The 5-HT2C receptor as a therapeutic target for alcohol and methamphetamine use disorders: A pilot study in treatment-seeking individuals

Abstract

Alcohol use disorder (AUD) and methamphetamine use disorder (MUD) are prevalent and have high adverse impacts on both the individual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5-HT2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants (n = 10 AUD; n = 8 MUD) received 10-mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment-emergent events, incidence of methamphetamine or alcohol withdrawal-related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self-reported alcohol or methamphetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to individuals with obesity. Lorcaserin reduced self-reported alcohol and amphetamine-type substance use and craving in AUD and MUD participants, respectively. Self-reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5-HT2C receptors as a therapeutic target for drug and alcohol abuse.

Full text

Pharmacol Res Perspect. 2021;9:e00767.  
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https://doi.org/10.1002/prp2.767
wileyonlinelibrary.com/journal/prp2
Received:5Februa ry2021
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Accepted:5March2021
DOI: 10.1002/prp2.767
ORIGINAL ARTICLE
The 5- HT2C receptor as a therapeutic target for alcohol and
methamphetamine use disorders: A pilot study in
treatment- seeking individuals
Erin J. Campbell1 | Yvonne Bonomo2 | Adam Pastor2 | Lisa Collins2 |
Amanda Norman2 | Peter Galettis3 | Janice Johnstone3 | Andrew J. Lawrence1
Thisisanop enaccessarticleundertheter msoftheCreativeCommonsAttributionLicense,whichpe rmitsuse,distributionandreproductioninanymedium,
provide d the original wor k is properly cited.
©2021TheAuthors.Pharmacology Researc h & Perspectivespublishe dbyJohnWiley&SonsLtd,BritishPharmacologicalSociet yandAmericanSocietyfor
PharmacologyandExperimentalTherapeutic s.
ErinJ.Ca mpbe llandYvon neBono moareco-firs tautho rs.
Abbreviations:AUD,Alcoho lusediso rder;B MI,bo dymassi ndex;FDA ,Fooda ndDru gAdmini strat ion;MU D,metha mphet amineu sedisor der.
1Florey Institute of Neuroscience and
MentalH ealth ,MelbourneBr ainCentre,
TheUniversityofMelbourne,Parkville,
VIC,Australia
2Depar tmentofAddictionMedicine,
StVincent'sHospitalMelbour ne,The
UniversityofMe lbourne,Parkville,VIC ,
Australia
3SchoolofMedicineandPub licHealth,
TheUniversityofNewcastle,C allaghan,
NSW,Austr alia
Correspondence
AndrewJ.Lawrence,FloreyInstitute
ofNeuroscienceandMentalHealt h,
MelbourneBrainCentre,TheUniversity
ofMelbourne,Pa rkville,VIC3052,
Australia.
Email:andrew.lawrence@florey.edu.au
YvonneBonomo,Departmentof
AddictionMedicine,StV incent'sHospital
Melbourne,TheUniver sityofMelbourne,
Parkville,VIC3010,Australia.
Email:yvonne.bonomo@svha.org.au
Funding information
AJLisaNHMRCPrincipalFellow
(1116930).YBreceivedaSeedingGrant
fromSVHMResearchEndowmentFund
(REF81803).
Abstract
Alcohol use d isorder (AUD) and met hamphetamine us e disorder (MUD) are prev a-
lent and have high adverse impacts on both the individual and society. Current treat-
mentstrategiesforthesedisordersareineffectiveatapopulationlevel.Lorcaserin,a
5-HT2Creceptoragonist,hasshownpotentialatreducingthesymptomsofsubstance
usedisorder.Thispilotstudy(initiatedpriortomarketwithdrawal)examinedfeasibility
andsafetyoflorcaserintreatmentinpeopleundergoingresidentialdetoxificationand
treatmentforAUDandMUD.Thiswasanopenlabelpilotstudyoflorcaserinwhere
participants (n=10AUD;n=8MUD)received10-mglorcaserindailyfor4daysthen
twicedailyfor1month.Primar youtcomemeasuresincludedrecruitmentandreten-
tionrate,incidenceoftreatment-emergentevents,incidenceofmethamphetamineor
alcoholwithdrawal-relatedevents,heartrate,andblood pressure.Secondarymeas-
uresincludedpharmacokinetic dataandself-reportedalcohol or methamphetamine
use,craving, and psychologicaldistress. AUDparticipantswererecruited fasterand
hadagreaterretentionratecomparedwithMUDparticipants.Lorcaserindidnotalter
vitalsigns,waswelltolerated,andhadasimilarpharmacokineticprofiletoindividuals
with obesity.Lorcaserin reduced self-reported alcohol andamphetamine-typesub-
stanceuseandcravinginAUDandMUDparticipants,respectively.Self-reportedpsy-
chological health also improved over the treatment period for all participants. Despite
thepilot nature of thisstudy,ourdata support thenotion of 5-HT2C receptors as a
therapeutic target for drug and alcohol abuse.
KEYWORDS
5-HT2Cagonist,alcohol,craving,lorcaserin,methamphetamine,serotonin

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1 | INTRODUC TION
Alcoholusedisorder(AUD)posesamajorsocialandeconomicbur-
dentosoci et y,accountingfor~5%ofde athsworl dwidein2016a nd
cost ingupwa rd of $3 6b illio n/ ye arinAus tra li a.1 With regard to illicit
druguse,methamphetamine is the second most regularly used drug
followingcannabisinAustralia,andintheUnitedStates,therewas
athreefoldincreaseinthenumberofmethamphetamine-associated
deaths between 2010 and 2015.2,3Asaresult,therecreationaluse
and abuse of d rugs continues to b e a major global public health is sue.
Importantly, poor retention and frequent relapse remain serious
obstacles for the treatment of subst ance use disorders with con-
tinuous and intense cravings persisting both during and following
treatment.4, 5TherearethreeFoodandDrugAdministration(FDA)-
approved pharmacotherapies for AUD,disulfiram, naltrexone, and
acamprosate.CurrentpharmacotherapeutictreatmentsforAUDre-
main inef fective at a population level due to a combination of limited
effectivenessandunder-prescribing.6,7TherearenoFDA-approved
pharmacotherapies specifically for methamphetamine use disorder
(MUD).Inarecentreview,mostmedicationsevaluatedwerefound
to not have a statistically significant benefit.8Clearly,thereisneed
for improved pharmacotherapeutic treatments aimed at reducing
drug-relatedcravingforbothAUDandMUD.
The neural circuitry surrounding craving and relapse to drug use
involves several brain structures including the ventral tegmental
area, st riatal comp lex, amygdala , hippoca mpus, and th e prefronta l
cortex.9,1 0Serotonin-containingcells (5-hydroxytryptamine[5-HT])
arelocatedpredominantlyintheraphenucleiofthemid/hind-brain,
including the dorsal and median raphe.11 From here , 5-HT fibers
widely innervate the central nervous system including multiple
nodes of reward-related circuitry.12 Indeed, the serotonergic sys-
tem has been implicated in substance use disorder and relapse for
several decades and may represent an avenue for future pharma-
cological interventions.1 3 – 1 8  Thereare14knownsubtypesof5-HT
receptors, andserotoninsignalingiswellknowntomodulatedopa-
mine activity.19Specifically,the5-HT2C receptorisexpressedinthe
hippocampus,striatum,andamygdalainbothratandhuman.2 0– 2 2
5-HT2C receptor signaling has been implicated in the development
andmaintenanceofAUDandMUD.Forexample,the5-HT2C receptor
agonist,Ro60-0175,decreased alcoholconsumptionin rats whereas
the5-HT2Creceptorantagonist, S B - 2 4 2  0 8 4 ,increased alcohol con-
sumption.23However,Ro60-0175reducedbothalcohol(gelsolution)
andvehicle(plaingelcontainingpolycose)operantself-administration
in rats suggesting possible nonspecific ef fects on caloric intake.24 5-
HT2C receptor signaling is also involved in methamphetamine use; for
example,Ro60-0175reversedmethamphetamineself-administration-
induced decreases in nucleus accumbens shell excitability.25
Additionally, methamphetamine-induced behavioral sensitization is
associatedwith a functional upregulation of5-HT2C receptors in the
ventral pallidum.26Together,thesepreclinicalstudies highlighta role
forthe5-HT2C receptor in both alcohol and methamphetamine use.
The development of therapeutic drugs that selectively target in-
dividual5-HT2receptorsubtypesisdifficult. Indeed, most5-HT2C
receptor a gonists also bi nd to 5-HT2A and/or 5-HT2B receptors.27
Lorcaserinisaselec tiveserotonin2C(5-HT2C) receptor agonist with
a 3-benzazepine scaffold,28 developed as an anti-obesity medica-
tion.Notably,lorcaserinreducestheconsumptionofalcoholinrats
andmethamphetamineuseinrhesusmonkeys,29, 30 implicating the
5-HT2C receptor as a potential treatment target for alcohol and sub-
stance use disorders.15Untilrecently,lorcaserin(Belviq®)wasFDA-
approved asananti-obesitymedication31 but was withdrawn from
the market af ter a safety trial indicated an increased occurrence of
cancer,where7.7%ofparticipantsreceivingdrugdevelopedcancer
relative to7.1%in the placeboarm.31Here, wecarried out a pilot
study, prior to market withdrawal, to evaluate the abilit y of lorca-
serin to suppress alcohol and methamphetamine craving and con-
sumptionintreatment-seekingAUDorMUDparticipants.
2 | MATERIALS AND METHODS
2.1 | Study design and participants
This was an open label pilot study. The protocol and amendments
were approved by the Human Research Ethics Committee of St
Vincent's Hospital Melbourne (HREC031/17).Eligibleparticipants
were males and females over the age of 18 years, diagnosed with
alcohol or methamphetamine substance use disorder (DSM5).
Exclusioncriteriaincludedpregnant(urineβHCGpositive)orbreast-
feeding; highly dependent on medical care for co-existing condi-
tions; other medical treatments for substance dependence including
anti-craving (e.g., acamprosate and naltrexone), aversive (e.g., di-
sulfir am), or substitu tion (e.g., atomoxetine, dexamphetamine, and
methylphenidate) treatments; known allerg y to lorcaserin; already
receivinglorcaserin;severeliverimpairment(ChildPughC);severe
renal impairment (creatinine clearance <30 ml/min); hypertension;
unstable diabetes; history of serotonin syndrome; low body mass
ind ex(BM I<20);andun st ablementals tate(in cludingac tivep sycho-
sisorschizophrenia).Written informedconsent was obtained from
all participants.
Thestudyprotocolspecifiedtherecruitmentof10AUDpartici-
pantsand10MUDparticipants.Recruitmentwasceasedwhenthe
initial FDA al ert was issu ed in Januar y 2020, resu lting in the f inal
recruitmentof10alcohol-and8methamphetamine-dependentpar-
ticipants.NotethattheHRECwasadvisedimmediatelybytheChief
InvestigatorsoftheoriginalFDA alertandthesubsequentproduct
withdrawal. All participants were advisedinwritingof theproduct
withdrawal and the health risks associated with their participation
in the study.
2.2 | Procedures
Participantswere treated with the lowest ef fective dose oflor-
caserin (immediate release) used in the treatment of obesity.
Participantsreceivedlorcaserin10mgoncedailyfor4daysthen

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twice da ily for 1 month. All pa rticipant s received symptom atic
treatment using the St Vincent 's Hospital standard protocol.
Withdr awal was acti vely managed as ei ther an outpat ient or, if
required, in a residential setting. Alcohol withdrawal was man-
agedina ccordancewithCl in icalIns tituteWit hd rawalAs sessm en t
of Alcohol (CIWA-Ar).32 Prescribed medications consisted of
5– 20 mg of diazepam2hourlywithamaximumof80mgper
24-hperiod, anti-emetics for nausea, andparacetamol and non-
steroidalanti-inflammatoriesforaches.Allmedicationswereused
onlyasrequiredandceased byDay7followingparticipants’ last
use of alcohol or methamphetamine and the commencement of
lorcaserin.
2.3 | Pharmacokinetic sampling
OnDay7oftreatment,4-mlEDTAbloodsamplesweretakenfor
assessmentofplasmaconcentrationlevelsoftheIP(lorcaserin)at
predose(time0),2,4,and8haf tertreatment.Bloodswererefrig-
erated at ≤4°Candcentrifuged at 2000g for 10 min within 12 h
after blood sampling. Immediately after centrifugation, plasma
were stored in two labeled polypropylene tubes and stored at
≤−20°C forplasma concentration analysis. Allplasma concentra-
tion analyses were performed after all participants had completed
the final visit.
2.4 | Measures
Measures were assessed over five treatment time points (base-
line, Day 7, Day 14, Day 21, and Day 28). A basel ine researcher-
administered questionnaire assessed demographic and clinical
characteristics anddetermined eligibility.Liver function andblood
glucose wereassessed every second week (baseline,Day 14, and
Day28).
The Obsessive Compulsive Drinking Scale was used to assess
alcohol craving.33 A total craving score was calculated by sum-
ming the 14 items of this questionnaire, which were ranked on
a Likert s cale rangin g from 1 to 7.Su mming Items 1–6 calculat ed
the obsessive subscale, and summing Items 7–14 calculated the
Compuls ive Subscale . A brief, 10-item Meth amphetami ne Craving
Quest ionnaire, based o n the Cocaine Craving Qu estionnaire , was
used to assess methamphetamine craving over time. Scores across
each item were averaged.34,35
The KesslerPsychologicalDistressScale(K10)yieldeda global
measureofdistress,whichwasthesumofall10items.
TheAustralianTreatmentOutcomesProfile (ATOP),a validated
Australianversion oftheUKTreatmentOutcomeProfile,was used
toassessself-reporteddruguseandhealthandwell-being.36Higher
scores on t he substan ce use questio ns, measure d using the time-
linefollow-backmethod,reflectedmoredaysofusewhereashigher
scores on h ealth and well-bein g questions indicated gre ater self-
rated health outcomes.
2.5 | Outcomes
Primaryendpoints wereprespecified.Feasibilityendpointswere
recruitment rate and retention in treatment at Days 7, 14, 21,
and28.Safetyendpointswereincidenceoftreatment-emergent
adverseevents (AEs);incidenceof methamphetamine oralcohol
withdrawal-related treatment-emergent events; heart rate; and
blood pressure.
Secondary endpoints weremethamphetamine use (self-report,
salivascreen,andurinedrugscreen)onStudyDays0,7,14,21,and
28;alcoholuse (self-report,breathalcohol,bloodtesting,andurine
drugscreen)onStudyDays0,7,14,21,and28;cravingmeasures—
ObsessiveCompulsiveScale forDrinking(AUDgroup)andCocaine
CravingQuestionnaire(MUDgroup)onStudyDays0,7,14,21,and
28; and K10 psycho logical dist ress and ATOP measures on St udy
Days0,7,14,21,and28.
Afinal outcomewastoassess thepharmacokineticsoflorca-
serin ina clinical population with normalBMI: AUC0–8 h, Cmax,
t½,tmax.
2.6 | Pharmacokinetic analysis
PharmacokineticdatawereanalyzedattheClinicalPharmacology
Laboratory, School of Medicine and Public Health, University
of Newcast le, Australia . Plasma samples we re analyzed using a
validated liquid chromatography with tandem mass spectrom-
etry (LCMSMS) method for lorcaserin. Plasma samples (50 µl)
were prepared by adding twice the volume of acetonitrile, sam-
ples were vortexed and then centrifuged, and the supernatant
was transferred to a vial and injected onto the LCMSMS. The
LCMSMS system consisted of a Shimadzu 8060 LCMS using a
Kinetex C18column anda gradient of 0.1%formic acidandace-
tonitrile. Lorcaserin was linear over the range of 10–50 0 ng/ml.
Usingtheconcentration–timeprofilesdeterminedbytheanalysis
oftheplasmasamples,thepharmacokineticparameters,maximum
plasma concentration (Cmax), time of Cma x (Tmax), area unde r the
plasmaconcentrationtimecur ve(AUC0–12),andplasmahalf-life
(t½),weredeterminedusingPKSolver.37 The data were fitted using
the NCA Extravascular module, with AUC0 − t calculated using
the log-line ar trapezoi dal method . The 12-h t ime point for ea ch
individual was predicted with a one compartment model using
PKSo lve r.
2.7 | Statistical analysis
Unlessotherwisestated,datawereanalyzedseparatelyforAUDand
MUDparticipants.
Demographic data were summarized as numbers and pro-
portions for categorical data and mean (±standard error of mean
[SEM]) for conti nuous data usi ng Microsoft O ffice Exce l 2016.
Clinical characteristics and vital signs were analyzed using a

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repeatedmeasuresANOVA.Duetothehighdropoutr ateofpar-
ticipa ntswithM UD,eit herthree(baselinetoDay14)orf ivetime
points(baselinetoDay28)wereassessed.Theoralfluidtestand
urinarydrugscreenwereanalyzedusingtheFriedmannonpara-
metrictest.ForparticipantswithAUD,baselineandDay21oral
fluid substance results were not detected for one participant and
baseline blood glucose levels were missing for another partici-
pant.ForparticipantswithMUD,Day7bloodpressuredatawere
missing for one participant, baseline weight data were missing
for two pa rticipants , and Day 7 weight data were mi ssing for
one participant. To allow for the inclusion of these participants
instatistical analyses,a meanimputationofmissing valueswas
conductedinSPSS.ForMUDparticipants, one participant had
all liver function and blood glucose data missing and three par-
ticipants had their urine drug screen data missing and were thus
excluded from analyses. The Obsessive Compulsive Drinking
Scale,MethamphetamineCravingQuestionnaire,andK10Scale
were analy zed using a repe ated measures AN OVA as the dat a
werenormallydistributedandANOVAassumptionswerenotvi-
olated. A re peated measure s ANOVA was used to analy ze the
ATOP data. For par ticipants w ith AUD, the ATOP data for the
numberofdaysparticipantsdrankalcoholandthetypicalquan-
tity of alcohol consumed were not normally distributed and thus
assessed using the Friedman nonparametric test. Two partici-
pantshaddatamissingfromthehealthandwell-beingquestions
andwereexcludedfromthisanalysis.Onlyt wotothreepartici-
pantswithMUD completedtheATOPself-reportquestionnaire
forthedurationofthestudy(baselinetoDay28);thus,datawere
also analyzed from baseline to Day 14, with five participants
completing the questionnaire at these timepoints. All analyses
wereperformedusingSPSSv27(α = .05). Data are presented as
mean±SEM.
2.8 | Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked
to corresponding entries in http://www.guide topha rmaco logy.
org, the comm on porta l for data from t he IUPHAR/B PS Guide to
PHARMACOLOGY,38 and are permanently archived in the Concise
GuidetoPHARMACOLOGY2019/20.39
3 | RESULTS
3.1 | Demographic information
The participants recruited with AUD were predominantly male
(8/10). The mean age wa s 48.1 years (SEM = 2 .1).Me an typic al
quantity of alcohol consumed on day used was 21.8 standard
drin ks(SEM=4. 4).T hepar tic ipa nt sre cruit edwit hM UDwer ep re-
dom inantlyma le(6/8)withame anage(M=36.6years,SEM=2.9)
of more than 10 yea rs younger tha n the AUD group. Th e mean
typical quantity ofmethamphetamine on aday usedwas 0.66 g
(SEM=0.22).
Table 1 describes further characteristics at baseline for both
participant groups. Age of use characteristics were younger for
AUD participants compared withMUD par ticipants. AUDpartici-
pantshadexperiencedmorewithdrawalsymptomscomparedwith
MUD par ticipants. The majority of AUD participants (90%) had at
leastone previoustreatmentfor dependence comparedwith50%
forMUDparticipants.ThetypesoftreatmentsforAUD were both
pharmacotherapiesandnonpharmacotherapies,but only nonphar-
macotherapiesforMUDparticipants.
3.2 | Primary endpoints
3.2.1 | Feasibility
Thefirst participantwas recruitedintotheclinical trialonthe24th
ofJuly 2018, and the last participant was recruited on the 2nd of
December2019,equatingtoatotalofjustover16months(496days)
torecruitthe18participants.Forthealcoholgroup(n=10),theme-
dian time between recruiting each participant was just over 1 month
(median=37 days, interquartilerange=16–59days),that is, arate
of0.82AUD participantspermonth. FortheMUDgroup (n=8), it
tooklongerbetweenparticipantstoberecruited(median=73days,
interquartilerange=44–98days),thatis,arateof0.42participants
permonth.FortheAUDparticipants,theretentionintreatmentrate
atDay7was100%,and 80%foreach weekly visit thereafter.For
theMUD participants, the retention rate at Days 7,14, 21,and 28
was87.5%,62.5%, 37.5%,and 50%,respectively.Themain reason
for participant s discontinuing the trial was due to failing to attend
appointments. Note that one patient missed Day 21 appointment
butrepresentedfor Day28,andthisaccountsforthedipin there-
tentionratesovertimeatDay21.Eachwasdeemed“losttofollow-
up” after multiple unsuccessful at tempts by a clinician to contac t the
participant.
3.2.2 | Safety
Treatment- emergent AEs
Eight AUD participants (80%) reported atleast oneAE, andseven
MUDparticipants(87.5%).Ofthese,sevenoftheAUDpar ticipants
(87.5%),andfiveMUDparticipants(71.4%),reportedatleastoneAE
that was considered by a study doctor to be related to lorcaserin.
Thes ei nc ludedra ti ngsofd efinite ly re late d,proba blyrelated,orpo s-
siblyrelated(Table2).OfallAEs(n=28),19wereconsideredtobe
treatmentemergent(67.9%).
Themostfrequentlyoccurringtreatment-emergentAEswere
“decreasedappetite”(21.1%, 4of19)andheadache(21.1%,4of
19).Theseoccur redthroughoutthe4weeksofstudymedication
administration.Thesecondmostfrequentlyoccurringtreatment-
emergentAEswere“lethargy”(15.8%, 3of19)and“dr ymouth”

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CAMPB ELL Et AL.
(15.8%, 3 of 19), again occurring through the duration of the
trial. None of the treatment-emergent AEs was classified as
TAB LE 1 Participantcharacteristicsatbaseline
Characteristic
Number (%)
Alcohol use
disorder (n = 10)
Methamphetamine
use disorder (n = 8)
Countr y of birth
Australia 8(80.0) 6 (75.0)
Other 2 (20.0)
(Yugoslavia,
United
Kingdom)
2(25.0)(Scotland,
SouthAfrica)
IndigenousAustralian 1 (10.0) 0
Livingstatus
Alone 4(40.0) 2 (25.0)
Partner(withatleast
1 child)
3 (30.0) 2 (25.0)
Partner(nochildren) 2 (20.0) 1 (12.5)
Relationship status
Single 4(40.0) 5 (62.5)
Livingwithspouse
(including
married,defac to,
life partner)
4(40.0) 3 (37.5)
Separated but not
divorced
2 (20.0) 0
Accommodation
Private
accommodation
10 (100.0) 8(100.0)
Employment
Employed 4(40.0) 4(80.0)
Disability support
pension
2 (20.0) 1 (12.5)
Currently
unemployed
1 (10.0) 1 (10.0)
Highestlevelofeducation
Secondary (years
7– 10 )
2 (10.0) 3 (37.5)
Secondary (years
11– 1 2 )
1 (10.0) 3 (37.5)
Tertiary 6 (60.0) 1 (12.5)
Postgraduate 1 (10.0) 1 (12. 5)
Medicalhistor y
Current conditions
Depression 4(40.0%) 3(37.5%)
Anxiety 4(40.0%) 3(37.5%)
Highcholesterol 2(20.0%) 0
Alcohol-relatedconditions
None 7(70.0%) 6(75.0%)
Seizures 2(20.0%) 0
Alcohol or
methamphetamine use
history Alcohol use
Methamphetamine
use
Estimated
amount
(standard
drinks)
Estimatedamount
(g)
(Continues)
Alcohol or
methamphetamine use
history Alcohol use
Methamphetamine
use
Mean(SE) 21.8(4.4) 0.66 (0.22)
Ageatfir st
drink (years)
Ageatfir stuse
(year s)
Mean(SE) 16.3(0.4) 24.0(3.1)
Ageatdaily
drinking
(year s)
Ageatproblematic
use (years)
Mean(SE) 31.6(2.8) 25.7(3.4)
Duration since
daily drinking
(year s)
Duration since
problematic use
(year s)
Mean(SE) 15.8(2.5) 10.4(2.5)
Previousdetoxifications
Atleast1
detoxification
9(90.0%) 4(50.0%)
Previouswithdrawalsymptoms
Sweating 9(15.0%) 1(1.7%)
Anxiety 8(13.3%) 3(5.0%)
Tre mor 7(11.7%) 1(1.7%)
Nausea 5(8.3%) 0
Agitation 5(8.3%) 3(5.0%)
Seizures 2(3.3%) 0
Vomiting 3(5.0%) 0
Diarrhea 2(3.3%) 0
Delirium tremens 1(1.7%) 0
Previoustreatmentfordependence
Atleast1treatment 9(90.0%) 4(50.0%)
Previoustypesoftreatment(oftenmultiple)
Counseling 9(100.0%) 4(100.0%)
Acamprosate
maintenance
9(100.0%) 0
Naltrexone
maintenance
8(88.9%) 0
Alcoholics
anonymous(AA)
7(77.8%) 0
Residential
rehabilitation
activities
4(44.4%) 1(25.0%)
Disulfiram
maintenance
2(22.2%) 0
Other 3(33.3%)
(recover y
and support
program,2×
baclofen)
1(25.0%)( The
Rewired
Program—self-
administered)
TAB LE 1 (Continued)

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CAMPBELL Et AL .
“severe.” One was classified as “moderate” severity.This event
of headache repor ted at Day 21 lasted 2 days and resolved spon-
taneously.Theremaining18treatment-emergentAEswereclas-
sified as “mild”severity. None of thetreatment-emergent AEs
wasaseriousAE.
Withdrawal- related treatment- emergent AEs (n = 1)
Oneeventwas“probablyrelated”tolorcaserin.AnAUDparticipant
exp er iencedongoingfatigue.Theydrop pe doutatDay9,an dnofur-
therfollow-upbythestudystaffwasachieved.
Vital signs
Forparticipantswith AUD, temperature,pulse, systolic anddias-
tolicblood pressure,andweightdidnotsignificantly changeover
time (Table S1). Respiratory rate (breaths/min) significantly in-
creased over the treatment period (Table S1). For par ticipants with
MUD,temperature, pulse, respiratory rate, systolicand diastolic
bloodpressure,andweightdidnot significantlychangeovertime
(Table S2).
3.3 | Secondary endpoints
3.3.1 | Substanceuse
Alcohol use
Self-repor t. FortheAUDgroup,thenumberofdaysdrinkingalcohol
in the past week did not change between baseline and Day 28
(Table3);however,thetypicalquantit yofalcoholconsumedonany
given day did decrease over time (Table 3).
Clinicalcharacteristics. FortheAUDgroup,breathalcoholcontent,
live rf unc t io n,b loo dg luc os eleve ls,an dur in arydrugsc ree nr esu lt s
did not change over the treatment period (Table S3).
Methamphetamine use
Self-report. FortheMUDgroup,frombaselinetoDay14,thenumber
of days using an amphetamine-typesubstanceinthepast weekdid
notchange(TableS4). FrombaselinetoDay28,the numberof days
usinganamphetamine-type substancein the past week decreased
(Table 3).
Clinicalcharacteristics. Forthe MUD group, liver function,blood
glucose levels, urinary drug screen results, and oral fluid test
results did not change over time (Table S5).
3.3.2 | Craving
Total craving scores for participants with AUD decreased over
time (F4, 28=7.299,p<.001;Figure1A).Scoresontheobsessive
subscale (F4,28=5.200, p = .0 03) and on the compulsive subscale
(F4, 28 = 7.689, p < .001) also significantly decreased over time
(Figure1A).
Methamphetamine craving for participants with MUD signifi-
cantly decreased frombaseline to Day 14 (F2 ,8 = 5.20 0, p = .036)
andapproachedsignificancefrombaselinetoDay28(F4,8=2.880,
p=.095;Figure1B).
TAB LE 2 Numberoftreatment-emergentadverseevents
(n=19)(definitelyrelated,probablyrelated,orpossiblyrelatedto
lorcaserin)groupedbySystemOrganClassandpreferredterm,for
both groups of participants
Event (System Organ Class/
preferred term)
Alcohol use
disorder
(n = 10)
Methamphetamine
use disorder (n = 8)
Number of participants with
≥1medication-related
adverse event
7 5
Gastrointestinaldisorders
Diarrhea 0 1
Dry mouth 2 1
Lipdry 1 0
Nausea 0 1
Generaldisordersandadministrationsiteconditions
Lethargy 3 0
Metabolismand
nutrition disorders
Decreased appetite 3 1
Nervous system disorders
Dizziness 2 0
Headache 2 2
TAB LE 3 ATOP self- report data from baseline to Day 28 for
participants with alcohol use disorder and methamphetamine use
disorder
ATOP self- report F statistic χ2p value n
Alcoholusedisorderparticipants
Number of days drank
alcohol in the last 7 days
5.756 .218 8
Typicalquantity(standard
drinks) of alcohol
consumed on day used
12.860 .012 8
Psychologicalhealthstatus 16.139 <. 001 6
Physicalhealthstatus 2.828 .052 6
Quality of life 5.689 .003 6
Methamphetamineusedisorderparticipants
Number of days used
amphetamine-type
substance in the last
7 days
4.214 .040 3
Psychologicalhealthstatus 51.000 .001 2
Physicalhealthstatus 1.370 .384 2
Quality of life 1.190 .435 2
Abbreviation:ATOP,AustralianTreatmentOutcomesProfile.

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CAMPB ELL Et AL.
3.3.3 | K10psychologicaldistress
K10 psychological distress scores significantly decreased over time
forparticipant swithAUD(F4,28=20.629,p < .001; Figure 1C).
K10 psychological distress scores did not change between
baselineandDay14(F2, 8=4.193,p = .057) or bet ween baseline
and Day 28 for pa rticipa nts with MUD (F4 , 8 = 1.537, p = .280;
Figure 1D).
3.3.4 | ATOPself-reporthealthandwell-beingdata
FortheAUDparticipants,psychological healthstatus and qual-
ityoflifesignificantlyincreasedacrosstheexperimentalperiod
between baseline and Day 28, and physical health status ap-
proachedasignificantimprovement(Table3;Figure1E).
FortheMUDparticipants,frombaselinetoDay14,theperceived
health a nd well-being i n the past wee k did not change ( TableS 4).
FIGURE 1 Self-reportedcraving,psychologicaldistress,andhealthandwell-beingafterlorcaserintreatmentinpar ticipantswithalcohol
usedisorder(AUD)andmethamphetamineusedisorder(MUD).Totalobsessivecompulsivedrinkingscoreoverthe28-daytreatmentperiod.
Tot a l n=8.**p<.01foreachcravingmeasure(A).Averagecravingscoreoverthe28-daytreatmentperiod.n=3–5.*p < .05 baseline to Day
14(B).KesslerPsychologicalDistressself-reportdataoverthe28-daytreatmentperiod.Totaln=8forAUDparticipants,n=3–5forMUD
participants.***p<.001(CandD).Psychologicalhealthstatusandqualityoflifeincreasedoverthetreatmentperiod;however,therewas
nosignificantchangeinphysicalhealthstatusforAUDparticipants.Totaln=8.**p<.01forpsychologicalhealthstatusandqualityoflife
(E).Psychologicalhealthstatusincreasedoverthetreatmentperiod;however,therewasnosignificantchangeinphysicalhealthstatusor
qualityoflife.n=2–5.***p=0.001forpsychologicalhealthstatus(F).Alldataarepresentedasmean±SEM

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FrombaselinetoDay28,thepsychologicalhealthstatusinthepast
week increased; however,physical health status and quality of life
did not change (Table 3; Figure 1F).
3.4 | Pharmacokinetics of lorcaserin
Pla sm aconcen tr at io ntimeprof il es(0,2,4, 8,and12h)forsixpar tic-
ipants are shown in Figure 2. The pharmacokinetic profile followed
an oral absorption profile (Figure S1) with a Tmax at 2 h and a Cmax
of102± 25ng/mlbeforefollowingaonephaseexponentialdecay,
resulting in a t1/2of7.9±2h.Pharmacokineticparametersaresum-
marizedinTable4.
4 | DISCUSSION
The aim of our pilot studywas to examine the safety and efficacy
of the 5-HT2C receptor agonist lorc aserin in people undergoing
resident ial withdrawa l and seeking tr eatment for AUD an d MUD.
There are l imited data on t he pharmaco kinetics of l orcaseri n, and
in genera l, this has been ob served in an ob ese populatio n with a
Tmaxof1.5h,Cmaxof80ng/mlwithavariabilityof26%,andat½ of
11.9 ± 1.5 h.40InAUDandMUDparticipants,weobservedaslightl y
longer Tmaxof2 .4h ,a highe rCmax of 102 ng/ml with similar variability
of26%,andashortert½of7.9±2h.Withthesmallsam plesizesand
similarvariabilit yofapproximately30%inbothstudies,itisunlikely
that there is a different pharmacokinetic profile between an obese
andAUD/MUDpopulations.
In the present study, AUD participants were recruited fas ter
andhadagreaterretentionratecomparedwithMUDparticipants.
There were no significant changes in vital signs over the treatment
period except respiratory rate did increase for AUD participants.
Importantly,lorcaserin was well tolerated, having few,if any,side
effects. Lorcaserin was not anorectic and had no cardiovascular
side effects. We also tested the effect of lorcaserin on alcohol and
Methamphetaminecraving andconsumption.Althoughnumberof
drinking days did not change, self-reported alcohol consumption
per session decreased for AUD participants and amphetamine-
type substance use decreased for those MUD participants who
weretained.However,therewasnochangeinclinicallymonitored
alcoholor amphetaminecontent,respectively.Notably,lorcaserin
treatme nt resulted in dec reased craving ove r time for both AUD
andMUDparticipants.MeanbaselinecravingscoresforAUDpar-
ticipant s in this study were high compared with those reported for
other similar populations 41andde cr ea se dbymorethan 50 %atDay
28. MUD participants’ craving scorestrended toward significance
butshowed considerable interparticipant variability.Self-reported
psychologicaldistress scores decreased for AUD participants,but
therewasnochangeinpsychologicaldistressforMUDparticipants.
Nevertheless,self-reportedpsychologicalhealthstatussignificantly
improvedoverthetreatmentperiodforbothAUDandMUDpartic-
ipants.K10scoresforAUDparticipantsdroppedtotheAustralian
national average by Day 7.42Overall,anddespitethepilotnatureof
thisstudy,ourdatado indicateclinicallysignificantimprovements
onkey outcomes and support thenotionof5-HT2C receptors as a
therapeutictargetfordrugandalcoholabuse.Clinically,28daysisa
shortdurationoftreatmentforbothalcoholandMethamphetamine
dependence.Longer treatment duration may haveseenimproved
outcomes on a number of physiological variables that were trending
positively(e.g.,GGTlevels).
Lorcaserin has shown promise at reducing symptoms of sub-
stance usedisorder in other,recentclinical trials. For example, lor-
caserin reduced cannabis intake compared with placebo controls.43
Lorcaserin, in combination with counseling, increased abstinence
rates in individuals with nicotine use disorder compared with those
treated with smoking cessation counseling alone.44However,lorca-
serin did not reduce cocaine or oxycodone use compared with pla-
cebo controls.45,46Lorcaserinalsodidnotimproveextended-release
naltrexone induc tion rates in an outp atient sample of individuals
with opioid use disorder compared with placebo.47 There are some
discrepancies regarding the effectiveness of lorcaserin at improving
treatmentoutcomesforthosewithsubstanceusedisorder,but the
reasons for these discrepancies are currently unknown and may be
due to the mechanistic impac t of lorcaserin and the interaction with
the drug of choice based on the neural circuits driving the behavior.
Nevertheless, at least foralcohol, nicotine, an d cannabis, t here is
supporting evidence.
FIGURE 2 Plasmaconcentrationtimeprofiles(0,2,4,8,and
12 h) after lorcaserin was administered. The pharmacokinetic
profile of lorcaserin followed a standard oral absorption profile
forthesixparticipantsexamined.The12-htimepointforeach
individual was predicted with a one compartment model using
PKSo lve r.37AUD,alcoholusedisorder;MUD,methamphetamine
use disorder
TAB LE 4 Pharmacokineticparametersummarydata
Parameter Unit Mean SD CV (%)
t1/2 h7.9 2.0 26
Tmax h2.4 0.8 34
Cmax ng/ml 102 26 26
AUC0–12 ng/ml·h 824 311 38
Css ng/ml 69 26 38

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Our findings are also somewhat consistent with preclinical liter-
ature showing reductions in alcohol consumption in rats following
chronic lorcaserin treatment.30 Lorcaserin can also decrease self-
administration of methamphetamine and cocaine in rhesus mon-
keys.29,48,49Similarly,lorcaserindecreasedheroinself-administration
andcue-inducedreinstatementinrhesusmonkeys.50, 51Finally,both
acute and chronic administration of lorcaserin plus pimavanserin,a
selective 5-HT2A receptor antagonist, decreased cocain e relapse-
like behavior in rats, suggesting that perhaps the actions of the
5-HT2C receptor alone are not straightforward.52
Althou gh lorcaser in was recently wi thdrawn from t he market
followingasafetyconcern,wecontendtheinvolvementof5-HT2C
receptors in substance use disorder are relevant and targeting
these receptors is still a viable avenue for treatment, particularly
givenourcurrent findingsandthose discussedabove.The5-HT2C
receptorhasbeenimplicatedinbothcompulsive-andimpulsive-like
behaviorsinrodents,cardinalfeaturesofsubstanceusedisorder.53
Additionally, 5-HT2C receptor activity can modulate dopamine
function.54, 55Ofnotehoweveristhecomplexityofthe5-HTsys-
tem, particularly regarding the interaction between 5-HT2C and
5-HT2Areceptorsandtheirrelationshiptoimpulsive-likebehavior.56
4.1 | Methodological considerations and
future research
Amethodological limitation ofthecurrentstudyisthatallpartici-
pants receivedlorcaserin treatment; thatis,therewasnoplacebo
control. Additionally,this study was open label, limiting the inter-
pretation of our findings. Although overall sample sizewas small,
particularlyforMUDparticipants,thosethatcompletedthestudy
seemingly benefitted from lorcaserin. The differential outcomes be-
tweenAUDandMUDparticipant sgosomewaytomitigateagainst
theseshortfalls;however,furtherstudiesareclearlywarranted.
MUDparticipants weremore difficult to retain and had lower
retention in treatment. The observed difficulty in recruiting and
maintainingMUDparticipantsinthetrialcouldpossiblybebecause
methamphetamine users seek treatment reluctantly due to a lack
of perceived effective treatments. It could also simply reflect that
there aremore people withAUD than MUD. Therewas no differ-
enceintheratesofAEsbetweenthetwogroups,sothisisunlikely
to be a factor. It is difficult to draw firm conclusions due to the small
numberofparticipantsinthestudy.Anyfuturestudyshouldinclude
design elements to improve recruitment rates and mitigate against
attrit ion. For exam ple, continge ncy manage ment approa ches have
been shown to be effective in the treatment of many substance use
disordersandholdpromiseforMUD.5 7, 58
5 | CONCLUSION
Insummary,ourdata suggestthatthe 5-HT2C system is still a vi-
able treatment option forsubst anceuse disorders, particularly
AUD.However,giventhecurrentFDAwithdrawaloflorcaserin,
other 5-HT2C agonists with high selectivity may be beneficial.
Alternatively, due to the conserved nature of the orthosteric
bindingsiteforserotoninat5-HT2f ami lyr ece pto rs, sel ecti vepos -
itiveallosteric modulators, analogoustothoseforacetylcholine
muscarinicreceptors,59mayprovideafruitfullineofenquiryand
enablemoreselectivetargeting.Another promisingtherapeutic
target may b e the use of psyched elics, target ing the serotonin
system,forsubstanceusedisordertreatment.6 0, 61However,ani-
malstudieshaverecentlyquestionedtheefficacyofpsychedelics
inmodelsof AUD.62Nevertheless,ourfindingsaddtothelitera-
ture supporting the 5-HT2C receptor as a therapeutic target for
AUDandMUD.
ACKNOWLEDGMENT
We acknowledge the Victorian State Government Operational
Infrastructure Scheme.
DISCLOSURE
The authors report no conflict of interest.
AUTHOR CONTRIBUTIONS
AJL andYB conceivedand designed research; YB,AP,LC,and AN
col le ctedth edat a;EJ Canaly zeddata;P GandJJcondu cted an dana-
lyzedpharmacokineticdata;EJCandAJLinterpreteddataandwrote
thefirst draftofthemanuscript;allauthorscontributedto,edited,
and approved the final manuscript.
DATA AVA ILAB ILITY STATE MEN T
The data that support the findings of this study are available
from the correspondingauthor upon reasonable request. Some
data may not be made available bec ause of privacy or ethical
restrictions.
ORCID
Erin J. Campbell https://orcid.org/0000-0002-4722-6897
Andrew J. Lawrence https://orcid.org/0000-0001-6836-727X
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: CampbellEJ,BonomoY,PastorA,et
al.The5-HT2C receptor as a therapeutic target for alcohol
andmethamphetamineusedisorders:Apilotstudyin
treatment-seekingindividuals.Pharmacol Res Perspect.
2021;9:e00767. https://doi.org/10.1002/prp2.767