Hallucinations in Psychoses and Affective Disorders A

Clinical and Biological Approach

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Editors
Paolo Brambilla Massimo Carlo Mauri
Fondazione IRCCS Ca’ Granda Ospedale Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico Maggiore Policlinico
University of Milan University of Milan
Milan Milan
Italy Italy

Alfredo Carlo Altamura

Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico
University of Milan
Milan
Italy

ISBN 978-3-319-75123-8    ISBN 978-3-319-75124-5 (eBook)

https://doi.org/10.1007/978-3-319-75124-5

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Presentation

Of all patients diagnosed with schizophrenia or related psychotic disorders, 60–80%

experience auditory hallucinations and a smaller proportion visual or other unimodal hal-
lucinations. Hallucinations can be dramatic and may have severe impact in affected indi-
viduals, and it might be associated with suicidality, violence, and sometimes homicide.
Currently, the abuse of substances with psychotomimetic properties, such as
cocaine, amphetamines, hallucinogens, ketamine and cannabis, represents one of
the main causes of hallucinogen perception disorders. Indeed, the use or the abuse
of these substances can result in psychotic reactions, including hallucinations, and
can therefore resemble a primary psychotic disorder. In general, the use of drugs has
increased during early adolescence, when the developing brain might be especially
sensitive to environmental exposures. In particular, the escalating use of metham-
phetamine and derivative substances throughout the world and their association
with psychotic symptoms in regular users has fuelled concerns. Specifically, the use
of cannabis and cocaine by young people has been increasing during these years,
and age at first use has dramatically decreased. Cannabis, is indeed the most com-
mon illegal substance used in most of the western countries. Indeed, nowadays,
about 20% of young people report heavy cannabis consumption (which means a use
in more than one hundred occasions) or at least one consumption per week.
Several studies suggest a high comorbidity of substance abuse and schizophrenia, asso-
ciated with higher relapse rates and higher frequency of hallucinations, unusual thought
content, depressive symptoms, cognitive impairment, poorer outcome and reduced treat-
ment response. A high incidence of substance abuse and related symptoms, particularly
verbal and visual hallucinations, is also observed immediately in first episode psychosis
patients. Among substance abusers, in most cases the onset of hallucinations precedes the
onset of a structured psychotic episode by several years. Accordingly, hallucinations have
traditionally been one of the main treatment targets for antipsychotic drugs and indeed the
positive psychotic symptoms of schizophrenia collectively are far more responsive to these
drugs than negative or other cognitive symptoms, although it is not always true. It is impor-
tant to outline that psychotic symptoms, such as delusions and hallucinations, may occur
in both major (affective and schizophrenic) psychoses and in substance-induced psycho-
sis, which are different diseases with diverse clinical trajectory and outcome.
The book starts with Part I (Neurotransmission and Psychopathology) by focus-
ing on the specific molecular mechanisms involved in substance-induced hallucina-
tions. Indeed, there are at least three different pharmacological ways to induce

v
vi Presentation

hallucinations: activation of dopamine D2 receptors (D2Rs) with cocaine and amphet-

amine-type stimulants, activation of serotonin 5HT2A receptors (HT2ARs) with psy-
chedelics, and blockage of glutamate NMDA receptors with dissociative anesthetics.
Moreover, it discusses verbal hallucinations as a specific diagnostic symptom charac-
terizing the psychopathological picture defined by French literature as “Chronic
Hallucinatory Disorder. Finally, it describes hallucinatory symptomatology among
substance-induced disorders, major psychoses and neurological diseases.”
In Part II (Genetics and Neuroimaging) references to recent genetic, neurochem-
ical, and neuroimaging data outlining hallucinations will be discussed. In schizo-
phrenia, the relative importance of NMDAR and D2Rs in the occurrence of
hallucinations is still debated. Slight clinical differences are observed for each etiol-
ogy. Auditory-verbal hallucinations (AVHs) are associated with an impaired con-
nectivity of large-scale networks and have a potential genetic basis. To examine the
relationship between white matter integrity and AVHs, it has been conducted a
meta-analysis of diffusion tensor imaging studies that compared patients with
schizophrenia and AVHs with matched healthy controls (HCs). The meta-­analysis
demonstrated a reduced fractional anisotropy in the left arcuate fasciculus (AF) of
hallucinators. The current meta-analysis confirmed disruptions of white matter
integrity in the left AF bundle of schizophrenia patients with AVHs.
The book concludes with Part III (Treatment) on the pharmacology and treat-
ment of hallucinations including electric and magnetic stimulation. In fact dysregu-
lated cortical plasticity has been demonstrated to underlie the pathogenesis of
positive symptoms like auditory hallucinations in schizophrenia. Transcranial direct
current stimulation (tDCS), a noninvasive brain stimulation technique, can modu-
late neuroplasticity. Add-on tDCS has also been shown to ameliorate auditory ver-
bal hallucinations in schizophrenia that are nonresponsive to antipsychotic treatment.
Preliminary evidence suggests a neuroplasticity modulation effect of tDCS to
improve treatment-resistant auditory hallucinations in schizophrenia.
Internationally recognized clinical scientists have contributed to this book which,
in our opinion, represents a novel and comprehensive contribution to the role of hal-
lucinations in major psychoses delineating the state of the art in this area from clini-
cal, neurobiological, and therapeutic perspectives.

Milan, Italy Alfredo Carlo Altamura

Milan, Italy Massimo Carlo Mauri
Milan, Italy Paolo Brambilla
February 2018

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2007;99(1–3):285.
Altamura AC, Glick ID. Designing outcome studies to determine efficacy and safety
of antipsychotics for ‘real world’ treatment of schizophrenia. Int J
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Presentation vii

Altamura AC, Mauri MC, Guercetti G, Cazzullo CL. Fluphenazine decanoate in

acute and maintenance therapy of schizophrenia. Prog Neuropsychopharmacol
Biol Psychiatry. 1987;11(5):613–23.
Altamura AC, Buoli M, Caldiroli A, Caron L, Cumerlato Melter C, Dobrea C,
Cigliobianco M, Zanelli Quarantini F. Misdiagnosis, duration of untreated i­ llness
(DUI) and outcome in bipolar patients with psychotic symptoms: a naturalistic
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E, Rovera C, Dobrea C, Arici C, Benatti B, Camuri G, Prunas C, Paoli RA,
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ferentiation between bipolar disorder with psychosis and substance induced psy-
chosis: an integrated MRI/PET study. Eur Psychiatry. 2016;41:85–94.
Altamura AC, Delvecchio G, Paletta S, Di Pace C, Reggiori A, Fiorentini A, Mirabile
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umes may predict the clinical response to paliperidone palmitate long-acting in
acute psychosis: a pilot longitudinal neuroimaging study. Psychiatry Res
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domized study. BMC Psychiatry. 2013;13:241–51.
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Frasch K, Wolf RC. Cortical folding abnormalities in patients with schizophrenia
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Contents

Part I Neurotransmission and Psychopathology

1 Substances of Abuse and Hallucinogenic Activity:
The Dopaminergic Pathway - Focus on Cocaine
and Amphetamine-type Stimulants��������������������������������������������������������    3
Matteo Lazzaretti, Gian Mario Mandolini, Alfredo Carlo Altamura,
and Paolo Brambilla
2 Substances of Abuse and Hallucinogenic Activity:
The Serotoninergic Pathway - Focus on Classical
Hallucinogens and Entactogens��������������������������������������������������������������   17
Matteo Lazzaretti, Gian Mario Mandolini, Alfredo Carlo Altamura,
and Paolo Brambilla
3 Substances of Abuse and Hallucinogenic Activity:
The Glutamatergic Pathway - Focus on Ketamine ������������������������������   33
Gian Mario Mandolini, Matteo Lazzaretti, Alfredo Carlo Altamura,
and Paolo Brambilla
4 Chronic Hallucinatory Disorder “an Equivalent”
of Delusional Disorder ����������������������������������������������������������������������������   43
Massimo Carlo Mauri, Silvia Paletta, Chiara Di Pace, Chiara
Rovera, Giorgio Marotta, and Alfredo Carlo Altamura
5 Hallucinations in the Substance-Induced Psychosis ����������������������������   57
Massimo Carlo Mauri, Silvia Paletta, and Chiara Di Pace
6 Hallucinatory Symptomatology in Major Psychoses
(Schizophrenia and Bipolar Disorders) ������������������������������������������������   85
Andrea Raballo, Michele Poletti, and Mads Gram Henriksen
7 Hallucinations in Neurological Disorders����������������������������������������������   99
Alessio Di Fonzo, Edoardo Monfrini, Paola Basilico,
and Andrea Arighi

ix
x Contents

Part II Genetics and Neuroimaging

8 Genetic Basis of Auditory Verbal Hallucinations
in Schizophrenia�������������������������������������������������������������������������������������� 133
Anushree Bose, Venkataram Shivakumar, and Ganesan
Venkatasubramanian
9 Imaging Genetics of Hallucinations ������������������������������������������������������ 149
Jacqueline Mayoral-van Son, Julio Sanjuan, and Benedicto
Crespo-Facorro
10 Dysconnectivity in Hallucinations���������������������������������������������������������� 159
Branislava Ćurčić-Blake, Josselin Houenou, and Renaud Jardri

Part III Treatment
11 Translating Neurocognitive Models of Auditory
Verbal Hallucinations in Schizophrenia into Novel
Therapeutic Interventions���������������������������������������������������������������������� 175
Natasza Orlov, Jane Garisson, and Paul Allen
12 Innovative Approaches to Hallucinations in Psychosis
and Affective Disorders: A Focus on Noninvasive Brain
Stimulation Interventions������������������������������������������������������������������������ 191
Bernardo Dell’Osso, M. Carlotta Palazzo,
and Alfredo Carlo Altamura
Contributors

Paul Allen Department of Psychology, University of Roehampton, London, UK

Department of Psychosis Studies, Institute of Psychiatry, Psychology and
Neuroscience, King’s College London, London, UK
Alfredo Carlo Altamura Department of Neurosciences and Mental Health,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of
Milan, Milan, Italy
Andrea Arighi Neurodegenerative Disease Unit, Department of Pathophysiology
and Transplantation, Centro Dino Ferrari, University of Milan, Fondazione IRCCS
Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Paola Basilico Neurodegenerative Disease Unit, Department of Pathophysiology
and Transplantation, Centro Dino Ferrari, University of Milan, Fondazione IRCCS
Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Anushree Bose InSTAR Program, Schizophrenia Clinic, Department of Psychiatry,
National Institute of Mental Health and Neurosciences, Bengaluru, India
Paolo Brambilla Department of Neurosciences and Mental Health, Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan,
Italy
Department of Psychiatry and Behavioural Neurosciences, University of Texas at
Houston, Houston, TX, USA
M. Carlotta Palazzo Department of Psychiatry, Fondazione IRCCS Ca’Granda,
Ospedale Maggiore Policlinico, Milano, Italy
Centro S. Ambrogio, Ordine Ospedaliero San Giovanni di Dio Fatebenefratelli,
Milan, Italy
Benedicto Crespo-Facorro University Hospital Marqués de Valdecilla, IDIVAL,
Santander, Spain
CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain
Department of Psychiatry, School of Medicine, University of Cantabria, Santander,
Spain

xi
xii Contributors

Branislava Ćurčić-Blake Department of Neuroscience, University Medical

Center Groningen, University of Groningen, Groningen, Netherlands
Bernardo Dell’Osso Department of Psychiatry, Fondazione IRCCS Ca’Granda,
Ospedale Maggiore Policlinico, Milano, Italy
Department of Health Sciences, CRC “Aldo Ravelli” for Neurotechnology and
Experimental Brain Therapeutics, University of Milan, Milan, Italy
Department of Psychiatry and Behavioral Sciences, Bipolar Disorders Clinic,
Stanford Medical School, Stanford University, Stanford, CA, USA
Alessio Di Fonzo Neurology Unit, Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, Centro Dino Ferrari, Neuroscience Section, Department of
Pathophysiology and Transplantation, University of Milan, Milan, Italy
Jane Garisson Department of Psychology, Behavioural and Clinical Neuroscience
Institute (BCNI), University of Cambridge, Cambridge, UK
Mads Gram Henriksen Faculty of Humanities, Department of Department of
Media, Cognition and Communication, Københavns Universitet, Copenhagen,
Denmark
Mental Health Center Glostrup, University Hospital of Copenhagen, Copenhagen,
Denmark
Josselin Houenou APHP, Hôpitaux Univ. Mondor, DHU PePsy, Pôle de psychia-
try, Faculty of Medicine, Université Paris Est Créteil, Créteil, France
INSERM U955 Equipe 15 “Psychiatrie Translationnelle”, Fondation FondaMental,
Créteil, France
NeuroSpin Neuroimaging Platform, UNIACT Lab, Psychiatry Team, CEA Saclay,
Gif Sur Yvette, France
Renaud Jardri Univ Lille, SCALab, CNRS UMR-9193 and School of Medicine,
Lille, France
CHU Lille, Fontan Hospital, CURE Platform, Lille, France
Matteo Lazzaretti Department of Neurosciences and Mental Health, Fondazione
IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan,
Italy
Gian Mario Mandolini Department of Neurosciences and Mental Health,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of
Milan, Milan, Italy
Giorgio Marotta Nuclear Medicine Department, Fondazione IRCCS Ca’ Granda,
Ospedale Maggiore Policlinico, Milan, Italy
Massimo Carlo Mauri Department of Neuroscience and Mental Health, Clinical
Psychopharmacology Unit, Fondazione IRCCS Ca’ Granda, University of Milan
Medical School, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
Contributors xiii

Edoardo Monfrini Neurology Unit, Fondazione IRCCS Ca’ Granda Ospedale

Maggiore Policlinico, Centro Dino Ferrari, Neuroscience Section, Department of
Pathophysiology and Transplantation, University of Milan, Milan, Italy
Natasza Orlov Department of Psychology, University of Roehampton, London,
UK
Department of Psychosis Studies, Institute of Psychiatry, Psychology and
Neuroscience, King’s College London, London, UK
Chiara Di Pace Department of Neuroscience and Mental Health, Clinical
Psychopharmacology Unit, Fondazione IRCCS Ca’ Granda, University of Milan
Medical School, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
Silvia Paletta Department of Neuroscience and Mental Health, Clinical
Psychopharmacology Unit, Fondazione IRCCS Ca’ Granda, University of Milan
Medical School, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
Michele Poletti Department of Mental Health, Reggio Emilia Local Health Trust,
Reggio Emilia, Italy
Andrea Raballo Division of Psychiatry, Department of Medicine, University of
Perugia, Perugia, Italy
Department of Psychology, Norwegian University of Science and Technology,
Trondheim, Norway
Chiara Rovera Department of Neuroscience and Mental Health, Clinical
Psychopharmacology Unit, Fondazione IRCCS Ca’ Granda, University of Milan
Medical School, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
Julio Sanjuan CIBERSAM, Centro Investigación Biomédica en Red Salud
Mental, Madrid, Spain
Hospital Clínico, University of Valencia, Valencia, Spain
Venkataram Shivakumar InSTAR Program, Schizophrenia Clinic, Department
of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru,
India
Jacqueline Mayoral-van Son Sierrallana Hospital, Torrelavega, Cantabria, Spain
Department of Psychiatry, University of Cantabria, Santander, Spain
CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain
Ganesan Venkatasubramanian InSTAR Program, Schizophrenia Clinic,
Department of Psychiatry, National Institute of Mental Health and Neurosciences,
Bengaluru, India
 Part I
Neurotransmission and Psychopathology
Substances of Abuse and Hallucinogenic
Activity: The Dopaminergic 1
Pathway - Focus on Cocaine
and Amphetamine-type Stimulants

Matteo Lazzaretti, Gian Mario Mandolini,

Alfredo Carlo Altamura, and Paolo Brambilla

1.1 Focus on Cocaine

Cocaine, the benzoate ester of 2-carbomethoxy-3beta-tropine (methylecgonine), is

a chemical compound extracted from a South American plant called Erythroxylum
Coca [1]. It belongs to the class of tropane alkaloids since its chemical substructure
is composed by a azabycylo[3.2.1]octane skeleton [2].
Cocaine is the one of most frequently used illicit drugs in Europe, especially in
southern and western Europe [3]. The prevalence of its use in the European Union
has been estimated at about 1% of the population aged 15–64 [4] and the number of
cocaine users from 1998 to 2014 has increased from 14 million to 18.8 million [4].
Chronic consumption of cocaine can generate psychotic symptoms, such as para-
noia or hallucinations, to configure what is called cocaine-induced psychosis (CIP)
[5]. Hallucinations induced by cocaine are not uncommon [6]. The most frequent
ones are auditory, followed by visual and tactile ones [7, 8]. Vergara-Moragues et al.
[9] described the presence of hallucinations in a cohort of 114 cocaine users, espe-
cially auditory (36%), visual (38%), somatic/tactile (29%), and olfactory (10%). The
prevalence of some psychotic symptoms in cocaine abusers has been reported at
about 29% [10], 53% [7], or even 86.5% [11]. It is essential to discriminate between
cocaine intoxication and CIP [9]. In fact, cocaine intoxication can provoke

M. Lazzaretti · G. M. Mandolini · A. C. Altamura

Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, University of Milan, Milan, Italy
e-mail: [email protected]
P. Brambilla (*)
Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, University of Milan, Milan, Italy
Department of Psychiatry and Behavioural Neurosciences, University of Texas at Houston,
Houston, TX, USA
e-mail: [email protected]

© Springer International Publishing AG, part of Springer Nature 2018 3

P. Brambilla et al. (eds.), Hallucinations in Psychoses and Affective Disorders,
https://doi.org/10.1007/978-3-319-75124-5_1
4 M. Lazzaretti et al.

perceptual and transient phenomena which last till abstinence but keep intact the
reality test [9]. On the contrary, CIP patients have more severe psychotic symptoms
which last beyond intoxication and alter the reality test [12].
Brady et al. [7] reported that 29% of 55 cocaine-dependent patients experienced
psychotic symptoms, 90% developed paranoid delusions directly related to drug
use, 96% experienced hallucinations (83% auditory, 38% visual, and 21% tactile),
and 29% of subjects developed transient behavioral stereotypes. In a large European
study Vorspan et al. [11] reported psychotic symptoms in 105 participants with
cocaine addiction: auditory hallucinations (44%), visual hallucinations (42%), tac-
tile hallucinations (32%), and olfactory hallucinations (23%). Previous reviews
reported colorful visual hallucinations and sensation of bugs or insects crawling
under the skin [13]. Abusers scraped and probed under the skin to find the bugs.
This phenomenon has been called “Magnan’s sign” or “cocaine bugs.” With chronic
use of cocaine, the user has been noted to see bugs (visual hallucinations) and hear
bugs buzzing around (auditory hallucinations) [14].
Siegel [13] showed that recreational cocaine users experienced auditory hallu-
cinations such as whispering voices and voices calling their names; visual halluci-
nations such as flashing lights, geometric patterns, duplication and multiplication
of objects, distortion of size and shape, and pulsating or fluid objects; olfactory
hallucinations (smoke, gasoline, natural gas, feces, urine, and garbage); and gusta-
tory hallucinations (failure to detect strong tastes) [14]. Recreational users can also
experience tactile hallucinations with a percentage of 15% [13] while in heavy
consumers a phase of prodromal symptoms (such as a moving itching from one
part of the skin to another) can occur before the hallucinations [15]. However,
patients from the Siegel sample didn’t believe that they really had insects under
their skin. For this reason these tactile experiences were called by Siegel “pseudo-
hallucinations” [13].
Both cocaine intoxication and delirium tremens have been considered for many
years a model for tactile hallucinations, even if these phenomena could occur in a,
more or less, conscious status [15].
Contrariwise, previous authors reported cases of tactile hallucinations in cocaine
users who tried to remove insects from under the skin [16] in a context of conscious-
ness [17].

1.1.1 Molecular Mechanism

Cocaine acts as a psychostimulant thanks to its capacity of inhibiting the reuptake

of monoamines, primarily increasing synaptic and brain concentration of dopa-
mine (DA), but also of serotonin and norepinephrine [18]. The synaptic concentra-
tion of these monoamines is regulated by monoamine transporters (MATs), proteins
that have the function of reuptaking dopamine (DAT), serotonin (SERT), and nor-
epinephrine (NET) [19]. These plasma membrane proteins are members of the
solute carrier 6 (SLC6) protein family and they are essential for the maintenance of
1 The Dopaminergic Pathway - Focus on Cocaine and ATS 5

neurotransmitter homeostasis [20]. SLC6 also includes transporters of GABA

(GAT1, GAT2, GAT3) and transporters of glycine (GT1 GLYT1, GLYT2) [21].
Even if cocaine has an effect on all these monoamine levels, DAT represents its
primary molecular blockade target and the increase of synaptic DA its main conse-
quence [22].
Indeed, the neurotransmitter DA is first released by dopaminergic neurons into
the extracellular space allowing DAT to actively pump DA again into the presynap-
tic neuron [23]. Therefore, DAT has the function of reuptaking DA, by translocating
it from the synapse back to the cytosol of dopaminergic neurons [24].
Cocaine binds strongly to the DAT, leading to a complex that blocks the DAT’s
function. In this way, DA increases in the synaptic space. Intravenous cocaine has
been demonstrated to block between 60 and 77% of DAT sites in humans and to
consequently mediate an augmented DA signaling, especially in nucleus accum-
bens (NAc) [25]. Moreover, the self-reported “high” sensations, experienced by
cocaine users, have also been correlated to the degree of DAT occupancy [25]. DA
also acts on DA receptors which include D1-like (D1 and D5) or D2-like (D2, D3,
and D4) subtypes, based on sequence homology and pharmacology [26]. D2 and D3
receptors are also presynaptic autoreceptors and their activation contributes to an
attenuation of the dopaminergic transmission by reducing DA release and by upreg-
ulating DAT function [27]. Cocaine seems thus to upregulate DAT concentration
and this mechanism could lead to depressive symptoms in chronic users during the
withdrawal period [27].
Cerebral distribution of DAT has been documented in regions implicated in
the dopaminergic circuitry such as the nigrostriatal, the mesolimbic, and the
mesocortical pathways, thus explaining its role in motor function, affect, cogni-
tion, and behavior [28]. The nigrostriatal pathway goes from the pars compacta
of the substantia nigra (SNc) to the dorsal striatum and DA release in these
regions is significant for the control of motor movements mediated by the basal
ganglia [29]. Degeneration of these neurons results in the motor symptoms of
Parkinson’s disease [30].
The mesolimbic pathway is part of the reward-mediating circuitry and it goes
from the ventral tegmental area (VTA) of the midbrain to the NAc in the forebrain
[31]. The release of DA from these pathways contributes to the motivational and the
reinforcement processes, such as in drug abuse and addiction [32].
The mesocortical pathway projects from the VTA and from the SNc to the pre-
frontal cortex (PFC) [33].
Chronic cocaine abuse is responsible for a DA signaling adaptation in the
mesocortical pathway that could lead to alterations in the PFC [25], by enhanc-
ing D1 receptor activity [34]. The main effect includes increased activation of
adenylyl cyclase, protein kinase A, and calcium release, thus modifying the PFC
physiological signaling and contributing to addictive behavior and cognitive
deficits [34].
Moreover, cocaine exposure could increase brain-derived neurotrophic factor
(BDNF) levels in those cerebral regions involved in the reward mechanisms, such as
6 M. Lazzaretti et al.

VTA, NAc, and PFC, causing behavioral changes in animal models of addiction
[35]. In addition, the synaptic plasticity modifications induced by chronic cocaine
abuse involve both GTPase signaling and AMPA receptor function [36].
The DAT, which is sensitive to cocaine inhibition, has a greater density in the
putamen than in the caudate nucleus [37] and putamen has been suggested to be an
area with a function on visual and tactile perception [38, 39].
Acute cocaine intoxication provokes a DA increase in the mesolimbic system,
especially in the NAc [40] and in the VTA [41].
Indeed, the striato-thalamo-parietal pathway has been suggested to be the altered
network in itching and tactile hallucinations [42].
Therefore, cocaine does not act as a direct agonist of DA receptors since it causes
an indirect increase of DA synaptic concentration and the consequent activation of
DA receptors, such as D1 and D2 [43].
D1 receptors are essentially located in the striatonigral neurons, while D2 are
more expressed in the striatopallidal neurons, representing, respectively, the direct
and the indirect pathways [44].
The development of hallucinatory symptomatology caused by cocaine could also
be linked to the presence of a genetic vulnerability [45]. In fact, the genetic trans-
mission and expression of those proteins involved in dopaminergic transmission
have been found to be implicated in the process of cocaine dependence. The most
studied genes are the gene coding for the D2 dopaminergic receptor (DRD2), the
gene coding for the DAT (SLC6A3), the gene coding for the catechol-O-­
methyltransferase (COMT), and the gene coding for DA beta-hydroxylase
(DßH) (DA metabolization enzyme) [45].
With regard to psychotic symptoms in cocaine abusers, Cubells et al. [46]
reported a correlation with haplotype Del-a (polymorphisms DßH*5-ins/del and
DßH*G444A) associated with a decreased activity of the enzyme DßH. Alterations
in Dßh levels could also be linked to other polymorphisms such as C-1012T [47]
and +1603C>T [48], even if the correlation with the CIP was found especially with
the first polymorphism [49].
A link between psychotic symptoms in cocaine abusers and polymorphism of the
gene SLC6A3 coding for the DAT (G2319A VNTR 9/9 and 9/10 repeat) has also
been reported [50]. Ujike et al. [51] found that the genotype A1/A1 of the gene
DRD2 could constitute a protection in relation to the psychotic symptoms induced
by psychostimulants.
Cocaine can also inhibit the reuptake of norepinephrine and serotonin, thus pro-
voking an increase of these two neurotransmitters [52]. The first neurotransmitter is
responsible for alertness and “fight-or-flight” situations, while the second one for
regulating affective states and physiological functions such as sleep and appetite
[52].
Recent diffusion tensor imaging (DTI) studies have also investigated the white
matter integrity in cocaine users. Willi and colleagues [53] found differences
between cocaine psychotic users and cocaine nonpsychotic users. The former group,
in fact, showed white matter alterations in the frontotemporal, fronto-thalamic, and
interhemispheric circuits.
1 The Dopaminergic Pathway - Focus on Cocaine and ATS 7

1.1.2 Conclusions

Cocaine abuse can lead to the development of psychotic symptoms such as paranoia
delusions and hallucinations. The most frequent type of hallucinations is repre-
sented by auditory ones, followed by visual, tactile, and olfactory. The main molec-
ular mechanism consists of the blockade of DAT which is the transporter responsible
for the reuptake of DA from the synapse into the presynaptic neurons. Therefore,
the main hallucinogenic effect of cocaine is due to a DA increase with a consequent
over-activation of D2 brain receptors in the mesocorticolimbic pathway. Moreover,
some cocaine users could face a greater risk of developing CIP. This could be related
to the presence of specific genetic polymorphisms such as D2D2, SLC6A3, COMT,
and Dßh, in these individuals (Table 1.1).

1.2 Focus on Amphetamine-Type Stimulants

Synthetic amphetamine was created in 1887 in Germany by the Rumanian chemist

Lazar Edeleanu as 1-methyl-2phenethylamine [54]. However, thousands of years
before their chemical synthesis in a laboratory, amphetamine derivatives had already
been found in nature and administered by extracting them from plants such as
Ephedra and from the tree Catha edulis [55].
From 1887 till today, an increasing number of derivatives with similar structures
and properties have been synthesized under the general name of “amphetamines”
[56].
In 1978 Biel and Bopp [57] specifically defined the structural characteristics of
amphetamine as composed by (1) an unsubstituted phenyl ring, (2) a two-carbon
side chain between the phenyl ring and nitrogen, (3) an alpha-methyl group, and (4)
a primary amino group.
However, not all the “amphetamines” strictly share these rules; instead they all
derive from the “mother compound” phenethylamine [58].
As illicit drug trafficking and consumption started to spread around the world,
“amphetamines” soon became a group of psychoactive and synthetic recreational
drugs manufactured in clandestine laboratories or even in special “kitchen labs” and
defined with the general name of “amphetamine-type stimulants” (ATS) [4].
Nowadays the term ATS includes a large group of various synthetic compounds,
such as amphetamine (AMPH), methylamphetamine (METH), and methylene-
dioxyamphetamine (MDA) derivatives [59].
Amphetamines (AMPH) and methylamphetamines (METH) share similar char-
acteristics which is why they are usually called “amphetamines” in most of the
datasets [3]. However they include various derivatives such as methylphenidate,
methcathinone, cathinone, fenethylline, ephedrine, and pseudoephedrine [60].
Contrariwise, methylenedioxyamphetamine (MDA) derivatives include three
main compounds: 3,4-methylenedioxymethamphetamine (also called MDMA or
with the street name “ecstasy”), 3,4-methylenedioxyethylamphetamine (MDEA),
and 3,4-methylenedioxyamphetamine (MDA) [61].
8 M. Lazzaretti et al.

MDMA and its derivatives have become more popular as recreational drugs due
to a typical psychedelic-like effect which gave them the name of “entactogens” [62].
The structural differences between these classes explain the different symptom-
atology. In fact, we should indeed underline that while the first group, including
AMPH and METH, has a prevalent psychostimulant effect, the second group which
includes MDMA, MDEA, and MDA is better considered by some authors, but not
all [63, 64], to have a more prominent hallucinogenic effect [65, 66]; in this book,
the class of amphetamines called “entactogens” will be better discussed in Chap. 2,
Sect. 2.2, with a focus on ecstasy.
In this section, we look at AMPH and METH compounds and we use the general
name of ATS to refer to them.
Overall, ATS represent the second most commonly used drug after cannabis [4].
The United Nations Office on Drugs and Crime [4] reported in 2014 35.7 million
users of ATS and prescription stimulants placed under international control, world-
wide. In fact ATS have also been used for the treatment of attention-deficit hyperac-
tivity disorder (ADHD), treatment-resistant depression, narcolepsy, and obesity
[67], given their capacity to induce euphoria, increase concentration and alertness,
reduce fatigue, and intensify wakefulness appetite [68].
The most common routes of consumption of ATS as recreational drugs are oral,
intravenous, snorting, smoking, or vapor inhalation [69].
To our knowledge, psychotic symptoms induced by ATS were reported for the
first time in 1938 [70]. Later there were many other reports of ATS-induced psycho-
sis [71–74] and the onset of psychotic symptoms in regular ATS users has been
calculated from 8 to 46% [68].
These symptoms include significant suspiciousness, unusual thoughts, delusions
of reference, delusions of persecution, and both auditory and visual hallucinations
[75–82] and they are usually transient and dose dependent [79, 80].

1.2.1 Molecular Mechanism

The main molecular effect of ATS is the augmentation of monoamine release, which
could take place through different ways. Indeed, the chemical structure of ATS is
similar to that of monoamine neurotransmitters; therefore they are able to bind to
the monoamine transporters (MATs) even with different affinities [83–85]. The
bond with MATs is responsible for the inhibition of the reuptake of dopamine (DA),
noradrenaline (NA), and partially serotonin (5-HT), by acting as a competitive sub-
strate of their membrane transporters DAT, NET, and SERT, respectively [86].
Even if ATS can bind to all MATs, it has been suggested that DAT represents its
main target in order to produce the behavioral stimulant effects of the drugs [87].
However, it has already been demonstrated that AMPH can induce DA release
independently from the bond to the membrane transporter [88].
ATS can then enter into the neuron cytoplasma and cause the disruption of those
vesicles containing monoamines by binding to the vesicular monoamine transport-
ers (VMAT1 and VMAT2) [89], causing a reversal of its activity [90]. The activity