NASDAQ: AXSM October 2018 © Axsome Therapeutics, Inc.

FLS Forward-Looking Statements & Safe Harbor Certain information co ntained in this prese ntatio n ma y include “forward-looking sta tements” within the meani ng of the Pri vate Securities Litigation Refo rm Act of 1995. We ma y, in some cases, use te rms such as “predicts,” “believes,” “pote ntial,” “conti nue,” “estimates,” “a nticipates,” “e xpects,” “pla ns,” “inte nds,” “ma y,” “could,” “might,” “will,” “should” or other wo rds that convey uncertainty o f future e ve nts or o utcomes to identify these forwa rd-looking state ments. In particular, the Company’s stateme nts regarding trends a nd pote ntial future results are e xamples of such forwa rd-looking sta teme nts. The forward-looking stateme nts include risks and uncertai nties, includi ng, but no t limited to, the success, timi ng a nd cost of our o ngoing clinical trials a nd a nticipated clinical trials for o ur curre nt prod uct ca ndidates, including stateme nts regarding the timing of initiation a nd comple tion of the trials, interim ana lyses and receipt of interim results; the timing of a nd o ur ability to obtai n a nd maintain U.S. Food a nd Drug Administra tion o r o ther regulatory a uthority appro val of, or other action with respect to, o ur product candidates; the Company’s ability to obtain additional capital necessary to fund its operations; the Company’s ability to gene rate re venues in the future ; the Company’s ability to successfully defe nd its intellectual property or obtain the necessary licenses a t a cost acceptable to the Company, if at all; the successful impleme ntation of the Company’s research and de velopme nt p rograms; the e nfo rceability o f the Company’s license agreeme nts; the accepta nce b y the marke t of the Company’s prod uct ca ndidates, if appro ved; and other factors, i ncluding genera l economic co nditions a nd reg ula tory developme nts, not withi n the Company’s control. These factors co uld ca use actual results a nd deve lopments to be mate rially different from those e xpressed in or implied by such stateme nts. Forward-looking stateme nts are no t g uara ntees o f future performa nce, a nd actual results ma y differ materially fro m those projected . The forward -looking sta teme nts are made o nly as of the date o f this presentation a nd the Company undertakes no obligation to p ublicly update such forward-looking sta tements to reflect subsequent events or circumstance. This prese nta tion also contains estimates a nd o the r statistical data made by i ndependent parties a nd by us re lating to ma rket size a nd other data about our i ndustry. This data i nvolves a number o f assump tions a nd limitations, a nd yo u are ca utio ned not to give undue weight to such estimates. Neither we no r any other perso n makes any representation as to the accuracy or completeness of such data o r undertakes a ny obligation to update such data after the da te of this presentation. In addition, these projections, assumptions and estimates are necessarily subject to a high degree of uncertainty and risk. © Axsome Therapeutics, Inc. 2

Axsome is addressing growing markets, where current treatment options are limited or inadequate, by leveraging well-characterized compounds to create nov el therapeutics to meet unmet medical needs and improve the lives of patients. © Axsome Therapeutics, Inc. 3

Overview Our Technologies Enabling new and innovative medicines to treat CNS conditions MoSEIC™ Delivery Metabolic Inhibition Chiral & Formulation Chemistry Chemical Synthesis & Analysis © Axsome Therapeutics, Inc. 4

Overview Our CNS Candidates and Pipeline • Four differentiated clinical-stage CNS assets targeting significant and growing markets. • Patent protection to 2034-2036, worldwide rights. epression: Fast Track Granted anted der phan Designation Abbrev iations: BUP = Bupropion; CNS = Central Nerv ous Sy stem; DM = Dextromethorphan; Mx = Meloxicam; Riz = Rizatriptan; S-BUP = Esbupropion. Conf idential and Proprietary 5 Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-05 (DM + BUP) Treatment Resistant D Agitation in Alzheimer’s Major Depressive Disor Smoking Cessation Disease: Fast Track Gr Ongoing Ongoing Ongoing Ongoing AXS-07 (MoSEIC™ Mx + Riz) Migraine AXS-12 (Reboxetine) Narcolepsy; U.S. Or AXS-09 (DM + S-BUP) CNS Disorders

Overview Axsome PPC Candidates and Pipeline • Two differentiated clinical-stage pain and primary care assets targeting growing markets. • Patent protection to 2034, worldwide rights. significant and SPA Received; Fast Track Granted Abbrev iations: BML = Bone Marrow Lesions; CLBP = Chronic Low Back Pain; DZT = Disodium Zoledronate Tetrahy drate; Eso = Esomeprazole; MC = Modic Changes; Mx = Meloxicam; OA = Osteoarthritis; RA = Rheumatoid Arthritis; SPA = Special Protocol Assessment Conf idential and Proprietary Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-02 (DZT) Knee OA with BMLs: CLBP with MCs Ongoing AXS-06 (MoSEIC™ Mx + Eso) OA and RA

© Axsome Therapeutics, Inc. 7 AXS-05 Dextromethorphan (DM) + Bupropion (BUP) Novel therapy for CNS disorders: • Treatment Resistant Depression (TRD) • Agitation in Alzheimer’s Disease (AD) • Major Depressive Disorder (MDD) • Smoking Cessation

AXS-05 CNS Disorders: Mechanisms of Action Pharmacodynamic Synergy Relevant Indications Related Agents • • Ketamine Memantine (Namenda®) • • Fluvoxamine (Luvox®) Donepezil (Aricept®) • • Duloxetine (Cymbalta®) Venlafaxine (Effexor®) • • • Escitalopram (Lexapro®) Fluoxetine (Prozac®) Sertraline (Zoloft®) • Bupropion (Wellbutrin®) • Bupropion (Wellbutrin®) DM = Dextrom ethorphan; BUP = Bupropion. Pres ent Relevant © Axsome Therapeutics, Inc. 8 Mechanism of Action DM BUP AXS-05 DM+BUP NMDA Receptor Antagonist Sigma-1R Agonist Norepinephrine Reuptake Inhibitor Serotonin Reuptake Inhibitor Dopamine Reuptake Inhibitor Nicotinic ACh Receptor Antagonist

AXS-05 CNS Disorders: Mechanisms of Action Pharmacodynamic Synergy Relevant Indications • Memantine (Namenda®) • Donepezil (Aricept®) • Venlafaxine (Effexor®) DM = Dextrom ethorphan; BUP = Bupropion. Pres ent Relevant 1. Indications listed are associated w ith the mechanism of action and are not related to either DM or BUP, unless specif ically noted. 2. Agents do not contain DM or BUP, unless specif ically noted. © Axsome Therapeutics, Inc. 9 Related Agents • Ketamine • Fluvoxamine (Luvox®) • Duloxetine (Cymbalta®) • Escitalopram (Lexapro®) • Fluoxetine (Prozac®) • Sertraline (Zoloft®) • Bupropion (Wellbutrin®) • Bupropion (Wellbutrin®) Mechanism of Action DM BUP AXS-05 DM+BUP NMDA Receptor Antagonist Sigma-1R Agonist Norepinephrine Reuptake Inhibitor Serotonin Reuptake Inhibitor Dopamine Reuptake Inhibitor Nicotinic ACh Receptor Antagonist

AXS-05 CNS Disorders: Novel Therapy for CNS Disorders DM Alone DXO Difficult to achieve plasma levels. potential therapeutic DM DM Rapid metabolism AXS-05 Inhibits DM metabolism DXO • • • Pharmacokinetic synergy Potential pharmacodynamic synergy Potential efficacy in CNS disorders DM BUP DM BUP DM concentration increased to therapeutic range DM = Dextrom ethorphan; DXO = Dextrorphan; BUP = Bupropion. BUP active at CNS receptors • Phase 1 trials with AXS-05 completed: – Significant increase in DM plasma levels. • Phase 3 trials in TRD and AD Agitation initiated. • Phase 2 trials in MDD and Smoking Cessation initiated. © Axsome Therapeutics, Inc. 10 IP Overview • 31 issued patents – protection through 2034.

AXS-05 CNS Disorders: Phase 1 Results Dextromethorphan AUC Dextromethorphan Cmax P<0.0001 P<0.0001 160.0 1700  $' DJLWDWLRQ, 'HSUHVVLRQ* 85 - 883 - 525 -  $EQRUPDO ODXJKLQJ/FU\LQJ† † 53 - 0 0.0 DM 60 mg DM 60 mg + BUP 150 mg (AXS-05) DM 60 mg DM 60 mg + BUP 150 mg (AXS-05) DM concentrations associated with reported therapeutic responses shown (dotted lines). * DM plasma concentrations reported with dose (DM 30 mg + Q 10 mg) resulting patients, and of depressive symptoms in AD and PBA patients. † DM plasma concentrations reported with dose (DM 20 mg + Q 10 mg) resulting PBA patients. Axsome data on f ile. Therapeutic DM concentrations f rom NDA 021879, FDA Clinical Pharmacology Review . DM, Dextromethorphan; Q, Quinidine; BUP, Bupropion; AD, Alzheimer’s disease; PBA, pseudobulbar af f ect in reduction of agitation symptoms in AD in reduction in emotional symptoms in © Axsome Therapeutics, Inc. 11 AUC0-12 ng*hr/mL Cmax ng/mL 1686 28  $' DJLWDWLRQ, 'HSUHVVLRQ* 158.1  $EQRUPDO ODXJKLQJ/FU\LQJ 3.8

AXS-05 CNS Disorders: TRD Overview • 63% and 44% of MDD patients have inadequate response to initial therapy and second line therapy, respectively.2 • Only 1 approved drug for TRD = unmet medical need. • AXS-05 combines the MOA of 4 distinct anti-depressant drug classes into one novel oral therapeutic. • DM antidepressant effects demonstrated preclinically clinically. • Phase 3 interim futility analysis: IDMC recommended continuation. • Phase 2 MDD trial ongoing. and trial 3M patients in the U.S.1-3 nt Depression: Fast Track Granted Disorder Abbreviations : DM = Dextrom ethorphan; BUP = Bupropion. 1. Marcus SC, Olf son M. Arch Gen Psychiatry 2010;67:1265-1273. 2. Rush AJ, et al. Am J Psychiatry 2006;163:1905-1917. 3. U.S. Census Bureau, Population April 1, 2010 to July 1, 2013. © Axsome Therapeutics, Inc. 12 Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-05 (DM + BUP) Treatment Resista Major Depressive Ongoing Ongoing

AXS-05 CNS Disorders: TRD Clinical Rationale Depressive Symptom Reduction in AD Agitation Patients Treated with DM and Metabolic Inhibitor2 DM+Q Symptom Reduction in TRD Patients Treated with DM and Metabolic Inhibitor1 Placebo (30/10 mg) 0 0.5 -5 0.0 -10 ** -15 -0.5 -20 Wk 1 Wk 2 Wk 4 Wk 6 Wk 8 Wk 12 Time (weeks) Failed 2 to 10 prior treatments 45% RI SDWLHQWV KDG • 50% UHGXFWLRQ LQ 0$'56 -1.0 P=0.002 • • ** P<0.01 versus baseline 1. Murrough J, et al. J Affect Disord. 2017;218:277-283. 2. Cummings J, et al. JAMA. 2015;314:1242-1254. © Axsome Therapeutics, Inc. 13 Change in Montgomery-Asberg Depression Rating (MADRS) Scale Change in Cornell Scale Score ** ** ** DM/Q Titration DM/Q 45/10 mg q 12 hrs

AXS-05 CNS Disorders: TRD Phase 3 Design A Phase 3 trial to assess the efficacy and safety of AXS-05 in the treatment of TRD. 1:1 randomization of inadequate responders Period 2, Double-blind (6 weeks) Period 1, Open-label (6 weeks) N=346 (BUP + DM) BUP = Bupropion; DM = Dextrom ethorphan. • Primary Endpoint: Change in depression score from randomization to end of study, measured using the Montgomery-Asberg Depression Rating Scale (MADRS). • Key Inclusion Criteria: – Male or female 18-65 years old – History of inadequate response to 1 or 2 adequate antidepressant treatments • Interim futility analysis: Conducted at approximately 40% target randomized subjects. IDMC recommended trial continuation. • Interim efficacy analysis: Planned at approximately 60% target randomized subjects. © Axsome Therapeutics, Inc. 14 Bupropion Arm B (n=173) Bupropion AXS-05 Arm A (n=173)

AXS-05 CNS Disorders: Agitation in AD Overview • Agitation and aggression seen in approximately 45% of AD patients during 5-year period.3 • Characterized by emotional distress, aggressive behaviors, disruptive irritability, disinhibition, and caregiver burden.4 • Associated with4,5: – – – Accelerated cognitive decline Earlier nursing home placement Increased mortality • No approved medication = unmet medical need. • Proof of concept: DM plus metabolic inhibitor reduced agitation in AD patients. • Phase 2/3 ongoing. 2M patients in the U.S.1,2 mer’s Disease: Fast Track Granted Abbreviations : DM = Dextrom ethorphan; BUP = Bupropion. 1. Ryu, SH, et al. Am J Geriatr Psychiatry. 2005;13:976-983. 2. Hebert, LE, et al. Neurology. 2013;80:1778-1783. 3. Steinberg M, et al. Int J Geriatr Psychiatry. 2008;2:170-177. 4. Antonsdottir IM, et al. Expert Opin Pharmacother. 2015;11:1649-1656. 5. Rabins PV et al. Alzheimers Dement. 2013; 9:204-207. © Axsome Therapeutics, Inc. 15 Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-05 (DM + BUP) Agitation in Alzhei Ongoing

AXS-05 CNS Disorders: Agitation in AD Clinical Rationale Change in Agitation/Aggression Scores in AD with DM and Metabolic Inhibitor Quinidine (Q) • Randomized, double-blind, placebo-controlled, two-stage trial. – Placebo (n=125), 30 mg DM + 10 mg quinidine (Q) (n=93), for stage 1. • DM+Q treatment reduced agitation/ aggression in AD by 46% vs. 24% for placebo (P<0.001)—primary endpoint. • Statistically significant improvement in multiple secondary endpoints. • DM plasma levels achieved with AXS-05 target therapeutic range. Placebo DM+Q 0.0 -1.0 -2.0 in -3.0 • Potential for additional contribution bupropion component of AXS-05. from -4.0 Cummings J, et al. JAMA. 2015;314:1242-1254. © Axsome Therapeutics, Inc. 16 Change in NPI Agitation/Aggression Domain P<0.001

AXS-05 CNS Disorders: Agitation in AD Phase 2/3 Design A Phase 2/3 trial to assess the efficacy and safety of AXS-05 in the treatment of Agitation in AD. Screening Double-blind Phase (5 weeks) (BUP + DM) N=435 1:1:1 randomization BUP = Bupropion; DM = Dextrom ethorphan. • Primary Endpoint: Cohen-Mansfield • Key Inclusion Criteria: Agitation Inventory (CMAI). – Diagnosis of probable Alzheimer’s disease – Clinically significant agitation • Interim futility analysis: Planned at approximately 30% target randomized subjects. • Interim efficacy analysis: Planned at approximately 60% target randomized subjects. © Axsome Therapeutics, Inc. 17 Placebo Arm C (n=145) Bupropion Arm B (n=145) AXS-05 Arm A (n=145)

AXS-05 CNS Disorders: Smoking Cessation Overview • Smoking is single largest cause of preventable death in the U.S.1 • 70% of smokers want to quit and only 3-5% who attempt to quit without assistance are successful for 6-12 months.2 • DM component of AXS-05 significantly reduced nicotine self-administration in nicotine-dependent rats. • Bupropion component of AXS-05 has been found to be effective for smoking cessation in clinical trials. • Axsome entered into a research collaboration with Duke 40M patients University to evaluate AXS-05 in a smokers attempting to quit. • Phase 2 trial ongoing. Phase 2 clinical trial in in the U.S.1 on Abbreviations : DM = Dextrom ethorphan; BUP = Bupropion. 1. U.S. Department of Health and Human Services. The Health Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon General. 2014. 2. Hughes JR, et al. Addiction. 2004;99(1):29-38. © Axsome Therapeutics, Inc. 18 Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-05 (DM + BUP) Smoking Cessati Ongoing

© Axsome Therapeutics, Inc. 19 AXS-07 MoSEIC™ Meloxicam + Rizatriptan Novel therapy for: • Migraine

AXS-07 AXS-07: MoSEIC™ Meloxicam + Rizatriptan for Migraine • Meloxicam is a new molecule for migraine—not currently approved or used for this indication due to prolonged Tmax • MoSEIC delivery enables its use in abortive treatment of migraine – Rapid Tmax of MoSEIC meloxicam is ideal for migraine treatment – Extended half-life of MoSEIC meloxicam should lead to lower symptom recurrence • AXS-07 combines unique PK of MoSEIC proven efficacy of rizatriptan • FDA Pre-IND written guidance received • Phase 3 initiation anticipated in 2018 meloxicam with 37M patients in the U.S.1 Abbreviations : Mx = Meloxicam ; Riz = Rizatriptan. 1. Pleis JR, et al., Summary health statistics for U.S. adults: National Health Interview Survey, 2009. National Center for Health Statistics. Vital Health Stat 10(249). 2010. © Axsome Therapeutics, Inc. 20 Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-07 (MoSEIC™ Mx + Riz) Migraine

AXS-07 Migraine: MoSEIC™Meloxicam Phase 1 Results Mean Meloxicam Concentrations Meloxicam Tmax after 15 mg Dose 2,500 Mobic® 2,000 MoSEIC™ - Oral 1,500 IV (bolus) IV (infusion) 1,000 IM 500 Mobic® - Oral - 0 1 2 3 4 5 0 1 2 3 4 5 6 7 8 9 10 11 12 14 24 Hours Hours Mobic® (0.5 hour versus 4.5 hours, respectively, • MoSEIC meloxicam Tmax 9 times faster than p<0.0001). • Therapeutic plasma levels achieved within 15 minutes of oral dosing of MoSEIC meloxicam. • MoSEIC meloxicam had higher mean Cmax (p=0.0018), faster time to therapeutic plasma concentration (p<0.0001), and time to half-maximal plasma concentration (p<0.0001) as compared to Mobic®. • Terminal half-lives were approximately 20 hours for MoSEIC meloxicam and 22 hours for Mobic®. Sources: Axsome data on f ile. IV and IM data f rom Euller-Ziegler et al., Inflamm Res 50, Supplement 1 (2001) S5–S9. © Axsome Therapeutics, Inc. 21 ng/mL MoSEIC™ Meloxicam

AXS-07 AXS-07: Differentiated Clinical Profile for Migraine Rapid absorption & onset of action Based on rapid absorption of MoSEIC meloxicam and expected additive effect of AXS-07 components Strong & consistent pain relief Potential for superior efficacy as compared to current treatments based on expected additive effect of AXS-07 components Sustained pain relief Based on extended MoSEIC meloxicam half-life and expected additive effect of AXS-07 components Pharmaco-economic benefits Potentially superior efficacy expected to result in reduced use of medication and medical services, reduced absenteeism and loss of productivity © Axsome Therapeutics, Inc. 22

© Axsome Therapeutics, Inc. 23 AXS-12 Reboxetine Novel therapy for: • Narcolepsy

AXS-12 CNS Disorders: Narcolepsy Overview • Debilitating sleep disorder characterized by excessive daytime sleepiness (EDS) and cataplexy. • Limited treatment options – All current approved drugs are scheduled – Only one approved agent for cataplexy. • AXS-12 showed potent activity in genetic narcolepsy, and positive effects in human narcolepsy patients. mouse model pilot trial in of Orphan Disease 185,000 patients in the U.S. • Phase 2 start anticipated 4Q 2018 with data estimated 1H 2019. • U.S. Orphan Drug Designation. readout © Axsome Therapeutics, Inc. 24 Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-12 (Reboxetine) Narcolepsy; U.S. Or phan Designation

AXS-12 CNS Disorders: Narcolepsy Scientific Rationale Number of narcoleptic episodes Total duration of narcoleptic episodes • Reboxetine dose-dependently reduced (orexin)-deficient mice (P<0.0001) the number of narcoleptic episodes in hypocretin Adapted from Schm idt et al. Behav Brain Res. 2016 Jul 15;308:205-10. © Axsome Therapeutics, Inc. 25

Corporate Barriers to Entry 29 Issued U.S. Patents 2 Issued O-U.S. Patents Claims extending to 2034 >45 pending 3 issued U.S. Patents 2 issued O-U.S. Patent Claims extending >30 pending to 2036 Proprietary Manufacturing Drug Product Formulation Proprietary Manufacturing Drug Product Formulation MoSEIC™ Meloxicam ( A XS-07, A XS-06) AXS-05 AXS-09 AXS-02 ( and relat ed compounds) 91 Issued U.S. Patents 50 Issued O-U.S. Patents Claims extending to 2034 >65 pending Proprietary Manufacturing API Synthesis © Axsome Therapeutics, Inc. 26

Corporate Our Team United Therapeutics Corp. Former President, COO Merck Former CFO Group at UBS Herriot Tabuteau, Chairman MD © Axsome Therapeutics, Inc. 27 Management Herriot Tabuteau, MD Founder & CEO Nick Pizzie, CPA, MBA CFO Cedric O’Gorman, MD, MBA SVP, Clinical Development & Medical Affairs Mark Jacobson, MA SVP, Operations Board of Directors Roger Jeffs, PhD Former President, Co-CEO, Director Prior positions at Amgen and Burroughs Wellcome Myrtle Potter Genentech Prior positions at Bristol-Myers Squibb and Mark Saad Bird Rock Bio, Inc. Former COO of the Global Healthcare Mark Coleman, MD Medical Director National Spine and Pain Centers Diplomat of the American Board of Anesthesiology

Corporate Key Financial Information Cash (Pro-Forma)1: $29.2 Million Debt (Face V alue)2: $8.1 Million Common Shares Outstanding (Pro-Forma)1: 29.2 Million Options and Warrants Outstanding3: 5.0 Million • Financial guidance: Cash anticipated to fund operating requirements into the first quarter of 2020. 1. Pro-Form a to include the effect of the equity capital financing com pleted in Sept 2018. 2. Book value of $8.5 m illion. 3. Cons is ts of 2.9 m illion options and 2.1 m illion warrants . © Axsome Therapeutics, Inc. 28 As of June 30, 2018

Overview Clinical Milestones 2020) Abbreviations: AD = Alzheimer’s Disease; BUP = Bupropion; DM = Dextromethorphan; MDD = Major Depressive Disorder; Mx = Meloxicam; Riz = Rizatriptan; TRD = Treatment Resistant Depression.  Accomplished milestone.  Upcoming milestone. © Axsome Therapeutics, Inc. 29 Product Candidat e I ndicat ion 2018 2019 AXS-05 (DM + BU P) TRD  STRIDE-1 interim analysis  STRIDE-1 interim efficacy analysis (4Q 2018)  STRIDE-1 top-line results (1H 2019) AD Agitation  ADVANCE-1 interim analysis (4Q 2018)  ADVANCE-1 interim efficacy analysis  ADVANCE-1 top-line results (2H 2019/1H M DD  Ph 2 trial start  Ph 2 top-line results (4Q 2018) Smoking Ce ssation  Ph 2 trial start  Ph 2 top-line results (1Q 2019) AXS-07 (MoSEIC™ Mx + Riz) M igraine  Ph 3 trial start (4Q 2018)  Ph 3 top-line results AXS-12 (Reboxetine) Narcole psy  Ph 2 trial start (4Q 2018)  Ph 2 top-line results (1H 2019)

For more information, please contact Mark Jacobson SVP, Operations 212-332-3243 mjacobson@A xsome.com axsome.com

APPENDIX – AXSOME PPC © Axsome Therapeutics, Inc. 31

Overview Axsome PPC Candidates and Pipeline • Two differentiated clinical-stage pain and primary care assets targeting growing markets. • Patent protection to 2034, worldwide rights. significant and SPA Received; Fast Track Granted Abbrev iations: BML = Bone Marrow Lesions; CLBP = Chronic Low Back Pain; DZT = Disodium Zoledronate Tetrahy drate; Eso = Esomeprazole; MC = Modic Changes; Mx = Meloxicam; OA = Osteoarthritis; RA = Rheumatoid Arthritis; SPA = Special Protocol Assessment Conf idential and Proprietary Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-02 (DZT) Knee OA with BMLs: CLBP with MCs Ongoing AXS-06 (MoSEIC™ Mx + Eso) OA and RA

© Axsome Therapeutics, Inc. 33 AXS-02 Disodium Zoledronate Tetrahydrate Novel therapy for chronic pain: • Knee Osteoarthritis (OA) with Bone Marrow Lesions (BMLs) • Chronic Low Back Pain (CLBP) with Modic Changes (MCs)

AXS-02 Chronic Pain: Differentiated Therapy AXS-02 Disodium Zoledronate Tetrahydrate Oral Dose Long-acting Targeted Therapy Non-opioid Nov el Mechanism Mechanisms of Action Inhibits bone-resorbing osteoclasts Downregulates acid-sensing† ion channels Reduces pro-inflammatory cytokine production Anti-angiogenic †Acid is a w ell know n cause of pain. © Axsome Therapeutics, Inc. 34

AXS-02 Chronic Pain: Knee OA with BMLs Overview • Bone marrow lesions (BMLs) on MRI are associated with pain in knee osteoarthritis (OA).1 • BMLs are regions of increased bone turnover, and reduced mineral density.2,3 • Zoledronic acid inhibits bone resorption and increases mineral density. • Phase 3 trial initiated based on positive Phase 2 results with IV zoledronic acid. • Phase 3 interim analysis: IDMC recommended continuation to full enrollment 7M patients in the U.S.4-9 Fast Track Granted Abbreviations : DZT = Dis odium Zoledronate Tetrahydrate. * MRI show ing BML in medial tibia f rom Driban, et al. Arthritis Res Ther. 2013;15:R112. 1. Driban JB, et al. Arthritis Res Ther. 2013;15:R112. 2. Hunter DJ, et al. Arthritis Res Ther. 2009;11:R11. 3. Kazakia GJ, et al. Osteoarthritis Cartilage. 2013;21:94-101. 4. Law rence RC, et al. Arthritis Rheum. 2008;58:26-35. 5. Zhang Y, Jordan. JM Clin Geriatr Med. 2010;26:355–69. 6. Tanamas SK, et al. Rheumatology. 2010;49:2413–19. 7. Guermazi A, et al. BMJ. 2012;345:e5339. 8. Jensen OK, et al. Spine J. Feb. 14, 2014;pii:S1529-9430(14)00214-9. 9. U.S. Census Bureau, Population April 1, 2010 to July 1, 2013. © Axsome Therapeutics, Inc. 35 Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-02 (DZT) Knee OA with BML s: SPA Received; Initiated

AXS-02 Chronic Pain: Knee OA with BMLs Phase 3 Design A Phase 3 trial to assess the efficacy and safety of AXS-02 in the treatment of pain of knee OA associated with BMLs. Clinical Knee OA Symptom Treatment 1 Study Screening, Baseline Double-blind Phase (24 weeks) Special Prot ocol A ssessment ( SPA ) receiv ed N=346 1:1 randomization • Primary Endpoint: Change in pain intensity from baseline to week 24, measured using the 0-10 Numerical Rating Scale (NRS). • Key Inclusion Criteria: – Male at least 50 years of age or postmenopausal female, with knee OA and BMLs – Moderate or worse knee pain • Dosage: Once per week for six weeks; no drug for remainder of double-blind phase. © Axsome Therapeutics, Inc. 36 Placebo Arm B (n=173) AXS-02 (disodium zoledronate tetrahydrate) Arm A (n=173)

AXS-02 Chronic Pain: CLBP with MCs Overview • Modic changes (MCs) type 1 (M1) on MRI are associated with chronic low back pain (CLBP).1 • Increased bone turnover on bone scan is seen in M1 lesions.2 • Increased pro-inflammatory cytokines, and vascular density seen in M1 lesions.3 • Zoledronic acid reduces bone turnover, suppresses the production of inflammatory mediators, and is anti-angiogenic. • Phase 2 results: Zoledronic acid reduced pain in patients with CLBP. • FDA clearance received for IND for Phase 3 trial – initiation planned following readouts from CREATE-1 and STRIDE-1. 1.6M patients in the U.S.4-7 • Issued U.S. patents: protection into 2034 – uses of acid for low back pain. oral zoledronic Abbreviations : DZT = Dis odium Zoledronate Tetrahydrate. * MRI show ing modic type 1 lesions f rom Luoma K, et al. European Congress of Radiology (ECR). 2014;Poster B-0458. 1. Zhang Y, et al. Eur Spine J. 2008;17:1289-1299. 2. Järvinen J, et al. Spine: ISSLS Society Meeting Ab stracts. Oct. 2011;Volume Suppl, Abstract GP127. 3. Rahme R, Moussa R. Am J Neuroradiol. 2008;29:838–42. 4. Law rence RC, et al. Arthritis Rheum. 2008;58:26-35. 5. Zhang Y, Jordan. JM Clin Geriatr Med. 2010;26:355–69. 6. Jensen OK, et al. Spine J. Feb. 14, 2014;pii:S1529-9430(14)00214-9. 7. U.S. Census Bureau, Population April 1, 2010 to July 1, 2013. © Axsome Therapeutics, Inc. 37 Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-02 (DZT) CLBP with MCs

© Axsome Therapeutics, Inc. 38 AXS-06 MoSEIC™ Meloxicam + Esom eprazole Novel therapy: • Osteoarthritis • Rheumatoid arthritis

MoSEIC™ OA and RA: MoSEIC™Meloxicam Overview • MoSEIC meloxicam is a potent, oral, rapidly-absorbed, once-daily, non-opioid, COX-2 preferential, pain therapeutic. (4-6 hours) which delays its onset of action.1,2 • Standard meloxicam has an extended Tmax • Axsome’s MoSEIC (Molecular Solubility Enhanced Inclusion Complex) technology substantially increases the rate of absorption of meloxicam while maintaining its approximately 20-hour half-life. and similar half-life, compared to Mobic®. • Phase 1 results: 9 times faster Tmax, • Potential utility for migraine, and the • AXS-06 is a fixed-dose combination higher Cmax signs and symptoms of OA and RA. of MoSEIC meloxicam and esomeprazole (to reduce risk of NSAID-associated ulcers). 1. Mobic® (meloxicam) FDA Package Insert. 2. Euller-Ziegler et al., Inflamm Res 50, Supplement 1 (2001) S5–S9. © Axsome Therapeutics, Inc. 39 IP Overview • 5 issued patents and 2 allowed application – protection through 2036. • Pharmacokinetic patents • More than 25 U.S. and international applications.

MoSEIC™ AXS-06: MoSEIC™ Meloxicam + Esomeprazole for OA & RA • AXS-06 is a fixed-dose combination of MoSEIC™ meloxicam and esomeprazole • Being developed to treat OA and RA, and to reduce the risk of NSAID-associated upper GI ulcers • Potentially best-in-class NSAID profile: – – – Oral administration with IV-like onset of action Long half-life for sustained effect and once-daily dosing Improved GI safety from esomeprazole component • Positive Phase 1 results: therapeutic meloxicam concentrations within 15 mins, gastroprotective esomeprazole concentrations • FDA Pre-IND written guidance received • AXS-06 is Phase 3-ready 120M NSAID TRx per U.S. year in the Abbreviations : Es o = Es om eprazole; Mx = Meloxicam ; OA = Os teoarthritis ; RA = Rheum atoid Arthritis . © Axsome Therapeutics, Inc. 40 Product Candidate Preclinical Phase 1 Phase 2 Phase 3 AXS-06 (MoSEIC™ Mx + Eso) OA and RA Phase 3 ready

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