argument for combination treatment as the default, not the exception.
In the first three-arm RCT for binge-eating disorder, combined CBT and lisdexamfetamine achieved 70.2% binge-eating remission — versus approximately 42% for either treatment alone. The synergy between restructuring cognition and dampening impulse is not theoretical. It is now quantified.
Single-site trial (Yale) — unknown whether results generalize to community settings with less specialized therapists or different patient populations. Twelve-week treatment period with no long-term follow-up reported in this primary paper — durability of combination advantage is uncertain. Sample was 83.7% women, predominantly White — limited generalizability to men and racial/ethnic minorities. BED with comorbid obesity only — does not address normal-weight BED. Lisdexamfetamine carries stimulant-class risks (potential for misuse, cardiovascular effects, insomnia) not applicable to CBT. No placebo arm — cannot distinguish LDX effect from general pharmacological placebo response. CBT produced no weight loss — this may reflect the specific CBT protocol used rather than CBT for BED generally.