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While the association between adult Attention Deficit/Hyperactivity Disorder (A-ADHD) and Substance Use Disorders (SUDs) has been widely explored, less attention has been dedicated to the various substance use variants. In a previous paper, we identified two variants: type 1 (use of stimulants/alcohol) and type 2 (use of cannabinoids). In this study, we compared demographic, clinical and symptomatologic features between Dual Disorder A-ADHD (DD/A-ADHD) patients according to our substance use typology, and A-ADHD without DD (NDD/A-ADHD) ones. NDD patients were more frequently diagnosed as belonging to inattentive ADHD subtype compared with type 1 DD/A-ADHD patients, but not with respect to type 2 DD/ADHD. NDD/A-ADHD patients showed less severe symptoms of hyperactivity/impulsivity than DD/A-ADHD type 1, but not type 2. Type 1 and type 2 patients shared the feature of displaying higher impulsiveness than NDD/A-ADHD ones. General psychopathology scores were more severe in type 2 DD/ADHD patients, whereas type 1 patients showed greater similarity to NDD/A-ADHD. Legal problems were more strongly represented in type 1 than in type 2 patients or NDD/A-ADHD ones. Our results suggest that type 1 and type 2 substance use differ in their effects on A-ADHD patients—an outcome that brings with it different likely implications in dealing with the diagnostic and therapeutic processes.
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J. Clin. Med. 2021, 10, 1481. https://doi.org/10.3390/jcm10071481 www.mdpi.com/journal/jcm
Article
Does Cannabis, Cocaine and Alcohol Use Impact Differently
on Adult Attention Deficit/Hyperactivity Disorder
Clinical Picture?
Vincenza Spera 1, Alessandro Pallucchini 2, Marco Carli 3, Marco Maiello 2, Angelo G. I. Maremmani 2,4,5,
Giulio Perugi 6 and Icro Maremmani 5,7,8,9,*
1 Psychiatric Clinic, Sociopsychiatric Organization, 6850 Mendrisio, Switzerland; e.spera@hotmail.it
2 PISASchool of Experimental and Clinical Psychiatry, 56100 Pisa, Italy; pallucchini.a@gmail.com (A.P.);
marcomaiello@aol.com (M.M.); angelo.maremmani@uslnordovest.toscana.it (A.G.I.M.)
3 School of Clinical Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa,
56100 Pisa, Italy; carlimarco@outlook.it
4 North-Western Tuscany Local Health Unit, Department of Psychiatry, Tuscany NHS, Versilia Zone,
55045 Viareggio, Italy
5 Association for the Application of Neuroscientific Knowledge to Social Aims (AU-CNS),
55045 Pietrasanta, Italy
6 2nd Psychiatric Unit, Department of Clinical and Experimental Medicine, Santa Chiara University Hospital,
University of Pisa, 56100 Pisa, Italy; giulio.perugi@med.unipi.it
7 Vincent P. Dole Dual Disorder Unit, 2nd Psychiatric Unit, Santa Chiara University Hospital,
University of Pisa, 56100 Pisa, Italy
8 G. De Lisio Institute of Behavioral Sciences, 56121 Pisa, Italy
9 Saint Camillus International University of Health and Medical SciencesUniCamillus, 00131 Rome, Italy
* Correspondence: icro.maremmani@med.unipi.it; Tel.: +39-050-993045
Abstract: While the association between adult Attention Deficit/Hyperactivity Disorder (A-ADHD)
and Substance Use Disorders (SUDs) has been widely explored, less attention has been dedicated
to the various substance use variants. In a previous paper, we identified two variants: type 1 (use
of stimulants/alcohol) and type 2 (use of cannabinoids). In this study, we compared demographic,
clinical and symptomatologic features between Dual Disorder A-ADHD (DD/A-ADHD) patients
according to our substance use typology, and A-ADHD without DD (NDD/A-ADHD) ones. NDD
patients were more frequently diagnosed as belonging to inattentive ADHD subtype compared
with type 1 DD/A-ADHD patients, but not with respect to type 2 DD/ADHD. NDD/A-ADHD pa-
tients showed less severe symptoms of hyperactivity/impulsivity than DD/A-ADHD type 1, but not
type 2. Type 1 and type 2 patients shared the feature of displaying higher impulsiveness than
NDD/A-ADHD ones. General psychopathology scores were more severe in type 2 DD/ADHD pa-
tients, whereas type 1 patients showed greater similarity to NDD/A-ADHD. Legal problems were
more strongly represented in type 1 than in type 2 patients or NDD/A-ADHD ones. Our results
suggest that type 1 and type 2 substance use differ in their effects on A-ADHD patientsan out-
come that brings with it different likely implications in dealing with the diagnostic and therapeutic
processes.
Keywords: attention deficit hyperactivity disorder; adult ADHD; substance use disorder; dual dis-
order
1. Introduction
Attention Deficit Hyperactivity Disorder (ADHD), which was originally identified
as a childhood neuropsychiatric illness, is now known to endure into adulthood in about
two-thirds of these patients, with adult prevalence rates estimated to be close to the 35%
Citation:
Spera, V.; Pallucchini, A.;
Carli,
M.; Maiello, M.;
Maremmani, A.G.I.; Perugi, G.;
Maremmani, I. Does Cannabis,
Cocaine and Alcohol Use Impact
Differently on Adult Attention
Deficit/Hyperactivity Disorder
Clinical Picture?
J. Clin. Med. 2021, 10,
1481. https://doi.org/
10.3390/jcm10071481
Received:
9 February 2021
Accepted:
22 March 2021
Published:
2 April 2021
Publisher’s Note:
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opyright: © 2021 by the author. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (http://c
rea-
tivecommons.org/licenses/by/4.0/).
J. Clin. Med. 2021, 10, 1481 2 of 11
range. Even if it has been defined as “a persistent pattern of inattention and/or hyperac-
tivity-impulsivity that interferes with functioning or development” (Diagnostic and Sta-
tistical Manual of Mental Disorders, 5th edition (DSM-5)) [1], in adults, ADHD (A-ADHD)
reflects a syndrome featuring mood instability, Emotional Dysregulation, impulsiveness
and addictive behaviours [2]. The comorbidity of ADHD and Substance Use Disorders
(SUD) has been widely documented and recognized in research studies, and the co-occur-
rence of the two disorders can be defined as Dual Disorder (DD). Indeed, the term Dual
Disorders refers to patients with both a Substance Use Disorder and a co-occurring mental
one. ADHD and SUD are often associated since they share common genetic underpin-
nings, neurobiological substrates, and risk factors [3–5]. A metanalysis showed an ADHD
prevalence of 23.1% among SUD population [6]; similarly, a multicenter study of treat-
ment seeking SUD patients revealed a 13.9% prevalence of adult ADHD [7]. The predis-
position to addictive behaviours and SUD that is often found in ADHD patients could be
explained by reference to several mechanisms. Subjects with ADHD usually report higher
levels of sensation-seekingtraits and impulsiveness that invariably activate psychoso-
cial risk factors, such as educational failures and interpersonal problems, and having been
exposed to an earlier contact with addictive drugs [8]. Furthermore, the ADHD syndrome
and SUD are both impacted by dopaminergic dysregulation of the motivational and re-
ward systems that leads directly to executive dysfunctions and impairment in response
inhibition. As a result of dopaminergic dysfunction, some ADHD patients might react by
using drugs, especially stimulants, in order to self-medicate, so as to cope with inattention
and restlessness symptoms according to the concept of relief craving[2]. The self-med-
ication hypothesisclaims to cover all cases in the same way, but people with ADHD
actually rely on a wide variety of illicit substances, among which the best represented are
cannabinoids, stimulants and alcohol [913]. Overall, in the medical literature, the associ-
ation of ADHD with SUD configures a worse clinical picture, comprising a more rapid
and severe SUD progression [14] in addition to more frequent hospitalizations and a
weaker response to treatment [15]. Research data are, however, lacking on the influence
of the different substances of abuse on ADHD clinical symptomatology in adult samples.
In a previous study with a sample of 72 patients entering treatment, we identified
two patterns of substance use: the first (type 1) centered on the recourse to stimulants/al-
cohol, and the second (type 2) on the use of cannabinoids (THC). Type 1 DD/A-ADHD
was found to occur in significantly younger people, who had to cope with more legal
problems than type 2 ones. The two patterns were similar in terms of ADHD-specific
symptomatology and its severity at treatment entry. No differences were found with the
other scales assessed, except for lower scores in answering the Morningness-Eveningness
Questionnaire (MEQ) in type 1 DD/A-ADHD patients. We concluded that, at treatment
entry, the presence of different comorbid SUD variants did not affect ADHD-specific
symptomatology or the severity of DD/A-ADHD [16].
The aim of the current study was to assess the influence of type 1 and type 2 substance
use on the A-ADHD clinical picture by comparing the demographic, clinical, and func-
tional features of patientsthose with and without a DD/A-ADHD.
2. Materials and Methods
2.1. Design of the Study
This was an observational, cross-sectional, non-interventional, retrospective study
based on data derived from two Italian psychiatric databases. Patients were recruited
from the ADHD Outpatient Clinic of the University of Pisa and from the ADHD Outpa-
tient Clinic of La Sapienza University in Rome. We merged the data, as the two clinics
adopted the same sample selection, assessment methods and assessment of clinical fea-
tures. This study was based on a single evaluation of adult patients admitted between
2016 and 2019. All the patients recruited in the study were evaluated through a clinical
interview, self-report questionnaires and scales by residents of the Department of Clinical
J. Clin. Med. 2021, 10, 1481 3 of 11
and Experimental Medicine, School of Psychiatry of the University of Pisa, and by resi-
dents of the Psychiatric Unit of La Sapienza University, in Rome, Italy, with at least 2 years
of experience in the adult ADHD field, and under the supervision of senior psychiatrists
active in the ADHD research group. Patients with schizophrenia spectrum disorders ac-
cording to DSM-5 criteria were excluded from the clinical sample.
The study was conducted according to the World Medical Association Declaration of
HelsinkiEthical Principles for Medical Research Involving Human Subjects. Both the
consent form and the experimental procedures were approved by the ethics committee of
the University of Pisa (study ID: 14003; code: ADHD-MOOD), in accordance with inter-
nationally accepted criteria for ethical research.
2.2. Sample
Out of 183 patients selected, 166 entered the study; five patients were excluded due
to schizophrenia comorbidity, and 12 refused to participate due to personal reasons.
Among the 166 patients recruited, 113 (68.04%) were males, and 53 (32.0%) were females,
mean age 28.30 ± 10.7 (min 18, max 55); of these, 85 were substance non-users (NDD/A-
ADHD), 56 (65.9%) males and 29 (34.1%) females, mean age 28.99 ± 11.5; a total of 81 pa-
tients, comprising 57 (70.4%) males and 24 (29.6%) females, mean age 27.58 ± 9.8, were
also affected by a Substance Use Disorder (Dual Disorder). Both conditions were diag-
nosed according to the DSM-5 criteria. Using our methodology, [16] 41 DD/A-ADHD pa-
tients (of whom 27 (65.9%) were males and 14 (34.1%) females, mean age 28.54 ± 10.2 (min
18, max 51) were diagnosed as type 1, and 40 (comprising 30 (75.0%) and 10 (25.0%) fe-
males, mean age 26.60 ± 9.4 (min 18, max 55)) as type 2. All the patients selected were
adults (age-range: 1865 years) whose ADHD was first diagnosed after entry into adult-
hood (i.e., after reaching the age of 18). Age (F = 0.68; p = 0.506) and sex (χ2 = 1.23; p = 0.583)
were homogenous between the three groups being compared. Legal problems were self-
reported and included crimes for drug possession or sale, burglary or stealing, aggression
or violence related or unrelated to drugs, and driving crimes.
2.3. Instruments
In addition to the application of DSM-5 criteria, ADHD diagnosis was further as-
sessed by means of the Adult ADHD Self-Report Scale (ASRS) for screening purposes [17]
and confirmed using the Diagnostic Interview for ADHD in adults (DIVA 2.0) [18,19].
The Conners’ Adult ADHD Rating ScalesObserver: Short Version (CAARS-O:S) was
completed by a close relative of the patient. This made the quantification of ADHD symp-
toms and the ADHD Index possible; high scores obtained on the ADHD Index suggest
clinically significant levels of ADHD symptoms [20].
Difficulties in the Emotion Regulation Scale (DERS) is a 36-item self-evaluation scale
comprising six subdomains of emotional regulation (awareness, clarity, goals, impulse,
non-acceptance, strategies). Answers range from 1 (“almost never”) to 5 (“almost al-
ways”), and higher total scores recorded in answering DERS reflect greater difficulties in
regulating emotions [21].
The Structured Clinical Interview for Axis I Disorders (SCID-I) was used for the as-
sessment of other psychiatric disorders, according to DSM-5 procedures.
The Barratt impulsiveness scale (BIS-11) is a 30-item questionnaire used for the as-
sessment of impulsiveness, which is factorialized into three second-order domains named
“Attentional”, “Motor” and “Non-planning” impulsivity [22].
For each patient, the clinician completed the 18-item version of the Brief Psychiatric
Rating Scale (BPRS-18)—a tool commonly used to assess general psychopathology. The
BPRS explores symptoms typically grouped into five subscales: Anxiety-Depression,
Anergia/negative factor, Thought Disturbance, Activation, Hostility-Suspiciousness and
Total Psychopathology Severity [23,24].
The Reactivity Intensity Polarity Stability Questionnaire (RIPoSt-40) is a self-report
questionnaire comprising 40 items that are used to measure Emotional Dysregulation
J. Clin. Med. 2021, 10, 1481 4 of 11
(ED), which can be further subdivided into four subscales known as “Emotional Impul-
sivity”, “Positive Emotionality”, “Negative Emotionality” and “Affective Instability” [25].
The World Health Organization Disability Assessment Schedule (WHODAS 2.0), de-
veloped directly by the WHO, is a 36-item self-administered questionnaire that is used to
explore functioning and disability in major life domains [26].
The 19-item MorningnessEveningness Questionnaire (MEQ) was used to assess pa-
tients’ chronotype: a total score of 41 or below is interpreted as indicating an “evening
chronotype”, whereas a score of 59 or above is considered to mark out a “morning chro-
notype” [27].
2.4. Data Analysis
We clustered our patients in different typologies of substance of use by adopting the
following procedure. We scaled the use of each substance by defining four ordinal levels:
0 = no lifetime use; 1 = past use (at least six months of abstinence); 2 = current (during the
previous 6 months) use; 3 = both past and current use. An exploratory factorial analysis
was performed on the substances investigated (cannabinoids, cocaine, amphetamines, 3,4-
methylenedioxymethamphetamine or MDMA, opiates, alcohol, illegal benzodiazepines)
in ADHD patients, in order to identify possible composite dimensions. The initial factors
were extracted by means of principal component analysis (PCA-type 2) and then rotated
according to Varimax criteria in order to achieve a simple structure. The criterion used to
select the number of factors was an eigenvalue > 1. Items loading with absolute values
>0.40 were used to describe the factors. This procedure makes it possible to minimize the
correlations between the factors, thus allowing their optimization as classificatory tools
for each subject. The factor scores were then standardized as z-scores to facilitate the com-
parison of scores occurring among the factorial measures. All the subjects were then
grouped into different subtypes on the basis of the highest z-scores obtained for each fac-
tor. This procedure gave the opportunity to classify groups of subjects on the basis of the
most statistically abnormal substance use cluster. In this way, it became possible to resolve
the problem of identifying a cut-off for the inclusion of patients in different identified
clusters. In this specific case, to be able to cluster patients in groups, we used correlations
between the substances used.
The three groups (NDD/A-ADHD, DD/A-ADHD Type 1 and DD/A-ADHD Type 2)
were compared for sociodemographic, clinical and functional characteristics by means of
the chi-square test for categorical variables (with z-test contrasts and Bonferronis correc-
tion), and one-way analysis of variance for continuous variables, a posteriori contrasts
according to the Scheffé’s procedure.
All analyses were carried out using the statistical package of SPSS (version 25.0).
Since this is an exploratory study, statistical tests were considered significant at the p <
0.05 level.
3. Results
Table 1 reports demographic characteristics. No differences were found in investi-
gating age, years of education, sex or civil status. Type 1 DD/A-ADHD patients showed a
greater number of legal problems than type 2 and NDD/A-ADHD ones.
J. Clin. Med. 2021, 10, 1481 5 of 11
Table 1. Demographic and clinical differences in adult Attention Deficit/Hyperactivity Disorder
(A-ADHD) patients with and without Dual Disorder (DD).
NDD/A-ADHD
N = 85
DD/A-ADHD
Type 1
N = 41
DD/A-ADHD
Type 2
N = 40
M ± SD
M ± SD
M ± SD
F
p
Age
28.99 ± 11.5
28.54 ± 10.2
26.60 ± 9.3
0.68
0.506
Years of education
13.63 ± 2.8
12.78 ± 2.9
13.51 ± 4.1
0.98
0.376
N (%)
N (%)
N (%)
χ
2
p
Male sex
58 (66.7)
27 (64.3)
30 (75.0)
1.23
0.538
Legal problems
3 (3.5) a
14 (35.0) b
3 (7.5) a
26.34
0.000
Single
65 (78.3)
34 (85.0)
32 (82.1)
0.82
0.661
NDD/A-ADHD = Non-Dual Disorder A-ADHD; DD/A-ADHD = Dual Disorder A-ADHD, M =
mean, SD = standard deviation. “a” and “b” letters denotes a subset of categories whose column
proportions differ significantly from each other at the 0.05 level.
Table 2 shows clinical and functional differences. In evaluating ADHD-specific
symptomatology by the CAARS-O:S, no differences were found in the scores for the se-
verity of inattentiveness or in the combined scores. The ADHD Index showed similarities
between NDD and DD/A-ADHD patients. Conversely, the NDD/A-ADHD group showed
less severe hyperactivity/impulsivity symptomatology than in DD/A-ADHD type 1 but
not in type 2 patients.
Using DIVA 2.0, NDD patients were found to have been more frequently diagnosed
with the inattentive ADHD subtype than type 1 DD/A-ADHD patients, but not with re-
spect to type 2 DD/A-ADHD ones.
No differences were found by comparing difficulties in emotion regulation (DERS)
or in its severity (RIPoSt-40); the degree of disability was very similar between the groups.
On symptoms of impulsiveness (BIS-11), type 1 and type 2 patients displayed greater
impulsiveness than NDD/A-ADHD ones. General psychopathology (BPRS) scores were
more severe in type 2 DD/A-ADHD patients, whereas type 1 showed similarities with
NDD/A-ADHD patients.
The presence of other psychiatric comorbidities was not statistically different among
the three groups.
J. Clin. Med. 2021, 10, 1481 6 of 11
Table 2. Demographic and clinical differences in A-ADHD patients with and without Dual Disor-
der.
NDD/A-ADHD
N = 85
Type 1
Type 2
M ± SD
F
p
CAARS-Inattentive
18.08 ± 5.6
0.82
0.438
CAARS-Hyperactive/Impulsive
12.84 ± 6.5 a
4.69
0.010
CAARS-Combined
30.77 ± 10.6
1.00
0.369
CAARS-Index
22.98 ± 6.6
0.69
0.501
Total DERS
2.94 ± 0.5
1.57
0.855
Total RIPOST
222.12 ± 43.2
0.39
0.679
Total BIS
75.46 ± 11.7 a
10.01
0.000
Total BPRS
38.04 ± 13.5 a
6.06
0.003
Total WHODAS
2.45 ± 0.7
1.74
0.178
N (%)
χ
2
p
DIVA combined
57 (67.9)
3.59
0.166
DIVA inattentive
25 (29.8) a
7.04
0.030
DIVA hyperactive/impulsive
3 (3.5)
0.21
0.896
MEQ typology
2.44
0.655
1-Indifferentiate
56 (65.1)
2-Evening chronotype
17 (19.8)
3-Morning chronotype
13 (15.1)
NDD/A-ADHD = Non-Dual Disorder A-ADHD; DD/A-ADHD = Dual Disorder A-ADHD; CAARS
= Conner’s Adult ADHD Rating Scales; DERS = Difficulties in Emotion Regulation Scale; RIPOST =
Reactivity Intensity Polarity Stability Questionnaire; BIS = Barratt Impulsiveness Scale; BPRS =
Brief Psychiatric rating scale; WHODAS = World Health Organization Disability Assessment
Schedule; DIVA = Diagnostic Interview for ADHD in adults; MEQ = Morningness-Eveningness
Questionnaire. “a” and “b” letters denotes a subset of categories whose column proportions differ
significantly from each other at the 0.05 level.
4. Discussion
In summary, DD/A-ADHD showed greater impulsivity than their peers without DD;
more specifically, type 1 and type 2 patients showed the same degree of impulsivity. Type
2 showed more general psychopathology (BPRS) than type 1, while their NDD/A-ADHD
peers, interestingly, showed the same degree of psychopathological severity. Type 1, but
not type 2 patients, were more hyperactive/impulsive and less often diagnosed as belong-
ing to the inattentive A-ADHD type. Type 1 also showed more frequent legal problems.
On the topic of legal problems, our patientsmore specifically, those abusing stim-
ulants and/or alcoholconfirmed data appearing in the literature that show a higher fre-
quency of violent behaviors, together with antisocial and illicit forms of conduct among
people with SUD and ADHD [28]. Again, in accordance with previous reports, a majority
of our NDD patients at the moment of entry into treatment showed a combined ADHD
subtype, with higher frequencies of inattentive symptoms, compared with those found in
users of stimulants/alcohol (type 1), and lower impulsivity [29,30].
Regarding our results, general psychopathology could help us discern the effects of
different substances on patients with ADHD. Cannabinoid users had a more severe psy-
chopathology, while displaying more activation, hostility, suspiciousness and thought
disturbances [31]. In the literature on adult ADHD patients, few studies have paid any
attention to the influence of specific substances on ADHD psychopathology, focusing in-
stead on worse all-inclusive outcomes in patients with Dual Disorder arising from sub-
stance polyuse and dependence. Our results are not at all surprising, since the use of THC
has been widely associated with psychosis, paranoia and aggressiveness in clinical popu-
lations, especially in chronic and heavy users [32]. The psychopathological burden seems
to be even worse in ADHD individuals, who are more vulnerable to cannabis effects be-
cause of the worsening of already present neurocognitive deficits, impulsivity and mood
instability.
J. Clin. Med. 2021, 10, 1481 7 of 11
Even if the association of SUD and ADHD has been widely studied in the literature,
few authors have ever examined the role played by specific substances in affecting psy-
chopathological domains. A recent study of ADHD patients seeking treatment for a SUD
(consumption of cocaine or cannabis, or both) showed a higher addiction severity in can-
nabis use groups, with similar ADHD features found between different groups [33]. To
the best of our knowledge, no other ADHD study has compared stimulant users with
cannabinoid usersto cite the two most frequently abused classes of drugs. The present
study did not, in any case, have the aim of comparing two different classes of substance
being regularly used.
When using the BIS scale to differentiate between two diverse typologies of substance
abuse, the results are unsatisfactory. Both groups show similar, higher scores of impul-
siveness compared with NDD/A-ADHD patients. This finding may suggest that, regard-
less of the substance of abuse, illicit drugs always have a negative impact on the behavior
of ADHD patients by enhancing impulsive behavior and loss of self-control. Alternatively,
it may be that ADHD patients with higher impulsivity levels at baseline (in youth) are at
more risk of developing SUD [34,35].
Our data raise the hypothesis of a distinctive form of substance use in a real-world
population of A-ADHD [36]. Users of stimulants might behave in this way to attenuate
their symptoms of inattentiveness [37]. If this is true, this new hypothesis might prove to
be useful when it comes to selecting patients who do not appear to be inattentive. On the
other hand, THC does not mask inattentiveness. According to Khantzian’s self-medica-
tionhypothesis, ADHD subjects may use stimulants as a way to manage symptoms of
impulsivity, restlessness and inattentiveness by obtaining a calmingeffect arising from
an increased, specifically dopaminergic transmission (which is dysfunctional in ADHD).
The effects of cocaine mainly involve structures that form part of the reward system (ac-
cumbens and ventral pallidum), working memory (amygdala and hippocampus), volition
(orbitofrontal and subcallosal cortices) and control (prefrontal cortex and cingulate gyrus)
[38]. Cocaine inhibits the reuptake of dopamine, norepinephrine and serotonin from the
synaptic cleft, enhancing the stimulation mediated by these monoamines [39]. The net ef-
fect, in non-ADHD individuals, is a global psychomotor activation involving increased
arousal, euphoria and increased vigilance and alertness. Cocaine acts on the systems that
appear to be damaged in ADHD patients which are, in fact, the primary target for the
pharmaceutical treatment of the disorder. Its use, therefore, may be supported by mecha-
nisms associated with craving for relief, by reducing the burden of executive and behav-
ioral dysfunctions typical of ADHD [40]. Support for this hypothesis can be found in a
recent study of ours about psychopathological typology and the severity of symptoms
affecting 24 Cocaine Use Disorder (CUD) patients without a Dual Disorder and 120 Co-
caine Use Disorder/A-ADHD patients, while assuming that CUD patients are mainly mo-
tivated by a craving for reward, whereas Cocaine Use Disorder/A-ADHD patients are
mainly driven by a craving for relief [41].
THC acts on the cannabinoid receptors within the brain that are usually responsible
for producing affective feelings of well-being, euphoria, reduction of anxiety, cognitive,
somatic and sensory effects, such as memory lapses, difficulty in concentration, time dis-
tortion, and increased sensitivity to external and internal stimuli [42]. THC is also in-
volved in modulating other neurotransmitters like dopamine, serotonin, glutamate, nore-
pinephrine, γ-aminobutyric acid (GABA), histamine, acetylcholine, prostaglandins and
opioid peptides [43]. In particular, its action on the dopaminergic system leads to a rein-
forcing effect on the conduct of abuse. In addition, through cannabinoid-1-receptors, lo-
cated in the striatum and substantia nigra, THC elicits striatal dopamine release, thus
playing a role in the salience attribution processes by increasing the salience of usually
non-salient stimuli [44]. With chronic and prolonged use, the dopaminergic system faces
depletion, faltering in an amotivational syndrome and leading to a subsequent impover-
ishment of executive functions (planning, working memory, etc.) [45]. ADHD patients,
J. Clin. Med. 2021, 10, 1481 8 of 11
therefore, may seek the relaxing and pleasurable effects that cannabis elicits, with a mo-
dality we would call reward craving, although the long-term effects ultimately lead to a
worsening of ADHD symptomatology [46]. This implies that the first typology of patients
(stimulant users) is easier to treat compared with the second typology (THC users), be-
cause the initiation of stimulant medications might produce the ending of the harm use of
illicit stimulants. Indeed, one of our previous studies showed a reduction in cocaine use
correlated with ADHD when stimulant or atomoxetine treatment was initiated [36]. In
any case, it should be recognized that all the stimulants, such as cocaine, may trigger im-
pulsivity and foster aggressive behaviours through the increase in dopamine levels in the
mesolimbic and mesocortical areas of the brain. Therefore, while the trait of inattentive-
ness is masked by the use of cocaine, levels of impulsivity prove to be similar in the type
1 and type 2 groups. In general, studies in the literature on the motivation to use sub-
stances in individuals with ADHD are controversial, because they suggest both self-ther-
apeutic and euphorigenic use [47]. Research findings regarding treatment options for
Dual Disorder patients are inconclusive since stimulant medicationsthe front-line treat-
ment for ADHD—have mainly shown benefits for ADHD symptomatology, but much less
so for SUD. Indeed, Notzon et al. observed an increased abstinence from cannabis in pa-
tients with both ADHD and cocaine use disorders after stimulant treatment with ex-
tended-release mixed amphetamine salts [48]. Other authors have demonstrated an im-
provement both in ADHD and cocaine use disorder after treatment with stimulant medi-
cations, suggesting a possible role for these specific treatments even when the medical
condition in question is SUD [49].
Clinical Implications
Cocaine, with its prodopaminergic effects, might mask several symptoms of ADHD,
and may thus constitute a confounding factor for the correct recognition of the underlying
disorder and the definition of a valid strategy for treating a Dual Disorder patient. On the
other hand, when impulsivity is indeed present, it becomes necessary to exclude the pos-
sibility that it may be due to the SUD. If this is the case, it is important to treat the sub-
stance use, and not only the impulsivity, with psychiatric medications. We suggested a
hierarchic approach, in which treatment of impulsiveness due to SUD should come first
[50,51]. When the treatment aims only to reduce the impulsivity deriving from ADHD,
the component due to SUD, without any specific treatment, it may continue to interfere
with these patients’ lives and lead to negative outcomes. We believe that people with
ADHD suffering from SUD may be driven either by a relief or a reward craving—two
different types that may even coexistespecially in advanced illnesses, so providing the
preconditions for the worst psychopathological syndromes. The predominance of relief
craving during the use of stimulants leads us to hypothesize a better response to specific
drugs for ADHD. Conversely, if reward drive is prevalent with the heavy use of canna-
binoids, we are often faced by major psychiatric complications, such as mood instability,
impulsivity and psychosis.
To our knowledge, our study is the first to analyze patterns of substance use among
DD A-ADHD patients and their relationship with the psychopathological outcomes. Alt-
hough our results are preliminary, and require further research, they may give an im-
portant contribution for the evaluation of DD patients with ADHD and their treatment.
Several limitations have to be addressed. First of all, the sample size was not big
enough to generalize our findings. All the patients evaluated were never diagnosed or
treated for ADHD before adulthood and presented with a severe clinical picture. To con-
firm our data, a wider sample should be enrolled. The second limitation is the self-assess-
ment of several features, such as impulsivity, Emotional Dysregulation and overall func-
tioning, which may lead to reporting biases. Finally, our sample did not include patients
treated exclusively at the “addiction units”; this is especially true for opioid addicts who,
J. Clin. Med. 2021, 10, 1481 9 of 11
indeed, were minimally represented in our sample. In Italy, psychiatric units and addic-
tion units work independently, resulting in poor communication between the two. These
sample selection biases limit the generalization of our data.
5. Conclusions
Testing the type 1 and type 2 substance modality of use is a useful tool for studying
the symptomatological variants of A-ADHD. These variants may be related to the differ-
ent concepts of craving that are experienced by individuals with a DD/A-ADHD, adding
different possible implications in the task of responding to the diagnostic and therapeutic
processes.
Author Contributions: Conceptualization, I.M. and G.P.; methodology, I.M., A.G.I.M.; formal anal-
ysis, I.M.; investigation, V.S., A.P., M.C., M.M.; data curation, I.M.; writingoriginal draft prepara-
tion, V.S., M.M.; writingreview and editing, V.S., I.M.; supervision, I.M.; project administration,
G.P. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki, and approved by the Ethics Committee of the University of Pisa (study ID:
14003; code: ADHD-MOOD).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the
study.
Data Availability Statement: The data are not publicly available due to the privacy reasons.
Conflicts of Interest: The authors declare no conflict of interest.
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... Aktywacja tych struktur w badaniach obrazowych była opisywana jako wyższa u osób używających konopi indyjskich w porównaniu z osobami nie używającymi, jednak tylko w grupach osób bez stwierdzonej ADHD 15 . W interakcje z endokannabinoidami może wchodzić kilka innych neuroprzekaźników, takich jak glutaminian, kwas γ-aminomasłowy i N-metylo-Dasparaginian, a także receptory CB2, co może mieć wpływ w modulacji impulsywności 13,16 . Coraz więcej dowodów wskazuje na istotną rolę ECS w regulacji funkcjonowania poznawczego i behawioralnego, sugerując jego potencjał terapeutyczny w leczeniu chorób psychiatrycznych 16 . ...
... W interakcje z endokannabinoidami może wchodzić kilka innych neuroprzekaźników, takich jak glutaminian, kwas γ-aminomasłowy i N-metylo-Dasparaginian, a także receptory CB2, co może mieć wpływ w modulacji impulsywności 13,16 . Coraz więcej dowodów wskazuje na istotną rolę ECS w regulacji funkcjonowania poznawczego i behawioralnego, sugerując jego potencjał terapeutyczny w leczeniu chorób psychiatrycznych 16 . ...
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Background: Attention-deficit/hyperactivity disorder (ADHD) is a disabling disorder. High rates of ADHD have been consistently reported among prisoners. The main objectives were (1) to estimate the prevalence of ADHD symptoms in a sample of male inmates and (2) to investigate the relationship between ADHD symptoms and socio-demographic/clinical features. According to the high prevalence of childhood trauma among inmates, we assessed whether exposition to childhood trauma can be related to the presence of ADHD symptoms. Methods: A total of 159 male prisoners admitted to Monza prison between January 2020 and June 2021 were included. Both Wender Utah ADHD rating scale and adult ADHD self-report scale were administered to assess ADHD symptoms. Moreover, inmates completed the childhood trauma questionnaire. Results: Data were available for 108 inmates. Thirty-five prisoners (32.4%) were found on screening to meet the criteria for symptoms of ADHD. Cocaine use disorder, prescription of mood stabilizers and a history of emotional abuse significantly increased the likelihood of having clinically significant ADHD symptoms. Furthermore, patients who experienced physical neglect resulted in meeting the criteria for ADHD symptoms. Conclusions: ADHD symptoms are widespread among inmates and are associated with specific risk factors. Screening for ADHD should be done to provide appropriate intervention strategies.
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Substance Use Disorders (SUDs) are often associated with Attention-Deficit Hyperactivity Disorder (ADHD) in adult populations due to multiple neurobiological, genetic, and psychosocial risk factors. This chapter provides a picture of the clinical aspects of adults with both ADHD and SUDs at treatment entry into a Dual Disorder Unit introducing the concept of different types of craving that may lead to substance use and abuse. At treatment entry, the presence of different comorbid SUD clusters, characterized by either stimulants/alcohol or by the use of cannabinoids, has not been shown to influence ADHD-specific symptomatology or severity, despite being crucial for the identification of a specific type of craving. We identified four clinical presentations of adult ADHD: Emotional Dysregulation, Substance Use, Core-ADHD Symptoms, and Positive Emotionality variants, that offer a practical guide in diagnosing and managing adult ADHD patients. Although the evidence of an effective medical treatment for Cocaine Use Disorder is insufficient, in our experience, toxicomanic behavior during stimulant treatment is sharply reduced in ADHD patients with cocaine addiction. Moreover, caffeinated compounds in military soldiers with ADHD may help reduce ADHD symptoms, making caffeine a potential pharmacological tool worth further investigation. Finally, substance use comorbidity does not influence treatment retention rate.
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Background: High risk of alcohol and drug use disorders in people with attention-deficit/hyperactivity disorder (ADHD) calls for exploratory research of relationships with clinical features of ADHD. Aim: To estimate prevalence of alcohol/drug use disorders and associations with ADHD symptom severity and emotional dysregulation, in adults with ADHD. Methods: This observational cross-sectional clinical study consisted of patients admitted to a private psychiatric outpatient clinic in Oslo, Norway (2014-2018). Five-hundred and fifty-eight eligible patients diagnosed with ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) agreed to participate. Alcohol and drug use disorders were diagnosed using the Mini International Neuropsychiatric Interview (MINI). Dependence and abuse were merged into "use" disorder as in MINI version 7.0/DSM-5. Questions were related both to lifetime and the past 12-mo. ADHD severity was assessed by the Adult ADHD Self Report Scale (ASRS). Subdivisions of the ASRS questionnaire as inattentive items and hyperactive/impulsivity items were recorded separately. Emotional dysregulation was assessed by the eight-item version of Barkley's Current Behavior Scale - Self Report. Results: The 12-mo prevalence was 5.3% for alcohol use disorder and 13.7% for drug use disorder. The lifetime prevalence was 12.0% for alcohol use disorder and 27.7% for drug use disorder. Men had higher rates of both alcohol use disorder and drug use disorder compared to women. The prevalence of drug use disorder was more than twice that of alcohol use disorder for both sexes. The drugs most participants reported having used were (in descending order): Amphetamine (19.1%), cannabis (17.1%), cocaine or ecstasy (7.4%), benzodiazepines (7.4%), and heroin or other opioids (2.9%). Lifetime drug use disorder was significantly associated with both hyperactivity-impulsivity symptoms and emotional dysregulation symptom severity. Lifetime alcohol use disorder, on the other hand, was not significantly associated with ADHD symptoms or emotional dysregulation when adjusted for gender and age. Conclusion: Patients with ADHD have a high lifetime prevalence of drug use disorder, which is associated with higher levels of hyperactivity-impulsivity symptoms and emotional dysregulation.
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Background: Attention deficit/hyperactivity disorder (ADHD), conduct disorder (CD), and sensation seeking (SS) have been consistently related to a higher risk of substance use (SU) and substance use disorder (SUD). Objectives: To investigate the relationship between ADHD and prevalence rates in males at age 20 and age 25, the initiation of SU and SUD after age 20, and the escalation of SU from age 20 to age 25, and to explore the role of CD and SS in the relation of ADHD with SU and SUD initiation and escalation. Method: Data were obtained as part of the Cohort Study on Substance Use Risk Factors (C-SURF), which focused on young Swiss men aged 20 years at baseline and 25 years at follow-up. Results: Participants who screened positive for ADHD at baseline exhibited a higher rate of SU and SUD than participants who screened negative. The presence of ADHD symptoms at age 20 predicted initiation of all SU between age 20 and age 25, except for alcohol and smoking. After controlling for self-reported CD and SS, ADHD still predicted this late initiation of use of hallucinogens, meth-/amphetamines, and ecstasy/MDMA; non-medical use of ADHD medication and sedatives, and alcohol use disorder (AUD). No escalation of weekly drinking and smoking or annual cannabis use was observed from age 20 to age 25. Conclusion: Screened-positive ADHD is an independent predictor of late SU and AUD, along with self-reported CD and SS. From a public health perspective, identifying ADHD is not only important in childhood and adolescence but also in early adulthood to guide specific interventions to lower risks of drug use initiation and the development of AUD in early adulthood.
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Background: While a large amount of medical literature has explored the association between Attention Deficit/Hyperactivity Disorder (ADHD) and Substance Use Disorders (SUDs), less attention has been dedicated to the typologies of SUD and their relationships with ADHD-specific symptomatology and general psychopathology in dual disorder patients. Methods: We selected 72 patients (aged 18-65) with a concomitant SUD out of 120 adults with ADHD (A-ADHD). Assessment instruments included the Diagnostic Interview for ADHD in adults (DIVA 2.0), Conner's Adult ADHD Rating Scales-Observer (CAARS-O:S): Short Version, the Structured Clinical Interview for Axis I and II Disorders (SCID-I), the Barratt Impulsiveness Scale (BIS-11), the Brief Psychiatric rating scale (BPRS), the Reactivity Intensity Polarity Stability Questionnaire (RIPoSt-40), the World Health Organization Disability Assessment Schedule (WHODAS 2.0) and the Morningness-Eveningness Questionnaire (MEQ). A factorial analysis was performed to group our patients by clusters in different typologies of substance use and correlations between SUDs, as made evident by their typological and diagnostic features; in addition, specific ADHD symptoms, severity of general psychopathology and patients' functionality were assessed. Results: Two patterns of substance use were identified: the first (type 1) characterized by stimulants/alcohol and the second (type 2) by the use of cannabinoids (THC). Type 1 users were significantly younger and had more legal problems. The two patterns were similar in terms of ADHD-specific symptomatology and its severity at treatment entry. No differences were found regarding the other scales assessed, except for lower scores at MEQ in type 1 users. Conclusions: At treatment entry, the presence of different comorbid SUD clusters do not affect ADHD-specific symptomatology or severity.
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Background: Cocaine use disorder (CUD) is a growing public health concern, but so far no effective pharmacotherapies have been demonstrated. Stimulant medications have proved to be promising in CUD treatment. The self-medication hypothesis (SMH) can help to explain this phenomenon better, especially in cases where CUD co-occurs with adult attention deficit hyperactivity disorder (A-ADHD). Methods: In the present retrospective study, a sample of 20 consecutive patients (aged from 18 to 65 years) with dual disorder (A-ADHD/CUD), under treatment with methylphenidate (MPH) or atomoxetine (ATM) medications, was followed to study the effects of A-ADHD treatment on cocaine use. Patients were followed for a mean period of 7 months (minimum 1, maximum 30 months). All individuals were assessed with standardized questionnaires to evaluate diagnosis, treatment efficacy, and clinical improvement. Results: the results showed that behaviors reflecting cocaine addiction were sharply reduced during the stimulant treatment of A-ADHD, and were not correlated with age, gender, familiarity, length of treatment, or medication used. CUD improvement was closely correlated with the A-ADHD improvement. This study supports the validity of the SMH in ADHD patients with co-occurring CUD.
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Background: Substance Use Disorder is, probably, the most common comorbid psychiatric condition in adult patients with Attention Deficit Hyperactive Disorder. As reported by many A-ADHD patients, the use of stimulants can be viewed as a response to ADHD symptoms, by at least temporarily alleviating or suppressing them, in line with the Self-Medica-tion Hypothesis theorized by Khantzian. This theory is supported by the fact that Cocaine Use Disorder (CUD) patients with Adult ADHD (CUD/A-ADHD) can show a reduction in the use of cocaine, a decrease in craving symptoms, and an improvement in social functioning, reaching higher levels of executive functionality, if treated with stimulants for ADHD. The V.P. Dole Research Group at the Santa Chiara University Hospital of the University of Pisa, Italy, has shed light on the possible definition of a specific psychopathy dimension in SUD, suggesting the trait-rather than the state-dependent nature of the five introduced psychopathological dimensions. Methods: In the present study we compared, at treatment entry, the psychopathological typology and the severity of symptoms affecting 24 CUD patients without a Dual Disorder and 120 CUD/A-ADHD patients, while assuming that CUD patients are motivated prevalently by a craving for reward and CUD/A-ADHD patients by a craving for relief. Results: The general indexes of psychopathology were more severe in CUD/A-ADHD than in CUD patients, and the same trend was observed regarding the five psychopathological dimen-sions. In CUD patients the Worthlessness/Being Trapped (W/BT) dimension, which should be a proxy for reward craving, acquired greater importance, especially when its severity was inversely correlated with that of the Violence/Suicide (V/S) dimension. In CUD/A-ADHD patients, on the other hand, their psychopathology was distinguished by the highest level of V/S severity and the lowest level of W/BT severity. Conclusions: The five SCL-90 psychopathological dimensions can differentiate reward from relief craving, while recognizing that both types of motivation mark out addictive disorders, though these do differ in severity and treatment outcome. Making this distinction allows further proof of the five dimen-sions’ specificity in separating types of addiction psychopathology.
Article
Objectives A widely used measure of emotion dysregulation, the Difficulties in Emotion Regulation Scale (DERS), may insufficiently cover a number of potentially important aspects of emotional dysregulation. A new measure of emotional dysregulation, the Emotional Dysregulation Questionnaire (EDQ) was therefore developed based upon an eight‐factor model of the construct. Design and Method The DERS and the EDQ were administered to a community sample (N = 362; 183 female, 179 male), along with a number of measures of psychopathology associated with emotional dysregulation. The capacity of the EDQ and the DERS to account for the emotional dysregulation associated with these different types of psychopathology was then compared. Results In several of the psychopathologies examined, the EDQ could account for more variation than the DERS, suggesting that it more comprehensively assessed the emotion regulation deficits associated with these issues. Conclusions Results suggest the EDQ possesses several advantages relative to the DERS, allowing for a more comprehensive and accurate assessment of emotional dysregulation. Practitioner points • Emotional dysregulation is a common component of many psychological disorders. • The Difficulties in Emotion Regulation Scale is one of the primary self‐report measures used to asses these difficulties, however, concerns exist that it may not comprehensively assess the construct of emotional dysregulation. • A new self‐report measure of comparable length, the Emotional Dysregulation Questionnaire has been developed, with this new measure possessing several advantages relative to the DERS with regard to the assessment of emotional dysregulation. • The use of this measure in clinical practice may more accurately identify the emotion regulation deficits present in clients.
Article
Aims: 1) To investigate whether genetic liability to attention-deficit/hyperactivity disorder (ADHD), indexed by polygenic risk scores for ADHD (PRS-ADHD), is associated with substance use disorders (SUD) in individuals with ADHD. 2) To investigate whether other individual- or family-related risk factors for SUD could mediate or confound this association. Design: Population-based cohort study SETTING AND PARTICIPANTS: ADHD cases in the iPSYCH sample (a Danish case-cohort sample of genotyped cases with specific mental disorders), born in Denmark between 1981 and 2003 (N = 13 116). Register-based information on hospital diagnoses of SUD was available until December 31, 2016. Measurements: We estimated odds ratios (ORs) with 95% confidence intervals (CIs) for any SUD as well as for different SUD types (alcohol, cannabis, and other illicit drugs) and severities (use, abuse, and addiction), with effect sizes corresponding to a comparison of the highest PRS-ADHD decile to the lowest. Findings: PRS-ADHD were associated with any SUD (OR = 1.30, 95% CI: 1.11-1.51). Estimates were similar across different types and severity levels of SUD. Other risk factors for SUD (male sex, age at ADHD diagnosis, comorbid conduct problems, and parental factors including SUD, mental disorders, and socio-economic status) were independently associated with increased risk of SUD. PRS-ADHD explained a minor proportion of the variance in SUD (0.2% on the liability scale) compared to the other risk factors. The association between PRS-ADHD and any SUD was slightly attenuated (OR = 1.21, 95% CI: 1.03-1.41) after adjusting for the other risk factors for SUD. Furthermore, associations were nominally higher in females than in males (ORfemales = 1.59, 95% CI: 1.19-2.12, ORmales = 1.18, 95% CI: 0.98-1.42). Conclusions: A higher genetic liability to attention-deficit/hyperactivity disorder appears to be associated with higher risks of substance use disorders in individuals with attention-deficit/hyperactivity disorder.
Article
Objective: The objective of this study was to compare psychiatric comorbidity and consumption-related variables in ADHD patients seeking treatment for cocaine, cannabis, or both. Method: Assessment was conducted using European Addiction Severity Index (EuropASI), Conners’ Adult ADHD Diagnostic Interview (CAADID), Structured Clinical Interview for DSM Disorders (SCID), Adult Self-Report Scale (ASRS), Wender Utah Rating Scale (WURS), Barratt Impulsiveness Scale-11 (BIS-11), and FIDI, with statistical analyses of analysis of variance (ANOVA), Student’s t test, chi-square test, and multinomial regression model. Results: In total, 1,538 patients with substance use disorder (SUD) were evaluated for ADHD; 239 (15.5%) had ADHD, with cannabis 41, cannabis/cocaine 36, and cocaine 74. Men represented 80%, with mean age of 32.9 ± 10 years. Significant variables were—in bivariate analysis—more years of cannabis use in cannabis group and younger age for cocaine use disorder in cannabis/cocaine group, and—in multivariate analysis—lifetime anxiety disorder and younger age at onset of any SUD in cannabis group and working affected scale in cannabis and polysubstance use in cannabis/cocaine group. Conclusion: Groups with cannabis use had higher severity. ADHD features were similar in all groups. The assessment of ADHD and comorbid disorders is important.
Article
Background: Emotional dysregulation (ED) is a heterogenous construct with great relevance in psychiatric research and clinical practice. In the present study, we validated a 40-items version of the Reactivity, Intensity, Polarity and Stability questionnaire (RIPoSt-40), a self-report measure of ED. Methods: A non-clinical sample (N = 396) and two clinical samples of patients with cyclothymia (N = 120) and ADHD (N = 54) were recruited. Items were selected and subscales were derived based on inter-item correlations and PCA with promax rotation in the non-clinical sample. Test-retest reliability was assessed in a subsample (N = 60). Internal consistency and concurrent validity with TEMPS-M factors were evaluated in each sample. The three groups results were compared to ascertain discriminant validity. Results: Four subscales were identified as measures of affective instability, emotional impulsivity, negative and positive emotionality. The first three subscales also sum up to a negative ED score comprising thirty items. Measures of reliability (test-retest r = 0.71-0.84) and internal consistency (Cronbach's α = 0.72-0.95) were generally high. Concurrent validity was supported by correlations with TEMPS-M factors. Discriminant validity was significant (p < 0.001) with cyclothymic and ADHD patients showing higher scores for each subscale, except for positive emotionality. Limitations: The non-clinical sample was recruited through a web-survey and mainly included young and highly educated subjects. Mood and anxiety comorbidity of the clinical samples were not taken into consideration. Conclusion: RIPoSt-40 questionnaire has proved to be a valid, reliable and useful tool to assess ED both in clinical and non-clinical contexts.
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Recreational and chronic cannabis use has been associated with a range of acute and chronic effects including; anti‐nociceptive actions, anxiety, depression, psychotic symptoms and neurocognitive impairments. The mechanisms underlying cannabinoid‐based drugs effects are not fully known but given the neuro‐modulatory functions of the endocannabinoid system, it seems likely that agonistic activity at the cannabinoid type‐1 receptors (CB1) might modulate the functions of other neurotransmitter systems. The present review has summarized the currently available pre‐clinical and clinical data on the interactions of CB1 and cannabinoid type‐2 receptors (CB2) with the central neurotransmitters; dopamine, serotonin, noradrenaline, GABA, glutamate and opioids. Acute and chronic exposures to cannabinoids exert pharmacological alterations in the mammalian brain that have profound implications for our understanding of the neuropharmacology of cannabinoid‐based drugs and their effects on mental health and the brain. A recent emergence uses of cannabis for medical purpose together with legalization and decriminalization of cannabis and increasing use of highly potent synthetic cannabinoids raise a growing concern over the effects of cannabinoids and their interaction with other neurotransmitters on physical and mental health. This article is protected by copyright. All rights reserved.