RECENT

ADVANCES IN
SUBSTANCE
USE
DISORDER
SACHIN BALIGA

JUNIOR RESIDENT

DEPARTMENT OF PSYCHIATRY

TNMC AND BYL NAIR CH HOSPITAL

DSM-5 : GENERAL CHANGES

DSM-5 does not separate the diagnoses of substance abuse and dependence
as in DSM-IV. Rather, criteria are provided for substance use disorder.
The DSM-IV recurrent legal problems criterion for substance abuse has
been deleted from DSM-5, and a new criterion, craving or a strong desire or
urge to use a substance, has been added.
The threshold for substance use disorder diagnosis in DSM-5 is set at two or
more criteria, in contrast to a threshold of one or more criteria for a
diagnosis of DSM-IV substance abuse and three or more for DSM-IV
substance dependence.
Severity of the DSM-5 substance use disorders is based on the number of
criteria endorsed: 23 criteria indicate a mild disorder; 45 criteria, a
moderate disorder; and 6 or more, a severe disorder.

Early remission from a DSM-5 substance use disorder is defined as at

least 3 but less than 12 months without substance use disorder
criteria (except craving), and sustained remission is defined as at
least 12 months without criteria (except craving).

Additional new DSM-5 specifiers include in a controlled

environment and on maintenance therapy

ALCOHOL

SEROTONERGIC SYSTEM AND

ALCOHOLISM
Serotonergic system known to mediate alcohol related
reward behaviour. Raphe nucleus connections to
dopaminergic system.

5-HTT is responsible for removing 5-HT from the synaptic

cleft.

SLC6A4 is located on chromosome 17q, the only known

gene encoding the 5-HTT in the human genome.

Functional polymorphism of SLC6A4, leading to three bialleles. s (short allele) has lower transcriptional activity)
compared to l (long)

L allele has been associated with low response to alcohol.

Early onset of AUDs, earlier age of first drink, higher rates
of AUD, a heavier drinking pattern, and higher alcohol
craving.

S allele has been associated with depression/anxiety in

response to negative events in life. More frequent and
heavier drinking in college students.

SEROTONERGIC SYSTEM AND

ALCOHOLISM
Ondansetron

5HT3 antagonist used in CINV.

Effective in cases of alcohol dependence in some clinical

trials and plays a promising role in early -onset alcohol
dependence.

A recent study revealed that Ondansetron is effective in

reducing the number of drinks in patients of alcohol
dependence possessing LL genotype.

SSRIs

Maybe useful as treatment for late-onset alcoholics, or

alcoholism complicated by comorbid major depression.

ALCOHOL RECENT ADVANCES

Dexmedetomidine

Centrally acting 2-adrenergic agonist. Given as an iv infusion.

Sedative and analgesic without risk of respiratory depression.

FDA approved in 2009 for sedation in ICU settings.

Recently found to be effective in the management of delirium

tremens where BZD -related oversedation is a concern, particularly
in elderly patients.

Nalmefene
Opioid antagonist with several potential advantages over naltrexone
including absence of dose-dependent liver toxicity, longer acting effects
and more effective affinity to central opiate receptors.
RCTs report a reduction of heavy drinking during nalmefene treatment.

Given in dose of 20 80mg/day. Lower doses better.

FDA approved in 2013.

CANNABIS

NEW GENERATION CANNABINOIDS

1.

Synthetic cannabinoids (SCBs)

o.

First synthesized in 1960s for study purposes.

o.

Spice, K2, herbal incense, Cloud9, Mojo

o.

Cheaper than marijuana and undetectable in routine drug

screens.

o.

Spice drugs or Legal highs plants such as indian warrior laced

with these substances are sold on internet hence thought to be
natural.

o.

nausea, anxiety, agitation/panic attacks, tachycardia, paranoid

ideation, and hallucinations

o.

almost nothing is known in terms of pharmacology, toxicology, and

safety.

NEW GENERATION CANNABINOIDS

Plant material (Indian warrior)

used as a carrier for synthetic
cannabinoids.

Commercial product with

synthetic marijuana.

Mills et al synthetic cannabinoids : a review

CANNABIS WITHDRAWAL
SYNDROME (CWS)
DSM-5 criteria for cannabis withdrawal:
Cessation

of cannabis use that has been heavy and prolonged (ie, usually
daily or almost daily use over a period of at least a few months).
Three or more of the following signs and symptoms develop within
approximately
1 week after cessation of heavy, prolonged use:
1. Irritability, anger or aggression
2. Nervousness or anxiety
3. Sleep difficulty (ie., insomnia, disturbing dreams)
4. Decreased appetite or weight loss
5. Restlessness
6. Depressed mood
7. At least one of the following physical symptoms causing significant
discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, or
headache
.
The signs or symptoms cause clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
.
The signs or symptoms are not attributable to another medical condition
and are not better explained by another mental disorder, including
intoxication or withdrawal from another substance.

CANNABIS AND PSYCHIATRIC

DISORDERSAS OF NOW:

Association of cannabis and SCZ has remained significant, though the

strength of association decreased.

Risk of psychosis increases by 2 times following exposure to cannabis as

young age. The age of onset of psychosis is about 2.7 years earlier in the
cannabis user as compared to alcohol user.

Long-term heavy cannabis asso with:

1.

reduced hippocampal and amygdala volume.

2.

smaller cerebellar white matter.

3.

Smaller thalamic volume.

Findings analogous to those found in SCZ. However these are nonspecific

and are also found other substance use disorders/psychiatric disorders
other than SCZ.

There is some evidence alluding to the disruption of the eCB system by

exogenous cannabis resulting into excess dopaminergic transmission in
the meso-limbic tract. The same eCB disruption by heavy cannabis use has
also been implicated in the altered neurogenesis, neuroplasticity,
maturation, migration, glia formation. Leads to disordered
neurodevelopment akin to SCZ.

However, causal association still not established.

CANNABIS AND PSYCHIATRIC

DISORDERSAS OF NOW:

Association between MDD and cannabis has been substantiated in

longitudinal studies.

Early cannabis use in the teens is also associated with increased

suicidal ideation and attempts in the early adulthood.

However, both adolescent exposure and the continued use during

adulthood are required for these associations suggesting that the
disease may be mitigated with cannabis cessation.

Ghosh et al Cannabis and psychopathology: The meandering journey of the last

decade

CANNABIS AND COGNITIVE

IMPAIRMENT

Acute effect: on attention, short-term memory, particularly immediate

memory and recall and retrieval following a lapse of time.

Chronic effect: on prospective memory and executive functions. Mediated

by early age of initiation and prolonged use.

Reversible?
Some studies have reported complete recovery of impairments even after
4 weeks of abstinence, whereas other studies describe persisting cognitive
deficits in attention, memory, and executive function. Meta analysis
suggests partial recovery with residual impairment in verbal memory.

Ghosh et al Cannabis and psychopathology: The meandering journey of the last decade

MANAGEMENT OF CANNABIS
WITHDRAWAL
1. Sativex (nabiximols)

Oromucosal spray

Contains THC + Cannabidiol

Initially developed for treatment of neuropathic

pain and MS

6 day regimen as CRT found to significantly reduced the overall severity of

cannabis withdrawal, including effects on withdrawal-related irritability,
depression, and cannabis cravings.

Limited, but still positive, therapeutic benefit on sleep disturbance,

anxiety, appetite loss, physical symptoms, and restlessness

Allsop et al Cannabinoid replacement therapy (CRT): Nabiximols (Sativex) as a novel treatment for
cannabis withdrawal.

MANAGEMENT OF CANNABIS
WITHDRAWAL

Anandamide deactivation inhibitors - FAAH (fatty-acid amide

hydrolase) inhibitors.

URB597

Prevents breakdown of endocannabinoids, preclinical studies : oppose the

anhedonic effects of stress and promotes normal positive responses to
pleasurable stimuli in rodents.

Might offer benefits in the treatment of acute cannabis withdrawal by

enhancing brain endocannabinoid activity.

CANNABIDIOL (CBD)

Endocannabinoids anandamide. Relation of CSF levels to psychosis.

How 9THC acts CB1 and 2 receptors a caricature of normal

action and alters entire brain in long-term use

Cannabidiol (CBD) upto 40% levels in marijuana extract

DOES NOT activate cannabinoid receptors, but moderately inhibits

the degradation of the endocannabinoid anandamide.

Facilitate neurogenesis. Anxiolytic, antidepressant, antipsychotic.

CBD significantly reduced psychotic symptoms in acute schizophrenia

with potency similar to Amisulpride but with fewer side effects such
as extrapyramidal symptoms, increase in prolactin, and weight gain.

CAFFIENE

DSM-V CRITERIA FOR CAFFEINE

WITHDRAWAL

A. Prolonged daily use of caffeine.

B. Abrupt cessation of caffeine use, or reduction in the amount of caffeine

used, followed within 24 hours by 3 or more of the following symptoms:
(1) Headache

(2) Marked fatigue or drowsiness

(3) Dysphoric mood, depressed mood, or irritability
(4) Difficulty concentrating
(5) Flu-like somatic symptoms, nausea, vomiting, or muscle pain/stiffness

C. The symptoms in criterion B cause clinically significant distress or

impairment in social, occupational, or other important areas of
functioning.

D. The symptoms are not due to the direct physiologic effects of a

general medical condition (eg, migraine, viral illness) and are not better
accounted for by another mental disorder.

TOBACCO

TOBACCO
o

NRT 1st line therapy. Gum, lozenges, oral strips, spray, inhaler,
patches (16- or 24-hour release) and sublingual tablets all have
comparable efficacy.

Combinations of NRT may be more effective than using a single

formulation eg. a transdermal nicotine patch along with a nicotine
inhaler/gum to supplement blood nicotine concentrations at times of
particular craving or risk of relapse.

NRTs increase the rate of quitting by 5070% regardless of the

setting or the intensity of additional support provided to the
individual. Also helps in reducing the habit size of nicotine use
among smokers not willing to quit.

NRT used in pregnancy for smoking cessation increases smoking

cessation rates measured in late pregnancy by approximately 40%.
There is no evidence that NRT used for smoking cessation in
pregnancy has either positive or negative impacts on birth
outcomes.

PHARMACOTHERAPY
o

Varenicline 1st line drug therapy. Partial agonist at 4 2nicotinic AchR. Should be started before patient stops smoking. 80%
more effective than bupropion.

Partial agonist. Hence alleviates symptoms of withdrawal.

Binds competitively, reducing ability of nicotine to bind. Hence less

dopamine release - makes smoking less rewarding.

Dosing: Day 1 3: 0.5mg OD

Day 4 7: 0.5mg BD
Day 8 end of week 12: 1.0 mg BD
Pts advised quit date between day 8 -14. Max upto day 35.

Need for further trials of the efficacy of varenicline treatment

extended beyond 12 weeks. Suicidal behaviour x 2014 review.

A systematic review and meta analysis of RCTs reported that

Combination therapy of varenicline with NRT is better than
varenicline alone. Behavioural therapy such as in-person advice
along with pharmacotherapy superior to pharmacotherapy alone.

PHARMACOTHERAPY
o

Cytisine is a naturally occurring alkaloid

4 2 nicotinic receptor partial agonist isolated from Cytisus
laburnum (Golden Rain acacia). More effective, less side effects as
well as more cost effective than varenicline.

Bupropion 2nd line drug therapy.

NDRI

Near double rate of smoking cessation compared to placebos

without NRT.

Reduces severity of withdrawal and urge to smoke.

Started 1 2 weeks before quit date at 150mg OD for 6 days. Then

150mg BD for max 7 to 9 weeks.

E-CIGARETTES

Electronic cigarette aka ENDS (Electronic Nicotine Delivery System)

Typically hand-held, battery-operated devices that deliver vaporised

liquid (e-juice) containing flavourings, nicotine, propylene glycol,
glycerol.

The vapour is inhaled by the user in a fashion similar to smoking but

without inhaling tobacco tar and carbon monoxide. The process of
inhaling these vapours is referred to as vaping.

Recent evidence including a Cochrane review suggests these devices

may help some people quit smoking. However they have not been
shown to be more effective than current smoking cessation drugs.

Limited safety data. Long-term health exposure to propylene glycol not

yet studied, but it is known that when propylene glycol heated to high
temperatures, toxic compounds such as formaldehyde and
acetaldehyde are formed concerns of pulmonary damage.

OPIOIDS

ADVANCES IN OPIOID DEADDICTION

Retention in treatment is considered to be a highly important

measure of the clinical feasibility of any treatment for heroin
addiction.

Low rates of treatment-seeking, poor adherence to treatment,

frequent relapse with oral naltrexone.

Extended release Naltrexone (XR-NTX)

1. Injections:

Based on the slow biodegrading of a 380mg polylactide and

naltrexone suspension, providing therapeutic blood levels of
naltrexone over a period of 28 days. According to challenge tests
done, 3mg of hydromorphone was blocked by the 300mg
formulation for 28 days.
2. Surgically implanted capsules:

Pellets with biodegradable solid polymer surgically inserted or

implanted under the skin or fatty tissue with the use of local
anaesthetic. The wound is then sealed with one to three sutures.
Max release period of 7 months when 30 pellets were used.

Feasible, safe, and effective option for assisting abstinence efforts.

OTHERS ROLE OF OXYTOCIN

Party drugs MDMA (ecstacy), GHB (fantasy), Mephedrone cause

strong release of oxytocin from SON and PVN.

Cause prosocial effects - strong feelings of love and closeness

towards other people, increased trust, and greater openness to the
views and feelings of others.

Repeated exposure to substances of abuse like cocaine, opiates,

alcohol, cannabis, MDMA and GHB cause long-term social deficits
and neuroadaptations in various markers of oxytocin function.
Changes seen are consistent with a loss of oxytocinergic function.
(decreased OT neurons in SON and VTA)

Exogenous oxytocin administration found to prevent development of

tolerance to alcohol and opiates, the induction of stereotyped,
hyperactive behavior by stimulants, and the withdrawal symptoms
associated with sudden abstinence from drugs and alcohol.

Potential to reverse the corrosive effects of long-term drugs abuse

on social behavior and to perhaps inoculate against future
vulnerability to addictive disorders.

ADDICTION IMMUNOTHERAPY

Structurally these vaccines are abused drug related

micromolecular compounds, haptens linked to a large
immunogenic carrier protein, which results in the generation of an
antigen-specific, IgG-mediated antibody response upon introduction
of the drug in future. First attempt in 70s.

TA-CD vaccine for cocaine Peak levels require 5 shots, then booster
every 3 months.

ADDICTION IMMUNOTHERAPY

Current research in addiction immunotherapy is focused on

developing vaccines or antibodies for managing dependence on
other addictive agents such as cocaine, nicotine (TA-NIC, NIC-VAX),
opioids, and methamphetamine.

Clinical trials of cocaine and nicotine vaccines have so far reported

modest efficacy.

Enhancing the proportion of responders and the magnitude of

antibody responses will be critical for achieving broad utility.

THANK YOU