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Clinical trials landscape

TL;DR — Among nine psychiatric disorders in a comparison of 90 recent high-quality RCTs, GAD had the second-largest pre-post placebo change: d_av 1.23 (95% CI 1.06–1.41), behind major depression (1.40) and above OCD (0.65) and schizophrenia (0.59) (Bschor 2024, PMID 38809560). This contextualises, but does not by itself explain, drug–placebo differences of 2.5–3.6 HAM-A points (Slee 2019, PMID 30712879) or failed programmes. Psychotherapy g=0.76 and medication g=0.38 across 79 GAD RCTs should not be ranked because medication studies generally used pill placebo while psychotherapy studies used inactive controls (Carl 2020, PMID 30760112). MM120 reported a −6.0-point HAM-A difference at 200 µg after one dose (Robison 2025, PMID 40906494) and has two phase 3 trials active but not recruiting (NCT06809595, n=245; NCT06741228, n=214). Other active programmes include ITI-1284 (NCT06480383, n=705; NCT06701903, n=570), ABBV-932 (NCT06846320, n=315) and psilocybin (NCT06969170, n=50). All NCT records on this page were retrieved live from the ClinicalTrials.gov API on 2026-09-02.

The placebo-response problem

Diagnosis Pooled pre-post placebo effect (d_av, 95% CI)
Major depressive disorder 1.40 (1.24–1.56)
Generalized anxiety disorder 1.23 (1.06–1.41)
Panic, ADHD, PTSD, social phobia, mania 0.68–0.92
OCD 0.65 (0.51–0.78)
Schizophrenia 0.59 (0.41–0.76)

Source: Bschor 2024, PMID 38809560 (90 RCTs, 9,985 placebo participants; differences across diagnoses statistically significant, Q=88.5, df=8, p<0.001).

Two consequences follow directly:

  1. Active-drug effects look small even when they are real. The Cochrane review's high-certainty response RR of 1.41 (NNTB 7) sits on top of a placebo arm that improves by more than one standard deviation (Kopcalic 2025, PMID 39880377; Bschor 2024, PMID 38809560).
  2. Cross-modality comparison is invalid without matching controls. Bandelow's pre-post analysis found medication effect sizes (d=2.02) larger than psychotherapy (d=1.22) while noting psychotherapy pre-post effects did not differ from pill placebo (d=1.29) (Bandelow 2015, PMID 25932596); Carl's GAD-specific meta-analysis found the reverse ordering (psychotherapy g=0.76 vs medication g=0.38) and explained why the two should not be compared directly (Carl 2020, PMID 30760112). Both are correct within their own control structures.

Other trial-design findings that shape the literature: for SSRIs a linear improvement model fits best across 12 weeks while for SNRIs a logarithmic model fits best (greatest early gain), higher SSRI doses (but not higher SNRI doses) give greater improvement, and higher doses of both increase side-effect dropout (Jakubovski 2019, PMID 30479005; 57 trials, N=16,056, pooled across anxiety disorders). Publication bias has been detected in the psychotherapy literature (Carl 2020, PMID 30760112; Cuijpers 2014, PMID 24487344).

Landmark completed trials

Trial NCT Phase / n What it established
MM120 dose-finding NCT05407064 Phase 2, n=198, started 2022-08-24, COMPLETED Single-dose lysergide: HAM-A LS mean difference −5.0 (95% CI −9.6 to −0.4) at 100 µg and −6.0 (−9.8 to −2.0) at 200 µg vs placebo at week 4; 25 µg and 50 µg not significant; visual perceptual changes in 46.2% (Robison 2025, PMID 40906494)
TAME (MBSR vs escitalopram) NCT03522844 Phase 4, n=276, COMPLETED MBSR non-inferior to escitalopram in anxiety disorders; AEs 78.6% vs 15.4% (Hoge 2023, PMID 36350591)
CAMS NCT00052078 Phase 3, n=488, COMPLETED Combination CBT+sertraline 80.7% response vs CBT 59.7%, sertraline 54.9%, placebo 23.7% in childhood anxiety (Walkup 2008, PMID 18974308)
Escitalopram in paediatric GAD NCT03924323 Phase 4, n=273, COMPLETED PARS-GAD LS mean difference −1.42, p=0.028, ages 7–17 (Strawn 2023, PMID 37074330)
Escitalopram in adolescent GAD (pharmacogenetics) NCT02818751 n=84 enrolled, COMPLETED PARS change −8.65 vs −3.52 (p=0.005); CYP2C19 phenotype altered escitalopram exposure (Strawn 2020, PMID 32857933)
MCT vs CBT NCT00426426 n=68 enrolled, COMPLETED MCT recovery 65% vs CBT 38%; advantage sustained to 9 years (Nordahl 2018, PMID 30294448; Solem 2021, PMID 34520637)
Troriluzole in GAD NCT03829241 Phase 3, n=881, started 2019-02-19, COMPLETED Registry results are posted; no PubMed-indexed journal report was located by an NCT-ID search on 2026-09-02
Vilazodone in GAD NCT01629966 (n=680), NCT01844115 (n=415), NCT01766401 (n=402) Phase 3, COMPLETED Meta-analysis of 3 RCTs (844 vilazodone / 618 placebo): HAM-A and CGI significantly superior to placebo, but NNT 10 for HAM-A response, NNT 12 for CGI-I, NNH 14; likelihood-to-be-helped-or-harmed 1.4 (0.48–3.33), i.e. inconclusive (Zareifopoulos 2017, PMID 28483071; Durgam 2016, PMID 27232052; Gommoll 2015, PMID 25891440)
Extended-release lorazepam NCT02305797 Phase 3, n=495, started 2015-01, COMPLETED Registry results are posted; no PubMed-indexed journal report was located by an NCT-ID search on 2026-09-02
ENX-102 NCT05749055 (Phase 2, n=252), NCT06653296 (Phase 2, n=38) COMPLETED Subunit-selective GABA_A programme in GAD; no PubMed-indexed report was located by NCT-ID searches on 2026-09-02
SEP-363856 (ulotaront) NCT05729373 Phase 2/3, n=434, started 2023-03-08, COMPLETED TAAR1 agonist tested in GAD; no PubMed-indexed report was located by an NCT-ID search on 2026-09-02
Toludesvenlafaxine SR NCT05970510 Phase 3, n=555, started 2023-08-04, COMPLETED Triple reuptake inhibitor in GAD
CYB004 (DMT analogue) NCT06051721 Phase 2, n=36, started 2024-05-10, COMPLETED Psychedelic programme in GAD

Active pipeline (retrieved 2026-09-02)

NCT Status Phase / n Intervention Note
NCT06809595 (Panorama) ACTIVE_NOT_RECRUITING Phase 3, n=245, start 2025-01-29 MM120 / DT120 vs placebo The confirmatory test of the lysergide phase 2b result
NCT06741228 (Voyage) ACTIVE_NOT_RECRUITING Phase 3, n=214, start 2024-12-11 DT120 vs placebo Second phase 3 in the same programme
NCT06480383 RECRUITING Phase 2, n=705 ITI-1284 10/20 mg vs placebo, adjunctive The largest active GAD drug trial
NCT06701903 RECRUITING Phase 2, n=570 ITI-1284 10/20 mg vs placebo, monotherapy Companion monotherapy programme
NCT06846320 RECRUITING Phase 2, n=315, start 2025-04-29 ABBV-932 added to antidepressant therapy Adjunctive design
NCT06969170 RECRUITING Phase 2, n=50 Psilocybin oral solution vs placebo Second psychedelic mechanism in GAD
NCT06243640 RECRUITING Phase 3, n=504, start 2023-07-25 Buagafuran capsules vs placebo Chinese phase 3 programme
NCT05772104 RECRUITING Phase 3, n=495, start 2023-04-17 Shugan Jieyu capsule vs placebo Traditional-medicine phase 3
NCT04221997 RECRUITING Phase 4, n=150, start 2019-11-01 Sertraline in youth with generalized, separation and/or social anxiety Paediatric
NCT06278909 RECRUITING n=10, start 2024-01-18 Trigeminal nerve stimulation in treatment-resistant GAD Feasibility
NCT04557891 RECRUITING n=48, start 2021-07-26 Low-intensity focused ultrasound pulsation vs sham Novel neuromodulation
NCT07121712 RECRUITING n=40, start 2025-09-09 Navigated continuous theta-burst stimulation vs sham cTBS had the largest severity effect in the NIBS network (Duan 2025, PMID 40203547)
NCT04895995 RECRUITING n=95, start 2022-02-02 Daylight digital CBT application Cardiovascular-disease population with generalized-anxiety symptoms, not a diagnosed-GAD-only trial
NCT07201844 RECRUITING n=440, start 2025-08-26 Patient preference between metacognitive and intolerance-of-uncertainty internet CBT Directly tests the two mechanism-derived protocols
NCT06942429 RECRUITING n=556, start 2025-06-19 Stepped versus stratified care for youth anxiety Service-delivery design
NCT06934525 RECRUITING n=501, start 2025-11-01 Team-delivered exposure-based CBT in community health settings Implementation
NCT07391020 RECRUITING n=300, start 2026-03-01 Text-message safety-behaviour fading for pathological worry vs progressive muscle relaxation Mechanism-targeted micro-intervention
NCT05427708 RECRUITING n=180, start 2022-08-22 Capnometry-guided respiratory intervention vs psychoeducation Transdiagnostic pathological anxiety
NCT06811311 RECRUITING n=60, start 2025-02-01 Ericksonian hypnotherapy with EEG in GAD —

Caution on searching this space: "GAD" also abbreviates glutamic acid decarboxylase, and a naive ClinicalTrials.gov query for GAD returns type 1 diabetes GAD-alum immunotherapy trials (e.g. NCT01785108, NCT05351879). Those are excluded here.

Who is in a GAD trial, and who is not

The generalisability problem in this condition has been quantified once, by accident, in the analysis of a trial that failed to recruit (Kalpakidou 2019, PMID 31126337):

Filter Effect
People with GAD-7 ≥10 at entry to an English IAPT service Reference population
…who would have been eligible for the trial 5%
…who were actually identified as potentially eligible by recruiting practitioners ~12% of those eligible
…who agreed to participate 25% of those approached; three-quarters declined, most refusing randomisation to medication

Compounding this, the Cochrane antidepressant review excluded participants with serious medical comorbidity and with regular benzodiazepine use and enrolled few with secondary psychiatric comorbidity (Kopcalic 2025, PMID 39880377), while substance use disorder co-occurs in about half of all lifetime GAD (Alegría 2010, PMID 20923623) and personality disorder cuts remission likelihood by 30% (Massion 2002, PMID 11982447). The trial population and the clinical population are not the same population, and no GAD trial programme has published a formal generalisability assessment [unverified as of 2026-09-02].

Endpoint choice decides the answer

Choice Consequence
Mean HAM-A change vs remission (HAM-A ≤7) Different drug rankings from overlapping literatures: quetiapine and duloxetine lead on mean change (Slee 2019, PMID 30712879), agomelatine leads on remission (OR 2.70, 1.74–4.19; Kong 2020, PMID 33343351)
Continuous vs responder analysis Antidepressant response NNTB 7 (Kopcalic 2025, PMID 39880377) alongside best-drug mean differences of 2.5–3.6 HAM-A points (Slee 2019, PMID 30712879)
LOCF vs observed cases In one three-arm trial, escitalopram separated from placebo on observed cases (−1.92, p=0.033) but not on the primary LOCF analysis (−1.52, p=0.09), while venlafaxine XR separated on both (Bose 2008, PMID 18050245)
Censoring at dropout vs conservative ITT In late-life GAD, escitalopram response was 69% vs 51% (p=0.03) under the primary strategy and 57% vs 45% (p=0.11) under conservative ITT (Lenze 2009, PMID 19155456)
Worry (PSWQ) vs GAD severity In primary-care CBT for older adults, worry severity improved significantly while GAD severity did not (Stanley 2009, PMID 19351943)
Drug trials vs psychotherapy trials Drug trials use HAM-A and placebo controls; psychotherapy trials use PSWQ and waitlist or TAU controls, which is why cross-modality effect sizes cannot be compared directly (Carl 2020, PMID 30760112; Bandelow 2015, PMID 25932596)

No general-adult GAD core outcome set was located in a PubMed search rerun on 2026-09-02. A paediatric anxiety-disorder set is under development (Monga 2023, PMID 37244653), and a 2026 patient-engagement study identified candidate outcomes for a perinatal GAD core set (Stallwood 2026, PMID 42003419). The broader adult field therefore still lacks a common endpoint standard.

What the pipeline says about the field

  • Mechanistic novelty is concentrated in psychedelics and GABAergic agents. MM120, psilocybin and CYB004 on one side; ENX-102, ITI-1284 and ABBV-932 on the other. The GABAergic direction is consistent with the 58-locus anxiety GWAS's GABAergic signal (Strom 2026, PMID 41634414) — though the drugs preceded the genetics (mechanism and models).
  • Single-dose designs break the placebo problem differently. A one-off intervention with a 4-week endpoint has a different placebo trajectory from 8 weeks of daily dosing, and MM120's −6.0 point difference is larger than any chronic-dosing agent's (Robison 2025, PMID 40906494; compare quetiapine −3.60 in Slee 2019, PMID 30712879). Functional unblinding by perceptual effects in 46.2% of dosed participants is the obvious confound.
  • Neuromodulation is entering GAD trials at small scale (n=10 to n=48), which is exactly the sample size that produced the implausibly wide intervals in the existing meta-analyses (treatment-resistant GAD).
  • Delivery-science trials now rival drug trials in size (NCT06942429 n=556; NCT06934525 n=501; NCT07201844 n=440), consistent with growing attention to service delivery (comorbidity and primary care).
  • Virtual-reality exposure, effective across anxiety disorders (g=0.90 vs waitlist, 0.78 vs psychological placebo, and no different from in vivo exposure; Carl 2019, PMID 30287083), is largely absent from the GAD-specific pipeline — unsurprising, since GAD lacks a discrete phobic stimulus.

Open questions

  • Will MM120's phase 2b effect replicate in Panorama (NCT06809595) and Voyage (NCT06741228)? A −6.0 HAM-A point difference from a single dose would be the largest effect ever measured in GAD.
  • How should trials handle functional unblinding when 46.2% of dosed participants experience perceptual changes (Robison 2025, PMID 40906494)?
  • Why do several completed phase 2/3 GAD programmes lack a PubMed-indexed journal report (troriluzole NCT03829241, ENX-102 NCT05749055, SEP-363856 NCT05729373, extended-release lorazepam NCT02305797)? NCT-ID searches on 2026-09-02 found none; NCT03829241 and NCT02305797 nevertheless have results posted in the registry. A PubMed search on the same date located no systematic audit confined to GAD trial reporting, leaving the magnitude of selective non-publication unknown.
  • Can the placebo response be reduced by design rather than accepted? GAD's d_av 1.23 (Bschor 2024, PMID 38809560) is a property of the trials, not necessarily of the disorder.
  • Should general-adult GAD adopt a core outcome set? Paediatric anxiety has one in development (Monga 2023, PMID 37244653), and perinatal GAD now has candidate outcomes derived with patients (Stallwood 2026, PMID 42003419), but general-adult endpoint pluralism still permits different rankings.
  • Does the head-to-head MCT-vs-IU internet CBT trial (NCT07201844) settle which mechanism-derived protocol works better (mechanism and models)?

References

  1. Bschor T, et al. Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders: A Systematic Review and Meta-Analysis. JAMA Psychiatry. 2024;81:757-768. PMID 38809560
  2. Carl E, et al. Psychological and pharmacological treatments for generalized anxiety disorder (GAD): a meta-analysis of randomized controlled trials. Cogn Behav Ther. 2020;49:1-21. PMID 30760112
  3. Jakubovski E, et al. Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders. Depress Anxiety. 2019;36:198-212. PMID 30479005
  4. Bandelow B, et al. Efficacy of treatments for anxiety disorders: a meta-analysis. Int Clin Psychopharmacol. 2015;30:183-92. PMID 25932596
  5. Cuijpers P, et al. Psychological treatment of generalized anxiety disorder: a meta-analysis. Clin Psychol Rev. 2014;34:130-40. PMID 24487344
  6. Robison R, et al. Single Treatment With MM120 (Lysergide) in Generalized Anxiety Disorder: A Randomized Clinical Trial. JAMA. 2025;334:1358-1372. PMID 40906494
  7. Hoge EA, et al. Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Adults With Anxiety Disorders. JAMA Psychiatry. 2023;80:13-21. PMID 36350591
  8. Walkup JT, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359:2753-66. PMID 18974308
  9. Strawn JR, et al. A Multicenter Double-Blind, Placebo-Controlled Trial of Escitalopram in Children and Adolescents with Generalized Anxiety Disorder. J Child Adolesc Psychopharmacol. 2023;33:91-100. PMID 37074330
  10. Strawn JR, et al. Escitalopram in Adolescents With Generalized Anxiety Disorder. J Clin Psychiatry. 2020;81:20m13396 (online). PMID 32857933
  11. Nordahl HM, et al. Metacognitive therapy versus cognitive-behavioural therapy in adults with generalised anxiety disorder. BJPsych Open. 2018;4:393-400. PMID 30294448
  12. Solem S, et al. Metacognitive therapy versus cognitive-behavioral therapy in adults with generalized anxiety disorder: A 9-year follow-up study. Brain Behav. 2021;11:e2358. PMID 34520637
  13. Zareifopoulos N, Dylja I. Efficacy and tolerability of vilazodone for the acute treatment of generalized anxiety disorder: A meta-analysis. Asian J Psychiatr. 2017;26:115-122. PMID 28483071
  14. Durgam S, et al. Efficacy and Safety of Vilazodone in Patients With Generalized Anxiety Disorder: A Randomized, Double-Blind, Placebo-Controlled, Flexible-Dose Trial. J Clin Psychiatry. 2016;77:1687-1694. PMID 27232052
  15. Gommoll C, et al. A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder. Depress Anxiety. 2015;32:451-9. PMID 25891440
  16. Carl JR, et al. Efficacy of digital cognitive behavioral therapy for moderate-to-severe symptoms of generalized anxiety disorder. Depress Anxiety. 2020;37:1168-1178. PMID 32725848
  17. Carl E, et al. Virtual reality exposure therapy for anxiety and related disorders: A meta-analysis of randomized controlled trials. J Anxiety Disord. 2019;61:27-36. PMID 30287083
  18. Duan N, et al. Evaluating the efficacy and acceptability of non-invasive brain stimulation for generalized anxiety disorder. Psychiatry Res Neuroimaging. 2025;349:111989. PMID 40203547
  19. Slee A, et al. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet. 2019;393:768-777. PMID 30712879
  20. Kopcalic K, et al. Antidepressants versus placebo for generalised anxiety disorder (GAD). Cochrane Database Syst Rev. 2025;1:CD012942. PMID 39880377

  21. Strom NI, et al. Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling. Nat Genet. 2026;58:275-288. PMID 41634414

  22. Kalpakidou AK, et al. Barriers to recruitment when conducting a commissioned randomised controlled trial of medication versus psychological therapy for generalised anxiety disorder: some lessons learned. Trials. 2019;20:284. PMID 31126337

  23. Alegría AA, et al. Comorbidity of generalized anxiety disorder and substance use disorders. J Clin Psychiatry. 2010;71:1187-95. PMID 20923623
  24. Massion AO, et al. Personality disorders and time to remission in generalized anxiety disorder, social phobia, and panic disorder. Arch Gen Psychiatry. 2002;59:434-40. PMID 11982447
  25. Kong W, et al. Comparative Remission Rates and Tolerability of Drugs for Generalised Anxiety Disorder. Front Pharmacol. 2020;11:580858. PMID 33343351
  26. Bose A, et al. Randomized placebo-controlled trial of escitalopram and venlafaxine XR in the treatment of generalized anxiety disorder. Depress Anxiety. 2008;25:854-61. PMID 18050245
  27. Lenze EJ, et al. Escitalopram for older adults with generalized anxiety disorder: a randomized controlled trial. JAMA. 2009;301:295-303. PMID 19155456
  28. Stanley MA, et al. Cognitive behavior therapy for generalized anxiety disorder among older adults in primary care: a randomized clinical trial. JAMA. 2009;301:1460-7. PMID 19351943
  29. Bandelow B, et al. Efficacy of treatments for anxiety disorders: a meta-analysis. Int Clin Psychopharmacol. 2015;30:183-92. PMID 25932596
  30. Monga S, et al. Study Preregistration: Measuring What Matters: Development and Dissemination of a Core Outcome Set for Pediatric Anxiety Disorders Clinical Trials. J Am Acad Child Adolesc Psychiatry. 2023;62:696-698. PMID 37244653
  31. Stallwood EM, et al. Developing a core outcome set for generalized anxiety disorder during the perinatal period: Identifying core treatment outcomes in perinatal anxiety. Br J Clin Psychol. 2026. PMID 42003419

Trial registry records (ClinicalTrials.gov API, all retrieved 2026-09-02): NCT05407064, NCT06809595, NCT06741228, NCT06480383, NCT06701903, NCT06846320, NCT06969170, NCT06243640, NCT05772104, NCT04221997, NCT06278909, NCT04557891, NCT07121712, NCT04895995, NCT07201844, NCT06942429, NCT06934525, NCT07391020, NCT05427708, NCT06811311, NCT03829241, NCT05749055, NCT06653296, NCT05729373, NCT05970510, NCT06051721, NCT02305797, NCT01629966, NCT01844115, NCT01766401, NCT03522844, NCT00426426, NCT02818751, NCT03924323, NCT00052078. NCT07233278 was also checked and excluded: its live record concerns recurrent pregnancy loss with anxiety, not a GAD-defined sample.