Bupropion perceived as a stimulant by two patients with a previous history of cocaine misuse

Bupropion perceived as a stimulant by two patients with a previous history of
cocaine misuse
Alessandro E. Vento,1,2,3 Fabrizio Schifano,4,5 Federica Gentili,6 Francesco Pompei,6 John M.
Corkery,4,5 Georgios D. Kotzalidis,1* & Paolo Girardi1,7
1. Dipartimento NESMOS, Sapienza – Università di Roma, Ospedale Sant'Andrea, Via di Grottarossa 1035- 1039, Roma, Italia 2. Dipartimento di Salute Mentale, ASL RM C, Via Monza 2, Roma, Italia 3. School of Psychology, Università "G. Marconi", Roma, Italia 4. School of Pharmacy, University of Hertfordshire, Hatfield, UK 5. National Programme on Substance Abuse Deaths, International Centre for Drug Policy, St George's University of London, London, UK 6. Clinica Neuropsichiatrica Villa von Siebenthal, Genzano, Roma, Italia
7. Villa Rosa, Suore Ospedaliere del Sacro Cuore di Gesù, Viterbo, Italia
Author for correspondence: Georgios D. Kotzalidis, Dipartimento NESMOS (Neuroscienze, Salute Mentale,
Organi di Senso), Facoltà di Medicina e Psicologia, Sapienza – Università di Roma, UOC Psichiatria, Ospedale
Sant'Andrea, Via di Grottarossa 1035-1039, Roma, Italia. Tel. +39-0633775951; fax: +39-0633775342; e-mail:

Type of publication: Brief Note (Nota breve).
Running head: Bupropion-induced cocaine-like cue Word count: Abstract: 129 (Riassunto: 136); Text: 1322 words; All-included: 2815 words; Running title: 34 characters (space included); 0 Figures, 0 Tables; 24 References; 5 key-words. Declaration of Interests: PG in the past three years has received research support from Lilly and Janssen, has
participated in Advisory Boards for Lilly, Organon, Pfizer, and Schering and received honoraria from Lilly and
Organon. Please further note that GDK is the recipient of an Italian Ministry of Education Ph.D. Grant for Early
Intervention in the Psychoses. FS is a full member of the Advisory Council on the Misuse of Drugs/ACMD in the UK
and that JC is a member of the ACMD New Psychoactive Drugs working group in the UK. None of these authors has
any relevant affiliation or financial involvement with any organization or entity with a financial interest in, or financial
conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies,
honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. All other
authors of this paper have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in, or financial conflict with the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or
pending, or royalties.

Authors' contribution.
All authors read, corrected and approved the manuscript in its current form and fulfil criteria
for authorship. Specifically, Alessandro E. Vento visited both patients and contributed to drafting of the case reports.
Fabrizio Schifano and Paolo Girardi supervised the writing of the paper. Federica Gentili and Francesco Pompei saw
the patients and performed the appropriate clinical testing. John M. Corkery contributed with data on drug adverse
effects and provided material for discussion. Giorgio D. Kotzalidis wrote the first and the final drafts of the paper and
carried out the relevant bibliographic searches.
Abstract. Background and objective. Despite animal studies have shown a generalisation of the
bupropion cue to cocaine, this drug has been used in cocaine abuse with mixed results. We here
aimed at describing two cases which contradict current knowledge. Case Reports. We describe two
cases of former cocaine abusers who reported a cocaine-like sensation upon taking bupropion.
Bupropion improved patients' depression without any increase in cocaine craving. One of the
patients increased without doctor consultation his dose on an as needed basis. Conclusions. The
issue of bupropion cue generalisation to cocaine needs further elucidation. People with past cocaine
addiction need to be informed on the potential of bupropion to elicit cocaine-like cues and be
invited to adhere to medical prescription, because bupropion has been associated with fatalities in
some cases.
Il bupropione percepito come uno psicostimolante da due pazienti con anamnesi pregressa di
abuso di cocaina. Riassunto
. Contesto e obiettivo. Sebbene studi su animali abbiano dimostrato
una generalizzazione del cue del bupropione alla cocaina, tale farmaco è stato utilizzato nell'abuso
di cocaina con risultati misti. Il nostro obiettivo è stato di descrivere due casi che contraddicono le
conoscenze attuali. Casi clinici. Riportiamo due casi di pazienti che hanno riferito una sensazione
cocaino simile in due ex-utilizzatori di cocaina. Il bupropione ha migliorato la depressione di questi
pazienti senza aumentare il craving cocainico. Uno di questi pazienti ha aumentato la dose, pro re
senza consultarsi col medico. Conclusioni. La questione della generalizzazione del cue del
bupropione alla cocaina va ulteriormente delucidata. Gli ex-cocainomani vanno informati sulla
possibile associazione del bupropione con cue cocaino simili e invitati ad aderire alle prescrizioni
mediche, perché l'assunzione di bupropione è stata associata in qualche caso con fatalità.
Key words: Bupropion; cocaine abuse; depression; internal stimulant cue; monoamine transporter inhibitors Parole chiave: Bupropione; abuso di cocaina; depressione; cue interno da psicostimolanti; inibitori dei trasportatori delle mono ammine Increased synaptic dopamine levels in the dorsal striatum appear to mediate cocaine craving in
cocaine-experienced individuals [1]. Cocaine craving predicts relapse to subsequent cocaine use [2].
The dopamine transporter inhibitor, amineptine, which has been used for some time as an
antidepressant, and which has been withdrawn due to its abuse/dependence potential, was shown to
generalise its cue to other weakly dopaminergic antidepressants, like fluoxetine [3] and venlafaxine
[4], hence inducing cross-abuse/dependence. The dopamine/noradrenaline-reuptake inhibitor
bupropion has long been used in the US as an antidepressant, before receiving approval for nicotine
dependence. Due to its mechanism, it could be expected to mimic other dopamine transporter
inhibitors and generalise its cue to them. In fact, it is long known that bupropion produces cocaine-
appropriate responses in the self-administration, lever pressing paradigm in several animals,
including the pigeon [5], the rat [6,7], and baboon and rhesus monkeys [7,8], substituting
completely for cocaine at the higher doses, although there has recently been a negative report in the
rat, in which only amphetamine and nicotine were found to substitute for the bupropion cue [9].
Bupropion has been used for cocaine addiction in individuals on methadone maintenance
programmes [10,11] with some success, but despite reducing reported cocaine use, open [12] and
controlled studies showed that bupropion did not significantly affect cocaine-related behaviour [13],
partly cooling the enthusiasm about its usefulness in cocaine addiction. However, this occurred at
therapeutic doses, not exceeding 300 mg/day. In a non-therapeutic human experiment, cocaine users
provided higher ratings for the positive subjective effects of cocaine while taking 100 or 200 mg
bupropion than when they were not taking bupropion, reducing simultaneously their cocaine
preference with respect to placebo [14]. Combined, these findings do not yield a definitive response
as to whether bupropion affects cocaine cues in the human. We report two cases showing that in
fact, in line with previous animal literature, bupropion elicits a cocaine-like cue without increasing
craving for cocaine.

Case Reports

Case1. A 28-year-old man with past history of drug misuse (including cocaine, alcohol,
tetrahydrocannabinol, and lysergic acid diethylamide, but not amphetamine (or its derivatives)
developed chronic depression with anhedonia, interrupted by brief periods of euphoria. The patient
was a socially withdrawn university student with poor academic performance, the reason for which
he sought psychotherapy. His psychotherapist referred him to us for pharmacotherapy, considering
psychotherapy alone to be insufficient to treat his patient's condition.
When he came to our attention he was 26. The patient was considerably anergic, with motor
retardation, decreased expressiveness, poverty of speech, reduced ideation, blunted affect, anxiety,
difficulties with concentration, intrusive thoughts, and somaesthetic disturbances. His depression
had developed subtly from the age of 19, reaching a peak when he was 25. About that time he had
started his polydrug misuse, including cocaine, until he reached the age of 23. He was poorly
motivated, anhedonic, with suicidal ideation, and suffering from sleep disturbances, scoring 30 on
the Hamilton Rating Scale for Depression (Ham-D) [15]. We diagnosed him with DSM-IV-TR
bipolar disorder, type II, moderate depressive episode, based on a SCID-I interview, comorbid with
borderline personality disorder, based on a SCID-II interview.
Treatment with both oral, slow-release bupropion, 150 mg/day, and immediate-release quetiapine,
25 mg at bedtime, was started. At the two-week follow-up, he reported thought acceleration and
restlessness when going to bed, which he described as similar to those post-cocaine binges he had
experienced in the past. This was paralleled by an increase in self-esteem and increased self-
confidence, as when he was abusing cocaine. He characteristically stated "This treatment reminds
me of when I was taking cocaine". This sensation lasted for about two weeks, and by the third week
these sensations disappeared. At the same time, his depressive and sleep symptoms had improved
considerably, with his Ham-D scores dropping to 24, and then to 20 after three months of treatment,
progressively reaching a score of 16 one year later (cut-off, 7).

Case2. A 56-year-old man reached our attention after a serious suicide attempt. He owned a
successful bookshop, but faced economic difficulties due to his pathological gambling and cocaine
addiction. He started developing cocaine abuse at the age of 52, increasing it with time to about 1 g
on three occasions per week in a short time, thereafter maintaining this weekly dose. His mood
rapidly deteriorated following his father's death four years ago, and then gradually worsened over
time. Following a serious suicide attempt, he was referred to our unit. On admittance, he had scored
26 on the Ham-D scale and was started on 150 mg/day slow-release bupropion, 1000 mg/day
controlled-release valproate, 10 mg oral olanzapine at bedtime, and diazepam p.r.n.. Based on
SCID-I and -II interviews we made diagnosis of bipolar disorder, type I, comorbid with
pathological gambling and cocaine use disorder; we diagnosed comorbid gambling because it
occurred also independently from manic episodes. One month later he had already stopped both
cocaine misuse and gambling activities; this was paralleled by mood improvement. Bupropion
dosage was then increased to 150 mg b.i.d. Two months later he had reached a score of 16 on the
Ham-D. However, marital conflicts did not improve. In coincidence with intense conflicts, his
depression worsened, prompting him to increase bupropion intake to 150 mg t.i.d. and olanzapine to
10 mg b.i.d. In particular, bupropion reportedly made him feeling overstimulated and active, as
when he was taking cocaine. Although his family and economic problems persisted eight months
later, his Ham-D scores had dropped to 10, which is mild depression.
Both patients gave free, informed consent for all treatment received as well as for the publication of
their cases.

. In line with the existence of overlap between the mechanisms of bupropion and cocaine
[5-8], our two cases seem to suggest that bupropion intake elicits cocaine-like cues in cocaine-
experienced humans. Bupropion acts by inhibiting dopamine and noradrenaline transporters, hence
increasing the intra-synaptic concentrations of these neurotransmitters [16]. Cocaine blocks both
these transporters and the serotonin transporter as well [17], while amphetamine is a dopamine
releaser and dopamine transporter blocker [18,19]. Hence, the theoretical basis for cross-elicitation
of their cues is sufficient to let us hypothesise that our cocaine-exposed patients were able to
identify a cocaine-like cue with bupropion intake. Hence, cocaine-exposed subjects are able to
identify bupropion intake as having a cue similar to cocaine. This is further backed by animal
studies showing generalisation of the bupropion cue to amphetamine, cocaine, and caffeine [5-8,20]
and substitution of both bupropion and cocaine for methamphetamine [21]. However, it is in
contrast with the results of another study, which found nicotine and methamphetamine, but not
cocaine substitution for bupropion in the rat [9].
Differently from previous reports [22,23] we observed no psychotic symptoms in these two
patients. Both our patients were on antipsychotic medication, and this might have prevented
psychotic symptoms. It should be stressed that antipsychotic drugs behave differently from one
another as regards co-administered bupropion, at least in facilitating smoking cessation, but the two
atypical antipsychotics used in our patients did not interact with bupropion at this respect [24].
Our second patient used bupropion not according to prescription; clinicians must inform their
patients about possible dangers arising from such practice, since five fatalities with bupropion
intake have been recorded by the National Programme on Substance Abuse Deaths in the UK
(Corkery, personal communication).

. Despite the neurochemical background of addictions and the mechanism of action of
bupropion, we did not observe negative effects of bupropion on cocaine craving in former cocaine
users, even in the case of inappropriate dose self-adjustment. However, a generalisation of the
bupropion cue to cocaine, which has not been previously reported in medical literature, was found
in two patients, leading us to question the universal validity of animal studies showing bupropion to
generalise to amphetamine, but not cocaine. Clinicians should be aware of the possibility that
bupropion may elicit cocaine-like cues in cocaine-experienced individuals and ask about it to their
patients, cautioning them for the dangers of non-prescription use of bupropion.
Acknowledgments. The authors wish to thank the late Tiziana Mattei, and Ms Mimma Ariano, Ms Ales Casciaro, Ms
Teresa Prioreschi, and Ms Susanna Rospo, Librarians of the Sant'Andrea Hospital, School of Medicine and Psychology,
Sapienza University, Rome, for rendering precious bibliographical material accessible, as well as their Secretary Lucilla
Martinelli for her assistance during the writing of the manuscript.
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