<?xml version="1.0"?>
<ownershipDocument>

    <schemaVersion>X0508</schemaVersion>

    <documentType>4</documentType>

    <periodOfReport>2026-02-26</periodOfReport>

    <issuer>
        <issuerCik>0001579428</issuerCik>
        <issuerName>Axsome Therapeutics, Inc.</issuerName>
        <issuerTradingSymbol>AXSM</issuerTradingSymbol>
    </issuer>

    <reportingOwner>
        <reportingOwnerId>
            <rptOwnerCik>0001934008</rptOwnerCik>
            <rptOwnerName>Murdock Hunter R.</rptOwnerName>
        </reportingOwnerId>
        <reportingOwnerAddress>
            <rptOwnerStreet1>C/O AXSOME THERAPEUTICS, INC.</rptOwnerStreet1>
            <rptOwnerStreet2>ONE WORLD TRADE CENTER, 29TH FLOOR</rptOwnerStreet2>
            <rptOwnerCity>NEW YORK</rptOwnerCity>
            <rptOwnerState>NY</rptOwnerState>
            <rptOwnerZipCode>10007</rptOwnerZipCode>
            <rptOwnerStateDescription></rptOwnerStateDescription>
        </reportingOwnerAddress>
        <reportingOwnerRelationship>
            <isDirector>false</isDirector>
            <isOfficer>true</isOfficer>
            <isTenPercentOwner>false</isTenPercentOwner>
            <isOther>false</isOther>
            <officerTitle>General Counsel</officerTitle>
        </reportingOwnerRelationship>
    </reportingOwner>

    <aff10b5One>false</aff10b5One>

    <derivativeTable>
        <derivativeTransaction>
            <securityTitle>
                <value>Restricted Stock Units</value>
            </securityTitle>
            <conversionOrExercisePrice>
                <footnoteId id="F1"/>
            </conversionOrExercisePrice>
            <transactionDate>
                <value>2026-02-26</value>
            </transactionDate>
            <transactionCoding>
                <transactionFormType>4</transactionFormType>
                <transactionCode>A</transactionCode>
                <equitySwapInvolved>false</equitySwapInvolved>
            </transactionCoding>
            <transactionAmounts>
                <transactionShares>
                    <value>16385</value>
                </transactionShares>
                <transactionPricePerShare>
                    <value>0</value>
                </transactionPricePerShare>
                <transactionAcquiredDisposedCode>
                    <value>A</value>
                </transactionAcquiredDisposedCode>
            </transactionAmounts>
            <exerciseDate>
                <footnoteId id="F2"/>
            </exerciseDate>
            <expirationDate>
                <value>2036-02-26</value>
            </expirationDate>
            <underlyingSecurity>
                <underlyingSecurityTitle>
                    <value>Common Stock</value>
                </underlyingSecurityTitle>
                <underlyingSecurityShares>
                    <value>16385</value>
                </underlyingSecurityShares>
            </underlyingSecurity>
            <postTransactionAmounts>
                <sharesOwnedFollowingTransaction>
                    <value>16385</value>
                </sharesOwnedFollowingTransaction>
            </postTransactionAmounts>
            <ownershipNature>
                <directOrIndirectOwnership>
                    <value>D</value>
                </directOrIndirectOwnership>
            </ownershipNature>
        </derivativeTransaction>
    </derivativeTable>

    <footnotes>
        <footnote id="F1">Each restricted stock unit (&quot;RSU&quot;) represents a contingent right to receive one share of the Issuer's common stock.</footnote>
        <footnote id="F2">25% of the RSUs will vest on the one (1) year anniversary of the date of grant. The remaining RSUs will vest in three substantially equal annual installments, such that the RSUs will be fully vested on February 26, 2030. Vested shares will be delivered to the reporting person upon the earlier of (i) the closing of a Change in Control (as defined in the Issuer's 2025 Long-Term Incentive Plan (&quot;2025 Plan&quot;)), (ii) the reporting person's separation of service from the Issuer (including termination with or without Cause (as defined in the 2025 Plan), or termination due to death or Total and Permanent Disability (as defined in the 2025 Plan)), or (iii) seven (7) years from the date of grant.</footnote>
    </footnotes>

    <ownerSignature>
        <signatureName>/s/ Hunter Murdock</signatureName>
        <signatureDate>2026-02-27</signatureDate>
    </ownerSignature>
</ownershipDocument>
