SEC Filing | GH Research

Exploring the Therapeutic Potential of Mebufotenin (GH001) Across Depressive Disorders ACNP 2026 Mini Panel Chair Michael E. Thase, MD Presenters Lisa Harding, MD Kristina M. Deligiannidis, MD Roger S. McIntyre, MD, FRCPC

Chair Michael E. Thase, MD Department of Psychiatry, University of Pennsylvania, and Corporal Michael J. Crescenz Veterans Affairs Medical Center Philadelphia, PA, USA GH001 Provides Rapid and Significant Antidepressant Effects in Patients with Treatment-Resistant Depression: Efficacy and Safety Results from a Phase 2b, Double-Blind, Randomized Controlled Trial with a 6-Month Open-Label Extension Lisa Harding, MD Mood Institute and Yale School of Medicine Milton, CT, USA Rapid Improvement in Anhedonia Following GH001 Treatment in Patients with Treatment-Resistant Depression, Postpartum Depression, and Bipolar II Disorder and a Current Major Depressive Episode Roger S. McIntyre, MD, FRCPC Department of Psychiatry, University of Toronto Toronto, ON, Canada GH001 Is Associated with Improved Self-Reported Maternal Functioning in Patients with Postpartum Depression and Rapid Elimination from Breastmilk Kristina M. Deligiannidis, MD Feinstein Institutes for Medical Research Northwell Health Manhasset, NY, USA

Author Disclosures Michael E. Thase Consultant – Axsome, Clexio Biosciences, Gerson Lehrman Group, GH Research, Janssen, Johnson & Johnson, Lundbeck, Luye Pharma, Merck, Otsuka, Pfizer, Sage, Seelos Therapeutics, Sunovion, and Takeda. Grant support – Acadia, Alkermes, Axsome, Intra-Cellular Therapies, Janssen, Myriad, National Institute of Mental Health, Otsuka, Patient-Centered Outcomes Research Institute (PCORI), and Takeda. Royalties – American Psychiatric Press, Inc., Guilford Publications, Herald House, Wolters Kluwer, and W. W. Norton & Company. Spouse’s employment – Dr. Diane Sloan is a Senior Vice President of OPEN Health, which does business with many companies Lisa Harding Advisory board – AbbVie, GH Research, Johnson & Johnson, and Otsuka. Consultant – GH Research and Johnson & Johnson Kristina M. Deligiannidis Consultant − Biogen, Brii Biosciences, Gerbera Therapeutics, GH Research, Lipocine, Neurocentria, Reunion Neuroscience, and Sage. Principal investigator for contracted research − DuKang Pharmaceuticals, Sage, and Woebot Health Roger S. McIntyre Consultant/speaker − AbbVie, Alkermes, Atai Life Sciences, Axsome, Bausch Health, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Intra-Cellular Therapies, Janssen, Kris, Lundbeck, Mitsubishi Tanabe, Neumora Therapeutics, NeuraWell, Neurocrine, NewBridge Pharmaceuticals, Novo Nordisk, Otsuka, Pfizer, Purdue, Sage, Sanofi, Sunovion, Takeda, and Viatris. Research grant support − Canadian Institutes of Health Research, Global Alliance for Chronic Diseases, National Natural Science Foundation of China, and the Milken Institute Disclosures

Psychoactive Molecules as Rapid-Acting Treatment for Depression Pharmacotherapy is the first-line treatment recommendation for people with moderate to severe MDD1,2; however, there is an unmet need for rapid and effective pharmacological treatments Less than half of patients with MDD treated in clinical trials with traditional antidepressant medications (SSRIs, SNRIs, or TCAs) achieve remission,3,4 and the proportion of patients achieving remission in clinical practice may be even smaller5 A growing body of evidence indicates that psychoactive molecules may provide rapid reduction in severity of symptoms in patients with psychiatric disorders including MDD, TRD, BDII depression, and PPD6-9 Psychoactive molecules including LSD, ayahuasca, psilocybin, MDMA, and mebufotenin have been assessed in clinical trials for those indications6-9 4 Abbreviations: BDII = Bipolar II disorder; LSD = Lysergic acid diethylamide; MDD = Major depressive disorder; MDMA = 3,4-methylenedioxymethamphetamine; PPD = Postpartum depression; SNRI = Serotonin-norepinephrine reuptake inhibitor; SSRI = Selective serotonin reuptake inhibitor; TCA = Tricyclic antidepressant; TRD = Treatment-resistant depression. 1. APA Clinical practice guideline for the treatment of depression across three age cohorts. 2019. Available at: https://www.apa.org/depression-guideline. Accessed Oct. 23, 2025. 2. Lam RW, et al. Can J Psychiatry. 2024;69(9):641-687. 3. Thase ME, et al. J Clin Psychiatry. 2005;66(8):974-981. 4. Machado M, et al. Curr Med Res Opin. 2006;22(9):1825-1837. 5. Moller HJ, et al. World J Biol Psychiatry. 2008;9(2):102-114. 6. Yao Y, et al. Psychiatry Res. 2024;335:115886. 7. Reckweg JT, et al. Front Psychiatry. 2023;14:1133414. 8. Aaronson ST, et al. JAMA Psychiatry. 2024;81(6):555-562. 9. Jairaj C and Rucker JJ. J Psychopharmacol. 2022;36(8):920-931.

GH001 Overview Abbreviations: 5-HT = Serotonin; 5-MeO-DMT = 5‐methoxy‐N,N‐dimethyltryptamine; BDII = Bipolar II disorder; MDE = Major depressive episode; PPD = Postpartum depression; TRD = Treatment-resistant depression. 1. Reckweg J, et al. Front Pharmacol. 2021;12:760671. 2. Reckweg JT, et al. Front Psychiatry. 2023;14:1133414. 3. Halberstadt AL, et al. Psychopharmacology (Berl). 2012;221(4):709-718. 4. Shen HW, et al. Curr Drug Metab. 2010;11(8):659-666. 5. Reckweg JT, et al. J Neurochem. 2022;162:128-146. GH001 Synthetic form of mebufotenin (5-MeO-DMT) for pulmonary inhalation GH001 has been well tolerated in early-stage trials1,2 and shows potential to induce a rapid remission of depressive symptoms in patients with TRD2 Non-selective 5-HT agonist with high affinity for the 5-HT1A receptor3-5 Target indications: TRD, PPD, and BDII + MDE Phase 2b trial complete in TRD; Phase 2a trials complete in PPD and BDII + MDE Median duration of psychoactive effects: 11 min 5

Psychoactive Molecules Are Not Alike: Pharmacology and Phenomenology Anxious ego-dissolution Visionary re-structuralization Oceanic boundlessness Mebufotenin5-8 Non-selective serotonin agonist with high affinity for 5-HT1A Experience of Unity Changed Meaningof Perception Audio-VisualSynesthesia ElementaryImagery ComplexImagery Anxiety Impaired Control Disembodiment Insightfulness BlissfulState SpiritualExperience 100 80 60 40 20 0 DMT3,4 Mixed 5-HT1A/5-HT2A agonist Experience of Unity 0 Meaning Audio-VisualSynesthesia ElementaryImagery ComplexImagery Anxiety Impaired Cognition Disembodiment Insightfulness BlissfulState SpiritualExperience 0.7 0.6 0.5 0.4 0.3 0.2 0.1 18 mg + 1.9 mg/min 14 mg + 1.5 mg/min 10 mg + 1.1 mg/min 6 mg + 0.6 mg/min Placebo LSD1,2 Non-selective serotonin and dopamine agonist Experience of Unity 100 80 70 60 50 40 30 20 10 0 90 Changed Meaningof Percepts Audio-VisualSynesthesia ElementaryImagery ComplexImagery Anxiety Impaired Controland Cognition Disembodiment Insightfulness BlissfulState SpiritualExperience LSD 200 µg p.o LSD 100 µg p.o LSD 75 µg i.v Abbreviations: 5-HT = 5-Hydroxytryptamine (serotonin); DMT = N,N-Dimethyltryptamine; i.v. = Intravenous; LSD = Lysergic acid diethylamide; p.o. = Oral administration. 1. Liechti ME, et al Neuropsychopharmacology. 2017;42:2114–2127 (Figure adapted from source). 2. Holze F, et al. Biol Psychiatry Cogn Neurosci Neuroimaging. 2024;9(5):472-489. 3. Luan LX, et al. J Psychopharmacol. 2024;38(1):56–67 (Figure adapted from source). 4. Nichols DE. Pharmacol Rev. 2016;68(2):264-355. 5.Uthaug MV, et al. Psychopharmacology. 2019;236:2653-2666 (Figure adapted from source). 6. Shen HW, et al. Curr Drug Metab. 2010;11(8):659-66. 7. Halberstadt AL, et al. Psychopharmacology (Berl). 2012;221(4):709-718. 8. Ermakova AO, et al. Sci Rep. 2025;15(1):38874. 6

7 GH001 Provides Rapid and Significant Antidepressant Effects in Patients with Treatment-Resistant Depression Efficacy and Safety Results from a Phase 2b, Double-Blind, Randomized Controlled Trial with a 6-Month Open-Label Extension Lisa Harding, MD Mood Institute and Yale School of Medicine Milton, CT, USA

TRD remains one of the most pressing challenges in psychiatry and affects approximately 30% of patients treated for MDD1 Current therapies for TRD are limited,2 and there is a large unmet need for treatments that are well tolerated and offer rapid reductions in depressive symptoms and long-term remission GH001, a synthetic form of mebufotenin for pulmonary inhalation, has been well tolerated in early-stage trials3,4 and shows potential to induce rapid remission of depressive symptoms in patients with TRD4 8 Background Abbreviations: IDR = Individualized dosing regimen; MDD = Major depressive disorder; TRD = Treatment-resistant depression. 1. Kubitz N, et al. PLoS One. 2013;8(10):e76882. 2. McIntyre RS, et al. World Psychiatry 2023;22:394-412. 3. Reckweg J, et al. Front Pharmacol. 2021;12:760671. 4. Reckweg JT, et al. Front Psychiatry. 2023;14:1133414. This analysis presents efficacy and safety data for GH001 from a Phase 2b double-blind, placebo-controlled trial, in which patients with TRD received up to five re-treatments of GH001 as an IDR

For re-treatment (up to five GH001 IDRsa), the patient must have met one of the following criteria: MADRS score >18 MADRS score >10 and ≤18 and MADRS score ≤10 not observed at Day 8 of the prior treatment or at any visit since MADRS score >10 and ≤18 and MADRS score >18 observed since the most recent observation of MADRS score ≤10 9 Trial Schematic Open-Label Extension (OLE; Part 2) N=81 Randomization 1:1 GH001 IDRa Placebo IDRa BL 2H Day 1 Primary endpoint ΔMADRS Day 8 During the OLE, patients attended visits at Day 15, Month 1, 2, 3, 4, 5 & 6c Additional clinic visits could be scheduled if required for medical reasons MADRS assessment Month 6 D2 Day 2 Double-Blind Part (Part 1)b This trial was conducted under the supervision of qualified healthcare professionals, providing psychological support per standard of care, but without any planned psychotherapeutic intervention before, during, or after dosing aA second or third dose was administered if the previous dose was well tolerated according to the trial physician’s judgement (based on vital signs and adverse events) and if the patient did not achieve an intense psychoactive effect (peak experience; defined as a mean score of ≥75 on the Peak Experience Scale) following the previous dose. bEfficacy assessments were carried out by independent blinded raters in the double-blind part. cPatients also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment. Abbreviations: BL = Baseline; D = Day; H = Hour; IDR = Individualized dosing regimen; MADRS = Montgomery–Åsberg Depression Rating Scale. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05800860, Accessed October 28, 2025. All patients directly transitioned from the double-blind part to the OLE

10 Eligibility Criteria aCurrent MDE confirmed by the Mini-International Neuropsychiatric Interview. Abbreviations: DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; MDD = Major depressive disorder; MDE = Major depressive episode; MGH-ATRQ = Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire; MGH-SAFER = Massachusetts General Hospital – Structured Assessment for Evaluation of Risk; TRD = Treatment-resistant depression.

11 Baseline Characteristics and Patient Disposition aGH001 was administered as a monotherapy and patients who started additional antidepressant treatment were discontinued from the trial. Abbreviations: BMI = Body mass index; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; MADRS = Montgomery–Åsberg Depression Rating Scale; MDE = Major depressive episode; OLE = Open-label extension; SD = Standard deviation. N=81 Baseline Demographics Age, years, mean (SD) 42.8 (11.2) Sex, female, n (%) 46 (56.8) Race, White, n (%) 81 (100) BMI, kg/m2, mean (SD) 26.2 (5.5) Previously used any psychedelic (lifetime), n (%) 9 (11.1) Baseline Disease Characteristics HAM-D-17 total score, mean (SD) 24.8 (2.5) MADRS total score, mean (SD) 28.6 (5.0) MDE History at Baseline Number of MDEs Mean (SD) 2.1 (1.3) ≥3, n (%) 27 (33.3) Time since first depressive episode, years, mean (SD) 11.7 (9.0) Duration of current MDE, weeks, mean (SD) 57.1 (78.4) Patient Disposition, n (%) Completed double-blind part 81 (100) Received GH001 in double-blind part 40 (49.4) Received placebo in double-blind part 41 (50.6) Completed OLE 63 (77.8) Reasons for Discontinuation During the OLE, n (%) 18 (22.2) Withdrawal of consent 7 (38.9) Started additional antidepressanta 6 (33.3) Protocol deviation 2 (11.1) Other 2 (11.1) Adverse event 1 (5.6)

LS mean differenceb vs placebo: −15.5 (P<0.0001) Effect size: Cohen’s d = −2.0 LS Mean (±SE) Change from Baseline in MADRS Total Score BL 2H Day 2 Day 8 Primary Endpoint: GH001 Led to −15.5 Mean MADRS Reduction from Baseline on Day 8a Compared with Placebo in the Double-Blind Period aFDA Guidance notes that efficacy with rapid-acting antidepressants generally should be demonstrated within 1 week, supporting a primary efficacy endpoint within this timeframe. bAdjusted for baseline severity of symptoms (MADRS total score). Abbreviations: BL = Baseline; FDA = Food and Drug Administration; H = Hour; LS = Least squares; MADRS = Montgomery–Åsberg Depression Rating Scale; SE = Standard error. GH001 (n=40) Placebo (n=41) 12 − − − − −

Response: ≥50% reduction from baseline in MADRS total score | Remission: MADRS total score ≤10 GH001 Led to 60.0% Response Rate and 57.5% Remission Rate at Day 8 vs 0% with Placebo in the Double-Blind Period Abbreviations: MADRS = Montgomery–Åsberg Depression Rating Scale; NNT = Number needed to treat. 13 ****P<0.0001 2 Hours Day 2 Day 8 Response Remission GH001 Placebo **** NNT=2 **** **** NNT=2 **** **** NNT=2 **** Response Remission Response Remission NNT=2 NNT=2 NNT=2

14 Reduction in MADRS with GH001 in Double-Blind Part Reproduced in Placebo Group with Their First Active GH001 Treatment in the OLE Abbreviations: BL = Baseline; D = Day; H = Hour; MADRS = Montgomery–Åsberg Depression Rating Scale; OLE = Open-label extension; SE = Standard error. Double-Blind Patients who received GH001 (n=40) Open-Label Extension First treatment of placebo group with GH001 (n=41) Mean (±SE) MADRS Total Score BL 2H D2 D8 Mean (±SE) MADRS Total Score BL 2H D2 D8

15 There Was a 73% Remission Rate at 6 Months in OLE Completers aIncludes 63 patients who completed the 6-month OLE per protocol (18 patients terminated early are excluded). bApproximately 6 months post-study start (median 168 days from Day 1 of double-blind part). cRemission defined as MADRS total score ≤10. Abbreviations: MADRS = Montgomery–Åsberg Depression Rating Scale; OLE = Open-label extension. Double-blind n=40 patients who received GH001 OLE n=63 OLE completersa Day 8 Month 6b Percentage of Patients in Remissionc Patients who completed the OLE received a mean of four treatments across the 6 months (double-blind part and OLE), with 63.5% (40/63) requiring one to four treatments during the 6 months

16 Remission Rate at 6 Monthsa in OLE Completersb a‘6 Months’ or ‘Month 6’ (end of trial) was at approximately 6 months post-study start (median 168 days from Day 1 of double-blind part). bIncludes 63 patients who completed the 6-month OLE per protocol (18 patients terminated early are excluded). cRemission defined as a MADRS total score ≤10. Abbreviations: MADRS = Montgomery–Åsberg Depression Rating Scale; OLE = Open-label extension. Of patients who had remission on Day 8 after their first GH001 treatment, 90% were in remission at 6 months Initial Remitters N=40 Initial Non-remitters N=23 Percentage of Patients in Remissionc

17 Overview of Adverse Events in the Open-Label Extension aTEAEs were classified according to the Medical Dictionary of Regulatory Activities (MedDRA) Version 26.0. Abbreviations: AESI = Adverse event of special interest; TEAE = Treatment-emergent adverse event. Patients, n (%) Overall (N=81) Overview of Adverse Events Any TEAEa 72 (88.9) Maximum severity of TEAEs Mild 28 (34.6) Moderate 42 (51.9) Severe 2 (2.5) Treatment-related TEAEs 65 (80.2) Serious TEAEs 1 (1.2) Treatment-related serious TEAEs 0 TEAEs leading to discontinuation 1 (1.2) AESIs 30 (37.0) Death 0 TEAEsa Occurring in >10% of Patients Overall Treatment-related TEAE Nausea 37 (45.7) 37 (45.7) Paresthesia 31 (38.3) 31 (38.3) Salivary hypersecretion 24 (29.6) 24 (29.6) Headache 16 (19.8) 11 (13.6) Muscle tightness 13 (16.0) 13 (16.0) Feeling cold 12 (14.8) 11 (13.6) Paresthesia oral 10 (12.3) 10 (12.3) Upper respiratory tract infection 10 (12.3) 0 Anxiety 9 (11.1) 8 (9.9)

18 GH001 Administration Was Well Tolerated in Patients with TRD up to 6 Months aTwo severe treatment-related TEAEs were reported in the OLE; affect lability occurred shortly after administration of GH001 and resolved within 4 minutes and one event of migraine, considered a serious TEAE not related to treatment, started 73 days after the patient’s most recent (fourth) administration of GH001. bAssessed using the Clinical Assessment of Discharge Readiness. Abbreviations: ECG = Electrocardiogram; OLE = Open-label extension; PT = Preferred term; SOC = System organ class; TEAE = Treatment-emergent adverse event; TRD = Treatment-resistant depression. During the OLE, TEAEs were observed in 72/81 (88.9%) patients and were mostly mild or moderatea; one non−treatment-related serious TEAE (migraine) was reported No TEAEs of suicidal intent or suicidal behavior occurred The median duration of psychoactive effects after GH001 administration was 11 minutes Patients were deemed discharge-readyb by 1 hour post-dose at 99% of visits

19 Conclusion Abbreviations: IDR = Individualized dosing regimen; MADRS = Montgomery–Åsberg Depression Rating Scale; OLE = Open-label extension; SAE = Serious adverse event; TEAE = Treatment-emergent adverse event; TRD = Treatment-resistant depression. The primary endpoint was met: GH001 administered as an IDR led to significant MADRS reduction from baseline to Day 8 (−15.5 vs placebo) GH001 can maintain long-term remission in TRD, with 73.0% of patients who completed the OLE in remission at 6 months GH001 was well tolerated during the 6-month OLE and no treatment-related SAEs or TEAEs of suicidal intent or suicidal behavior occurred

20 GH001 Is Associated with Improved Self-Reported Maternal Functioning in Patients with Postpartum Depression and Rapid Elimination from Breastmilk Kristina M. Deligiannidis, MD Feinstein Institutes for Medical Research Northwell Health Manhasset, NY, USA

We present data from this Phase 2a trial on antidepressant effects, maternal functioning, and safety in patients with PPD receiving GH001 as well as breastmilk concentrations of mebufotenin in lactating patients PPD is defined as an MDE with onset of mood symptoms during pregnancy or within 4 weeks following delivery1 PPD is associated with adverse effects on maternal well-being and mother-infant relationships that can negatively impact infant development2 Breastfeeding is associated with positive maternal and infant physical and mental health outcomes3,4; however, women with depressive disorders may be concerned about initiating pharmacotherapy while breastfeeding5 The potential antidepressant effects and safety of GH001, a synthetic form of mebufotenin for pulmonary inhalation, were investigated in a Phase 2a, single-arm, open-label trial in patients with PPD 21 Background Abbreviations: MDE = Major depressive episode; PPD = Postpartum depression. 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013. 2. Field T. Infant Behav Dev. 2010;33(1):1-6. 3. Palancı Ay Ö and Aktaş S. Health Care Women Int. 2024;45(2):236-250. 4. Modak A, et al. Cureus. 2023;15(10):e46730. 5. Fitelson E, et al. Int J Womens Health. 2011;3:1-14.

22 Trial Schematic aA second or third dose was administered if the previous dose was well tolerated according to the trial physician’s judgement (based on vital signs and adverse events) and if the patient did not achieve an intense psychoactive effect (peak experience; defined as a mean score of ≥75 on the Peak Experience Scale) following the previous dose. Abbreviations: BIMF = Barkin Index of Maternal Functioning; BL = Baseline; D = Day; H = Hour; IDR = Individualized dosing regimen; MADRS = Montgomery–Åsberg Depression Rating Scale; PK = Pharmacokinetics; PPD = Postpartum depression. This trial was conducted under the supervision of qualified healthcare professionals, providing psychological support per standard of care, but without any planned psychotherapeutic intervention before, during, or after dosing Day −60 to Day −2 Day 1 MADRS PK BIMF Safety Day −1 Screening Pre-dosing day Day 2 MADRS PK Safety Single-day IDR Patients with PPD N=10 Dose 1 6 mg GH001 Dose 2a 12 mg GH001 Dose 3a 18 mg GH001 1-hour interval 1-hour interval MADRS PK BIMF Safety Day 8 MADRS assessment BL 2H Primary endpoint ΔMADRS D2

23 Eligibility Criteria aConfirmed by the MINI. Abbreviations: DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; MADRS = Montgomery–Åsberg Depression Rating Scale; MDD = Major depressive disorder; MINI = Mini-International Neuropsychiatric Interview; PPD = Postpartum depression.

24 Key Assessments Abbreviations: 5-MIAA = 5-methoxyindole-3-acetic acid; BIMF = Barkin Index of Maternal Functioning; LC-MS/MS = Liquid chromatography with tandem mass spectrometry; MADRS = Montgomery–Åsberg Depression Rating Scale; PK = Pharmacokinetics. 1. Montgomery SA, Asberg M. Br J Psychiatry. 1979;134:382-9. 2. Barkin JL, et al. J Womens Health (Larchmt). 2010 Dec;19(12):2239-46. MADRS1 Primary endpoint: change from baseline to Day 8 in MADRS total score Total score range, 0−60 Higher scores indicate more severe depression BIMF2 Patient-centered self-report of maternal functioning Total score range, 0–120 Higher scores indicate better functioning PK inBreastmilk Concentrations were measured using LC-MS/MS in lactating patients: Mebufotenin Bufotenin (psychoactive metabolite) 5-MIAA (non-psychoactive terminal metabolite) Safety Adverse events were assessed throughout the trial

25 Demographics and Baseline Clinical Characteristics an=8 patients. Abbreviations: BIMF = Barkin Index of Maternal Functioning; MADRS = Montgomery–Åsberg Depression Rating Scale; MDE = Major depressive episode; SD = Standard deviation. N=10 Demographics Sex, female, n (%) 10 (100) Age, years, mean (SD) 31.6 (5.2) Ethnicity, n (%) Hispanic or Latino 1 (10.0) Not Hispanic or Latino 9 (90.0) Race, n (%) White 9 (90.0) Black or African American 1 (10.0) Parity, mean (SD) 2 (1.0) Baseline Disease Characteristics Duration of current MDE, weeks, mean (SD) 30.9 (12.9) MADRS total score, mean (SD) 36.7 (4.8) BIMF total score, mean (SD)a 68.8 (15.6)

26 Primary Endpoint: GH001 Was Associated with Significant Reductions from Baseline on Day 8 in Mean MADRS Total Score in Patients with PPD aSecondary efficacy endpoint. Abbreviations: BL = Baseline; H = Hours; MADRS = Montgomery–Åsberg Depression Rating Scale; PPD = Postpartum depression; SD = Standard deviation. At Day 8 All patients were in remission (MADRS total score ≤10) ****P<0.0001 vs BL BL Primary endpoint **** 2Ha Day 2a Day 8 **** **** − − − − − − − − −

27 Primary Endpoint: GH001 Led to Substantial Reduction from Baseline on Day 8 in MADRS Total Score in All Patients with PPD Individual patient data are plotted in the figure, with each color representing 1 patient. bSecondary efficacy endpoint. Abbreviations: BL = Baseline; H = Hours; MADRS = Montgomery–Åsberg Depression Rating Scale; PPD = Postpartum depression; SD = Standard deviation. Remission (MADRS total score ≤10) 0 5 10 15 20 25 30 35 40 45 50 MADRS Total Score in Individual Patients BL 2Hb Day 2b Day 8 At Day 8 Mean (SD) reduction from baseline: −35.4 (5.5); P<0.0001 Primary endpoint

28 BIMF Total Score Improved by a Mean of 34.1 Points from Baseline on Day 8 Abbreviations: BL = Baseline; BIMF = Barkin Index of Maternal Functioning; SD = Standard deviation. Baseline (n=8) Day 8 (n=9) Mean (±SD) BIMF Total Score Better maternal functioning 56% improvement in maternal functioning with GH001 ***P<0.001 vs BL *** Improvement from baseline was observed in 6 of 7 BIMF domains on Day 8

GH001 6+12 mg (n=3) Pre-dose Day 1 1 h post-dosea 2.5 h post-dosea ~8 h post-dosea Day 2 Day 8 Mebufotenin, ng/mL Median (range) BLQ (BLQ−BLQ) 2.2 (0.2−3.1) 0.3 (BLQ−0.6) BLQ (BLQ−0.04) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) Bufotenin, ng/mL (psychoactive) Median (range) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) 5-MIAA, ng/mL (non-psychoactive) Median (range) BLQ (BLQ−BLQ) 15.4 (13.9−28.5) 12.8 (8.1−13.2) 0.4 (BLQ−0.9) 0.04 (0.03−0.2) BLQ (BLQ−BLQ) GH001 6+12 mg (n=3) GH001 6+12+18 mg (n=1) Pre-dose Day 1 1 h post-dosea 2.5 h post-dosea ~8 h post-dosea Day 2 Day 8 Pre-dose Day 1 1 h post-dosea 2.5 h post-dosea ~8 h post-dosea Day 2 Day 8 Mebufotenin, ng/mL Median (range) BLQ (BLQ−BLQ) 2.2 (0.2−3.1) 0.3 (BLQ−0.6) BLQ (BLQ−0.04) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ 1.5 0.3 BLQ BLQ BLQ Bufotenin, ng/mL (psychoactive) Median (range) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ BLQ BLQ BLQ BLQ BLQ 5-MIAA, ng/mL (non-psychoactive) Median (range) BLQ (BLQ−BLQ) 15.4 (13.9−28.5) 12.8 (8.1−13.2) 0.4 (BLQ−0.9) 0.04 (0.03−0.2) BLQ (BLQ−BLQ) BLQ 25.1 13.5 0.1 BLQ BLQ 29 Mebufotenin and its Metabolites Were Rapidly Eliminated from Breastmilk aTime after final dose on Day 1. Abbreviations: 5-MIAA = 5-methoxyindole-3-acetic acid; BLQ = Below the limit of quantitation; H = Hour; IDR = Individualized dosing regimen. Of the four lactating patients, three received GH001 6+12 mg and one received GH001 6+12+18 mg as part of the IDR

Safety Summary 30 Patients, n (%) Overall (N=10) Overview of Adverse Events Any TEAE 8 (80.0) Mild 7 (70.0) Moderate 1 (10.0) Severe 0 Treatment-related TEAEs 7 (70.0) Serious TEAE 0 Death 0 TEAEs by Preferred Term Headache 5 (50.0) Abdominal pain 1 (10.0) Nausea 1 (10.0) Vomiting 1 (10.0) Diarrhea 1 (10.0) Dizziness 1 (10.0) Dysgeusia 1 (10.0) Tachycardia 1 (10.0) Paresthesia 1 (10.0) All patients were deemed ready for discharge within the same day of dosing Abbreviation: TEAE = Treatment-emergent adverse event.

Conclusions 31 In adult patients with PPD enrolled in this open-label trial, GH001 as an IDR was associated with significant reduction in MADRS total score from baseline to Day 8 Improvements were observed across BIMF domains of self-reported maternal functioning Mebufotenin and its metabolites (bufotenin and 5-MIAA) were rapidly eliminated from breastmilk GH001 was generally well tolerated in patients with PPD Abbreviations: 5-MIAA = 5-methoxyindole-3-acetic acid; BIMF = Barkin Index of Maternal Functioning; IDR = Individualized dosing regimen; MADRS = Montgomery–Åsberg Depression Rating Scale; PPD = Postpartum depression.

32 Rapid Improvement in Anhedonia Following GH001 Treatment in Patients with Treatment-Resistant Depression, Postpartum Depression, and Bipolar II Disorder and a Current Major Depressive Episode Roger S. McIntyre, MD, FRCPC Department of Psychiatry University of Toronto Toronto, ON, Canada

Anhedonia is a core symptom of MDD, characterized by a lack of enjoyment from and engagement in life’s experiences, and a deficit in the ability to feel pleasure1 In patients with MDD, anhedonia at baseline is often a predictor of TRD2 Anhedonia is also associated with suicidality,3,4 poor quality of life,5 and functional impairment5 Improvement in anhedonia symptoms in patients with MDD has been correlated with improvements in physical, psychological, and social functioning and quality of life6,7 Safety and efficacy of GH001 were investigated in three patient populations: One Phase 2b trial in patients with TRD Two Phase 2a trials: one in patients with PPD and one in patients with BDII and a current MDE (BDII + MDE) In each of the trials, GH001 has demonstrated a rapid onset of antidepressant effects and a favorable safety profile This analysis examined the effect of treatment with GH001 on anhedonia in patients with TRD, PPD, or BDII + MDE in these three trials 33 Background Abbreviations: BDII = Bipolar II disorder; MDD = Major depressive disorder; MDE = Major depressive episode; PPD = Postpartum depression; TRD = Treatment-resistant depression. 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013. 2. McIntyre RS, et al. World Psychiatry. 2023;22(3):394-412. 3. Gillies ES, et al. Psychiatr Res. 2023;158:209-215. 4. Ballard ED, et al. J Affect Disord. 2017;218:195-200. 5. Wong S, et al. J Affect Disord. 2024;356:684-698. 6. Cao B, et al. Front Psychiatry. 2019;10:17. 7. McIntyre RS, et al. J Affect Disord. 2024;363:430-435.

aIn the TRD trial, during the OLE, patients attended visits at Day 15, Month 1, 2, 3, 4, 5 & 6, and also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment; MADRS assessment was performed at each visit. bMDD episode (per DSM-5 criteria) without psychotic features, current MDE confirmed by the MINI and validated based on the MGH-SAFER criteria interview; nonresponse to antidepressant treatments assessed using the MGH-ATRQ. cPer MINI diagnostic criteria. dPer DSM-5 diagnostic criteria. Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; H = Hour; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; IDR = Individualized dosing regimen; M = Month; MADRS = Montgomery–Åsberg Depression Rating Scale; MDD = Major depressive disorder; MDE = Major depressive episode; MGH-ATRQ = Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire; MGH-SAFER = Massachusetts General Hospital – Structured Assessment for Evaluation of Risk; MINI = Mini-International Neuropsychiatric Interview; OLE = Open-label extension; PPD = Postpartum depression; R = Randomization; TRD = Treatment-resistant depression; YMRS = Young Mania Rating Scale. Trial Schematics 34

aIn the TRD trial, during the OLE, patients attended visits at Day 15, Month 1, 2, 3, 4, 5 & 6, and also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment; MADRS assessment was performed at each visit. bMDD episode (per DSM-5 criteria) without psychotic features, current MDE confirmed by the MINI and validated based on the MGH-SAFER criteria interview; nonresponse to antidepressant treatments assessed using the MGH-ATRQ. cPer MINI diagnostic criteria. dPer DSM-5 diagnostic criteria. Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; H = Hour; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; IDR = Individualized dosing regimen; M = Month; MADRS = Montgomery–Åsberg Depression Rating Scale; MDD = Major depressive disorder; MDE = Major depressive episode; MGH-ATRQ = Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire; MGH-SAFER = Massachusetts General Hospital – Structured Assessment for Evaluation of Risk; MINI = Mini-International Neuropsychiatric Interview; OLE = Open-label extension; PPD = Postpartum depression; R = Randomization; TRD = Treatment-resistant depression; YMRS = Young Mania Rating Scale. Trial Schematics 35

aIn the TRD trial, during the OLE, patients attended visits at Day 15, Month 1, 2, 3, 4, 5 & 6, and also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment; MADRS assessment was performed at each visit. bMDD episode (per DSM-5 criteria) without psychotic features, current MDE confirmed by the MINI and validated based on the MGH-SAFER criteria interview; nonresponse to antidepressant treatments assessed using the MGH-ATRQ. cPer MINI diagnostic criteria. dPer DSM-5 diagnostic criteria. Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; H = Hour; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; IDR = Individualized dosing regimen; M = Month; MADRS = Montgomery–Åsberg Depression Rating Scale; MDD = Major depressive disorder; MDE = Major depressive episode; MGH-ATRQ = Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire; MGH-SAFER = Massachusetts General Hospital – Structured Assessment for Evaluation of Risk; MINI = Mini-International Neuropsychiatric Interview; OLE = Open-label extension; PPD = Postpartum depression; R = Randomization; TRD = Treatment-resistant depression; YMRS = Young Mania Rating Scale. Trial Schematics 36

aIn the TRD trial, during the OLE, patients attended visits at Day 15, Month 1, 2, 3, 4, 5 & 6, and also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment; MADRS assessment was performed at each visit. bMDD episode (per DSM-5 criteria) without psychotic features, current MDE confirmed by the MINI and validated based on the MGH-SAFER criteria interview; nonresponse to antidepressant treatments assessed using the MGH-ATRQ. cPer MINI diagnostic criteria. dPer DSM-5 diagnostic criteria. Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; H = Hour; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; IDR = Individualized dosing regimen; M = Month; MADRS = Montgomery–Åsberg Depression Rating Scale; MDD = Major depressive disorder; MDE = Major depressive episode; MGH-ATRQ = Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire; MGH-SAFER = Massachusetts General Hospital – Structured Assessment for Evaluation of Risk; MINI = Mini-International Neuropsychiatric Interview; OLE = Open-label extension; PPD = Postpartum depression; R = Randomization; TRD = Treatment-resistant depression; YMRS = Young Mania Rating Scale. Trial Schematics 37

The MADRS 5-item anhedonia subscale1 includes the following MADRS items: Score range, 0−30; lower scores indicate less severe anhedonia Clinically meaningful improvement in anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on a published analysis of patients with MDD2 38 Anhedonia Assessment MADRS 5-item anhedonia subscale Abbreviations: MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disorder. 1. Cao B, et al. Front Psychiatry. 2019;10:17. 2. McIntyre RS. J Affect Disord. 2024;363:430-435. Item 1 Apparent sadness Item 2 Reported sadness Item 6 Concentration difficulties Item 7 Lassitude Item 8 Inability to feel

39 Baseline Characteristics and Disposition Abbreviations: BDII = Bipolar II disorder; BMI = Body mass index; CGI-S = Clinical Global Impression-Severity; MADRS = Montgomery–Åsberg Depression Rating Scale; MDE = Major depressive episode; OLE = Open-label extension; PPD = Postpartum depression; SD = Standard deviation; TRD = Treatment-resistant depression. TRD Trial N=81 PPD Trial N=10 BDII + MDE Trial N=6 Baseline Demographics Age, years, mean (SD) 42.8 (11.2) 31.6 (5.2) 44.2 (9.3) Sex, female, n (%) 46 (56.8) 10 (100) 4 (66.7) Race, n (%) White 81 (100) 9 (90) 6 (100) Black or African American 0 1 (10) 0 BMI, mean (SD), kg/m2 26.2 (5.5) 27.6 (6.6) 24.8 (5.0) Baseline Disease Characteristics MADRS total score, mean (SD) 28.6 (5.0) 36.7 (4.8) 32.0 (5.1) Anhedonia subscale score, mean 17.5 20.8 19.2 CGI-S score, mean (SD) 4.9 (0.7) 4.8 (0.8) 5.0 (0.89) Number of MDEs, mean (SD) 2.1 (1.3) 1.3 (1.3) 14.0 (12.4) Duration of current MDE, weeks, mean (SD) 57.1 (78.4) 30.9 (12.9) 20.8 (22.7) Disposition Completed trial, n (%) ‒ 10 (100) 6 (100) Double-blind part 81 (100) ‒ ‒ OLE part 63 (77.8) ‒ ‒

40 Patients with TRD Who Received Double-Blind Treatment with GH001 Had Rapid and Clinically Meaningfula Improvements in MADRS Anhedonia Scores aClinically meaningful improvement in anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on an analysis of patients with MDD.1 Abbreviations: BL = Baseline; D = Day; MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disorder; SD = Standard deviation; TRD = Treatment-resistant depression. 1. McIntyre RS. J Affect Disord. 2024;363:430-435. Mean (±SD) Change from Baseline in MADRS Anhedonia Subscale Score BL D1 D2 D8 MADRS Anhedonia Subscale Score MCIC for MADRS anhedonia subscale MADRS Anhedonia Subscale Item Scores Apparent sadness Reported sadness Concentration difficulty Lassitude Inability to feel Mean (SD) Change from Baseline at Day 8 **** ****P<0.0001 vs placebo **** **** **** **** **** **** ****

41 aClinically meaningful improvement in anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on an analysis of patients with MDD.1 Abbreviations: BL = Baseline; MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disorder; OLE = Open-label extension; SD = Standard deviation; TRD = Treatment-resistant depression. 1. McIntyre RS. J Affect Disord. 2024;363:430-435. In OLE completers (n=63), mean (SD) change from baseline in MADRS anhedonia subscale score was −12.2 (4.9) at Month 6 (P<0.0001) MADRS Anhedonia Subscale Item Scores Among Patients Who Completed the TRD Study OLE (n=63), Clinically Meaningfula Improvement in MADRS Anhedonia Score Was Maintained at Month 6 Mean (SD) Change from Baseline at Month 6 in OLE Completers Apparent sadness Reported sadness Concentration difficulty Lassitude Inability to feel **** **** **** **** **** ****P<0.0001 vs BL

42 In Patients with PPD, Clinically Meaningfula Improvement in MADRS Anhedonia Score was Observed at Each Assessment aClinically meaningful improvement in anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on an analysis of patients with MDD.1 Abbreviations: BL = Baseline; D = Day; MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disorder; PPD = Postpartum depression; SD = Standard deviation. 1. McIntyre RS. J Affect Disord. 2024;363:430-435. MADRS Anhedonia Subscale Score MADRS Anhedonia Subscale Item Scores BL D1 D2 D8 Mean (SD) Change from Baseline at Day 8 ****P<0.0001 vs BL **** **** **** **** **** Mean (±SD) Change from Baseline in MADRS Anhedonia Subscale Score MCIC for MADRS anhedonia subscale **** Apparent sadness Reported sadness Concentration difficulty Lassitude Inability to feel

Patients with BDII + MDE had Clinically Meaningfula Improvement in MADRS Anhedonia Score at Day 8 Post-Dose BL D1 D2 D8 MADRS Anhedonia Subscale Score MADRS Anhedonia Subscale Item Scores Mean (±SD) Change from Baseline in MADRS Anhedonia Subscale Score aClinically meaningful improvement in anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on an analysis of patients with MDD.1 Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disorder; MDE = Major depressive episode; SD = Standard deviation. 1. McIntyre RS. J Affect Disord. 2024;363:430-435. Mean (SD) Change from Baseline at Day 8 MCIC for MADRS anhedonia subscale *P<0.05 vs BL * * * * * * 43 Apparent sadness Reported sadness Concentration difficulty Lassitude Inability to feel

44 GH001 was Well Tolerated in Patients with TRD, PPD, or BDII + MDE No treatment-related serious TEAEs were reported across the TRD, PPD and BDII + MDE trialsa In all three trials, TEAEs were mostly mild or moderate in severity The most common TEAE in patients treated with GH001 was nausea in the double-blind (17/40 [42.5%]) and OLE (37/81 [45.7%]) parts of the TRD trial; headache was the most common TEAE in the PPD (5/10 [50.0%]) and BDII + MDE (3/6 [50.0%]) trials; no TEAEs of of flashbacks were observed No TEAEs of suicidal intent or suicidal behavior occurred in any of the trials In the TRD trial, the median duration of psychoactive effects after GH001 administration was 11 minutes and patients were deemed discharge-ready by 1-hour post-dose at 99% of visits aTEAEs were observed in 29/40 (72.5%) patients who received GH001 in the double-blind part of the TRD trial and 72/81 (88.9%) patients in the OLE, 8/10 (80.0%) in the PPD trial, and 5/6 (83.3%) in the BDII + MDE trial. Abbreviations: BDII = Bipolar II disorder; MDE = Major depressive episode; OLE = Open-label extension; PPD = Postpartum depression; TEAE = Treatment-emergent adverse event; TRD = Treatment-resistant depression.

Abbreviations: BDII = Bipolar II disorder; MADRS = Montgomery–Åsberg Depression Rating Scale; MDE = Major depressive episode; OLE = Open-label extension; PPD = Postpartum depression; TRD = Treatment-resistant depression. 45 Conclusion The presented trials investigating GH001 for the treatment of TRD, PPD, and BDII + MDE demonstrated rapid reductions in MADRS anhedonia subscale scores Improvements in anhedonia subscale scores were clinically meaningful across each of the depressive disorders at Day 8 and were maintained at Month 6 in the OLE of the TRD trial Mean reductions were observed in scores for all five items included in the anhedonia subscale GH001 was generally well tolerated in patients with TRD, PPD, or BDII + MDE These findings suggest that GH001 improves patients’ ability to feel pleasure and engage in activities and may improve overall functioning

46 Acknowledgments These trials were sponsored by GH Research Ireland Limited The sponsor would like to thank the participants in the trials The sponsor would also like to thank the investigators who conducted these trials Under the guidance of the authors, medical writing and editorial support were provided by Brian Brennan, PhD, of GH Research, and Kathleen M. Dorries, PhD, of OPEN Health

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