1. Gilberto Gerra Chief Drug Prevention and Health Branch UNODC
Re-conceptualizing the Aetiology of Substance Use Disorders: Implications for Prevention and Treatment
Gilberto Gerra
Chief
Drug Prevention and Health Branch
UNODC

2. Unaffected siblings carried the risk… Did not develop the disorder…
Acta Psychiatr Scand.
Alpha-1- and 2-adrenoceptor sub-sensitivity in siblings
of opioid addicts with personality disorders and depression.
Gerra et al., 1994
1997
Unaffected siblings carried the risk…
Did not develop the disorder…
Same family, same school…
The mystery of different trajectories

3. Denial
Moralism
Ignorance
Good boy
Bad boy

5. Run, do not walk!

6. Monitoring the Future, 2016 A minority experimenting with drugs
8 Graders
10 Graders
12 Graders
Cannabis lifetime
12.8
29.7
44.5
Cannabis past year
9.4
23.9
35.6

7. 20-40 %

8. Individual vulnerability underlying drug initiation and alcohol abuseNo
mental health
disorders/SUD
No drug availability
Low peer pressure
Bonding
to family and school
Early childhood wellbeing,
care social inclusion
Parent child
secure
attachment
Gene variants,
positive
temperament
Pregnancy:
mother wellbeing
Individual vulnerability underlying
drug initiation and alcohol abuse
Pregnancy:
mother stress
Gene variants,
problematic
temperament
Parent child
insecure
attachment
Early childhood adversity,
stress neglect abuse
trauma social exclusion
Lack of bonding
to family and school
Early onset
mental health
disorders/SUD
Drug availability
peer pressure

9. Prenatal stress as a candidate to explain SUD vulnerability
Neurotox Res.
Unravelling the Link Between Prenatal Stress, Dopamine and Substance Use Disorder.
Pastor et al., 2017
The development of the
mesocorticolimbic
dopaminergic
system is disrupted
by prenatal stress.
Prenatal stress
as a candidate
to explain SUD
vulnerability
Prenatal stress induces
behavioral abnormalities
that are similar to those
observed in individuals
with Substance Use Disorders

10. Inherited vulnerability
Genotypes and alleles at risk
Affecting neurotransmission
Modulating temperament/
Behavioural attitude
Externalizing behaviour
reward sensitivity/deficit,
novelty seeking,
impulsivity/inhibitory control
Internalizing behaviour
depressive anxious attitude
Egervari et al., 2017

11. D2 Receptors expression Taq IA A1 allele: reward deficit, SUD
Dopamine transporter (DAT) gene: reward deficit, aggressiveness
P-ENK gene (striato-pallidal neurons): neuroticism, anxiety, cannabis use
Pro-dynorphine gene: novelty seeking, alcohol intake
5-HTT gene: impulsiveness, aggressiveness, antisocial personality, cannabis, cocaine
GABA Receptor: anxiety, reward perception, inhibitory control
OPR-M1: extraversion, openness, SUD

12. Hypo-dopaminergic functioning predicted drug use in males.
J Subst Abuse Treat.
Genetic, personality, and environmental predictors of drug use in adolescents.
Conner et al., 2010
Hypo-dopaminergic functioning
predicted drug use in males.
A deleterious environment
was the salient predictor in females.

13. irritable babies develop an anxious attachment
Psychiatr Enfant.
The development of attachment according to the temperament of the newborn
Balleyguier, 1991
Infant Behav Dev.
Infant and parent factors associated with early maternal sensitivity:
a caregiver-attachment systems approach.
Mills-Koonce et al., 2007
irritable babies develop
an anxious attachment
avoidant children reduce
maternal sensitivity
temperament at birth
influences mother's attitude

14. through epigenetic changes Adverse Childhood Experiences
(ACEs) may aggravate the situation…
Physical/sexual abuse
Physical neglect
Emotional abuse
Emotional neglect
Household dysfunction
through
epigenetic changes

15. stress drugs early and adult stressful life events
Mol Neurobiol.
Epigenetics of Stress, Addiction, and Resilience: Therapeutic Implications.
Cadet, 2016
Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research
Program, National Institutes of Health
early and adult stressful life events
are risks factors for the development of addiction
and serve as cues that trigger relapses
stress
drugs

16. Epigenetic mechanisms in vulnerability
Profiling of childhood adversity-associated DNA methylation changes
in alcoholic patients and healthy controls.
Childhood adversities could induce
methylation alterations
in the promoter regions
of specific genes and
changes in gene transcription
with increased
risk for substance use disorders
(Zhang et al., 2013)

17. the association was greatly reduced by involved-supportive parenting
J Consult Clin Psychol. 77(1):1-11.
Parenting moderates a genetic vulnerability factor in longitudinal increases
in youths' substance use. Brody et al., 2009
5-HTTLPR status SS
linked with increases
in substance use
over time
the association was greatly
reduced by involved-supportive parenting

18. - Am. J. Med Genet Part B
Perceived Parenting Behaviour in the Childhood of Cocaine Users:
Relationship With Genotype and Personality Traits. Gerra et al., 2007
- Am J Med Genet Part B Relevance of perceived childhood neglect, 5-HTT gene variants and hypothalamus-pituitary-adrenal axis dysregulation to substance abuse susceptibility. Gerra et al., 2010
Substance
initiation
HPA Axis
dysfunction
Mother Father
Neglect
CECA-Q
Serotonin
Transporter
Gene
S- allele

19. Lancet Psychiatry.
Early life adversity, genomic plasticity, and psychopathology.
Turecki et al., 2014

20. genotype may sometimes influence epigenetic outcomes
Dev Psychopathol.
Exploring genetic moderators and epigenetic mediators
of contextual and family effects: From Gene × Environment
to epigenetics.
Beach et al., 2016
the association between family context
and mental and physical health outcomes
early environments may influence epigenetic
motifs that potentially serve as mediators
of long-term effects of early family and
community environments
genotype may sometimes influence
epigenetic outcomes

21. 9.0% 4 or more ACEs in the general population
National household survey of adverse childhood experiences and their relationship with resilience to health-harming behaviours in England
Bellis et al., 2014
58.7 % of heroin crack cocaine use could be attributed to ACEs
ACEs and health-harming behaviours
both associated to social deprivation/poverty
9.0% or more ACEs in the general population
4.3% or more ACEs among the most affluent
12.7% or more ACEs among the most deprived

22. in socially deprived regions were found to carry
Addict Biol.
Polygenic risk for alcohol dependence associates with alcohol consumption,
cognitive function and social deprivation in a population-based cohort.
Clarke et al., 2015
Individuals living
in socially deprived regions
were found to carry
more alcohol dependence
risk alleles which may
contribute to the
increased prevalence
of problem drinking.

23. Poverty and stress during childhood:
- hyperactive amygdala (emotions store)
- hypoactive prefrontal cortex (behavioural regulation)
Luan Phan et al., 2013

24. Blair, C. (2010), Stress and the Development of Self-Regulation.
Child Development Perspectives
early stress in the context of poverty
affects the functioning of neural networks
that underlie executive functions
and self-regulation

25. Pharmacogenetic factors and individual history
Schizophr Bull.
Gene-environment interplay between cannabis and psychosis.
Henquet et al., 2008

26. Dialogues Clin Neurosci.
Early life adversity and the epigenetic programming
of hypothalamic-pituitary-adrenal function.
Anacker et al., 2014
Epigenetic mechanisms,
affecting the expression
of genes implicated in stress
responses.
Social adversity
involving parent-offspring
interactions alters
the expression of
a wide range of genes
regulating HPA axis function.

27. unique susceptibility to using drugs initially, sustaining drug use,
genetic factors,
environmental,
social factors
contribute to
the determination
of a person’s
unique susceptibility
to using drugs initially,
sustaining drug use,
undergoing the progressive
changes in the brain
that characterize addiction
Volkow et al., 2016

28. - Parents
unemployed
low level of
education
- Adolescents
depression

29. - Parents
unemployed
low level of
education
- Adolescents
depression

30. Drug availability
Peer pressure
PFC dysfunction
HPA axis dysfunction
Drug use
Reward deficit
Novelty seeking
Impulsivity
Anxious/depressive
Gene variants at risk
Epigenetic changes:
altered genes expression
Child problematic
temperament/
behavioural attitude
Stress/frustration
Parents problematic
temperament
Social deprivation
Parents reaction
Adverse childhood
experiences
Insecure attachment
No bonding
to family and school