Psychoactive Sustances 2021

Tox i c o l o g y o f P s y c h o a c t i v e
Substances
Lara Prisco, MD, MSc, AFRCA, AFFICMa,b,*, Aarti Sarwal, MD, FNCS, FCCM
c
,
Mario Ganau, MD, PhD, MBA, FRCS(Ed), FEBNSd,
Francesca Rubulotta, MD, PhD, MBA, FRCA, FFICMe,f
KEYWORDS
Psychoactive substances Antidepressants Selective serotonin reuptake inhibitors
antipsychotics Mood stabilizers Hallucinogens
KEY POINTS
Monitoring agencies have reported a significant increase in the introduction, production,
and nonmedical use of new psychoactive substances paralleled by increasing use of long-
time available psychoactive drugs (PADs) from licit channels as well as illegal
manufacturers.
With increasing antidepressant and antipsychotic use, intensive care providers need to be
cognizant of cardiac and neurologic toxicity of these drugs and be able to differentiate the
anticholinergic syndrome, serotonin syndrome, tyramine crisis, and neuroleptic malignant
syndrome.
A high index of suspicion with careful attention to history taking is emphasized, given
emerging synthetic cannabinoids and new psychoactive substances that may not be de-
tected on conventional drug screens. Mixed ingestions are not infrequent.
Reducing exposure and supportive care are the cornerstones of management of toxic in-
gestions of most PADs. Benzodiazepines are the drug of choice for delirium and seizures
related to most PADs.
Extracorporeal treatments (hemodialysis and hemoperfusion) are possible options for hy-
perammonemia associated with valproic acid toxicity and lithium poisoning.
a
Neurosciences Intensive Care Unit, Oxford University Hospitals NHS Foundation Trust, John
Radcliffe Hospital, Level 1 West Wing, Headley Way, Oxford OX3 9DU, UK; b Nuffield
Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Level 6
West Wing, Headley Way, Oxford OX3 9DU, UK; c Neurocritical Care Unit, Wake Forest Baptist
Medical Center, Medical Center Boulevard, Winston Salem, NC 27157, USA; d Neurosciences
Department, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Level 2
West Wing, Headley Way, Oxford OX3 9DU, UK; e Critical Care Program Department of
Anesthesia, McGill University, 845 Sherbrooke St W, Montreal, Quebec H3A 0G4, Canada;
f
Department of Anesthesiology and Intensive Care Medicine, Health Centre, Intensive Care
Unit, Imperial College NHS Trust, Charing Cross Hospital, Fulham Palace Road, London W6
8RF, UK
* Corresponding author. Neurosciences Intensive Care Unit, Oxford University Hospitals NHS
Foundation Trust, John Radcliffe Hospital, Level 1 West Wing, Headley Way, Oxford OX3
9DU, UK.
E-mail address: Lara.prisco@ouh.nhs.uk
Crit Care Clin 37 (2021) 517–541

https://doi.org/10.1016/j.ccc.2021.03.013 criticalcare.theclinics.com
0749-0704/21/ª 2021 Elsevier Inc. All rights reserved.
Descargado para Anonymous User (n/a) en University of the Rosary de ClinicalKey.es por Elsevier en julio 14, 2021. Para uso personal
exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados.
518 Prisco et al
Table 1
Neurotransmitter pathways, major systemic effects, and interfering substances (mimics and
blockers)
Neurotransmitter Effects Substances

Norepinephrine [ Heart rate Mimics: amphetamines, cocaine,
[ Euphoria TCAs, SNRIs, MAOIs, LSD,
[ Alertness and responsiveness pseudoephedrine, pyridostigmine
[ Pain threshold Blockers: propranolol, clonidine,
phentolamine, lithium
Dopamine [ Euphoria Mimics: amphetamines, cocaine,
[ Alertness and responsiveness MAOIs, ergolines
Y Hunger Blockers: antipsychotics,
tetrabenazine, lithium
Serotonin (5-HT) [ Euphoria Mimics: amphetamines, cocaine,
[ Happiness LSD, psychedelics, SSRIs, SNRIs,
[ Pain threshold TCAs, MAOIs, lithium
Blockers: AAs, ondansetron
Acetylcholine Y Heart rate Mimics: nicotine, muscarine,
[ Sweat, salivation physostigmine, pilocarpine
[ Enhanced memory Blockers: benzodiazepines,
[ Muscle tone/contraction scopolamine, benztropine,
TCAs, AAs
Glutamate [ Enhanced learning and Mimics: none
memory Blockers: phencyclidine,
[ Diffuse neuronal ketamine, dextromethorphan,
depolarization (seizures)
g-aminobutyric [ Drowsiness Mimics: alcohol, barbiturates,
acid Y Anxiety benzodiazepines, GHB, muscimol,
Y Alertness and responsiveness lithium
Y Memory Blocker: flumazenil
Y Muscle tone/contraction
Cannabinoids [ Hunger Mimics: tetrahydrocannabinol
Y Nausea and vomiting (marijuana, hashish), nabilone
Y Cognition and memory Blocker: rimonabant
Y Neuroinflammation
[ Pain threshold
Histamine [ Alertness and responsiveness Mimics: opiates, betahistine
[ Gastric acid production Blockers: TCAs, AAs, ranitidine
[ Pruritis
Y Hunger
INTRODUCTION
Health care providers increasingly need to be aware of toxic effects of prescribed and
illicit psychoactive drugs (PADs).1–4 This article reviews the epidemiology, pharma-
cology, adverse effects, and management of toxicity related to PADs. The neurotrans-
mitter pathways, major systemic effects, and interfering substances (mimics and
blockers) for the known licit and illicit PADs are listed in Table 1.
EPIDEMIOLOGY OF PSYCHOACTIVE SUBSTANCES
Although typically seen as a disease of the young, the proportion of older adults using
PADs and seeking treatment of a PAD-related condition is increasing.5 Data on
gender-based differences in the use of PADs support an increasing prevalence of
Psychoactive Substances 519
use in women of all ages, and women seem to be the fastest growing population of
substance abusers in the United States.6–9 Women are more likely to seek treatment
of misuse of central nervous system (CNS) depressants.10,11 Young people in high-
income countries tend to use club drugs, such as ecstasy, methamphetamine,
cocaine, ketamine, lysergic acid diethylamide (LSD), and g-hydroxybutyrate (GHB),
for recreational experiences, whereas those living in poverty tend to choose PADs
for their low price, availability, and ability to rapidly induce a sense of euphoria,
such as inhalants (eg, paint thinner, gasoline, paint, correction fluid, and glue).12
ANTIDEPRESSANTS
Antidepressants were the drugs prescribed most frequently to young patients (18–
44 years) between 2005 and 2008 in the United States and were the third most pre-
scribed drugs among patients of all ages.13 The American Association of Poison Con-
trol Centers reported antidepressants to be among the top 5 substances involved in
human exposures in 2019, with a 3.9% increase per year in cases with serious out-
comes over the past 10 years.14
Tricyclic Antidepressants
Pharmacology and use
Newer antidepressants have replaced tricyclic antidepressants (TCAs) in manage-
ment of depression, limiting their use to treatment of depression refractory to newer
agents. Despite this, there is an increase in TCA overdose–associated hospitalization
and lethality, predominantly in patients with chronic pain and neuropsychiatric disor-
ders, because of the narrow therapeutic index.15 The pharmacology of TCAs is shown
in Table 2.16,17
Toxicity
TCA intoxication can be rapidly fatal, with life-threatening dysrhythmias and death
occurring within 24 hours of ingestion. The rapid absorption in the gastrointestinal (GI)
tract is promoted by alkaline conditions of the small intestine. The ingestion of 10 mg/
kg to 20 mg/kg is potentially life-threatening with onset of initial symptoms in 30 minutes
to 40 minutes and signs of toxicity becoming clinically apparent within 2 hours.18 History
of coingestion with other medications like acetaminophen, aspirin, and alcohol is
frequent and may confound the clinical presentation. Mixed overdose causing delayed
gastric emptying may delay onset of symptoms. Initial signs and symptoms are attribut-
able to the anticholinergic effects of TCAs: dry mouth, blurred vision, urinary retention,
constipation, decreased or absent bowel sounds, dizziness, and vomiting. Plasma con-
centrations of TCAs greater than 450 ng/mL can lead to agitation, confusion, memory
impairment, and anxiety. Toxicity and death are reported at plasma levels of 2000 ng/
mL to 3000 ng/mL with most TCAs; dothiepin levels as low as 1000 ng/mL can be
fatal.19 The most severe cases may present with CNS depression with reduced level
of consciousness, hypoventilation, coma, and seizures.20 Cardiac effects include con-
duction abnormalities with prolonged QRS, QT, and PR intervals that can lead to ven-
tricular tachycardia, torsades de pointes, and ventricular fibrillation. Hypotension
results from a combination of reduced myocardial contractility and reduced systemic
vascular resistance due to a-adrenergic blockade.21 TCA toxicity is worsened by acid-
emia, hypotension, hypoxia, and hyperthermia.
Management
Treatment of TCA overdose depends on the severity of symptoms. It is important to
assess for evidence of anticholinergic syndrome (Table 3), cardiac toxicity, and
520
Prisco et al
Table 2
Antidepressant drugs
Class Drugs Mechanism of Action Medical Use Pharmacology

TCAs Dibenzazepines (imipramine, Norepinephrine reuptake Depressive disorder (refractory to Time to onset of signs of toxicity:
desipramine, clomipramine, inhibitors SSRI, SNRI, MAOI), migraine 30–40 min for initial symptoms;
trimipramine, lofepramine), Serotonin reuptake prophylaxis, neuralgic pain, signs of toxicity clinically
dibenzocycloheptadienes inhibitors obsessive-compulsive disorder, apparent within 2 h
(amitriptyline, nortriptyline, Acetylcholine receptor nocturnal enuresis (children Half-life: average elimination t1/2
protriptyline, butriptyline), antagonist (muscarinic) only) w1 d (up to 3 d for protriptyline)
dibenzoxepins (doxepin), H1 histamine receptor Metabolism: substantial
dibenzothiepines (dosulepin), antagonists presystemic first-pass
dibenzoxazepines (amoxapine) metabolism, large volume of
distribution, extensive protein
binding, metabolized by hepatic
cytochrome P450 oxidative
enzymes
MAOIs Isocarboxazid, phenelzine, MAOIs Panic disorder with agoraphobia, Time to onset of signs of toxicity:
tranylcypromine, selegiline depression or anxiety disorders, symptoms slowly apparent
bulimia, posttraumatic stress within first 24–48 h
disorder, borderline personality Half-life: irreversible MAOIs are
disorder, obsessive-compulsive rapidly absorbed and quickly
disorder, bipolar depression, eliminated, with plasma
Parkinson disease (selegiline), elimination t1/2 1.5–4 h
migraine prophylaxis, dysthymia Metabolism: because of
complicated by panic disorder or irreversible inhibition of MAO,
hysterical dysphoria the physiologic effects of
phenelzine, isocarboxazid, and
tranylcypromine persist for up
to 2–3 wk
SSRI Citalopram, escitalopram, Serotonin reuptake Depression, panic attacks and Time to onset of signs of toxicity:
fluvoxamine, paroxetine, inhibitors panic disorders, anxiety, 1–2 wk

sertraline agoraphobia Half-life: elimination half-life is
approximately 24 h
Metabolism: good oral
absorption, highly protein
bound, large volume of
distribution (12–97 L/kg),
hepatic metabolism to water
soluble and less active
metabolites
SNRI Atomoxetine, duloxetine, Norepinephrine reuptake Generalized anxiety disorders, Time to onset of signs of toxicity:
venlafaxine, desvenlafaxine inhibitors social anxiety disorder, panic 3–6 wk
Serotonin reuptake disorder, agoraphobia Half-life: 5–11 h (depending on
inhibitors metabolites half-life)
Metabolism: good oral
absorption, large volume of
distribution, metabolites might
need long time to eliminate
Psychoactive Substances
521
522 Prisco et al
neurologic toxicity to guide proper management while addressing immediate resusci-

tation needs.22 Activated charcoal adsorbs the drug in the GI tract and, therefore, is
most effective if given within 1 hour to 2 hours of TCA ingestion. Other decontamina-
tion methods (gastric lavage, whole-bowel irrigation, or ipecac-induced emesis) are
not recommended.
TCAs are protein-bound and become free in acidic conditions. Increasing arterial or
venous pH to greater than or equal to 7.45 significantly reduces available free drug and
may ameliorate toxicity. An intravenous sodium bicarbonate (SB) bolus of 1 mEq/kg to
2 mEq/kg followed by infusion using 150 mEq/L diluted in a 5% dextrose solution
titrated to blood pH and QRS is recommended in cases of metabolic acidosis along
with mild hyperventilation until the QRS falls below 100 milliseconds. The sodium
load in SB solutions also helps reverse the sodium channel blocking effects of TCAs
and is the treatment of choice to prevent seizures and dysrhythmias. SB should be
given in all cases of metabolic acidosis, QRS prolongation (even in the absence of
metabolic acidosis), malignant dysrhythmias, hypotension, and cardiac arrest due
to TCAs.23 Hypertonic saline or lipid emulsion can be used in patients not responding
to standard therapies.24
Continuous cardiac monitoring is essential in TCA overdose, and lidocaine may be
used for dysrhythmias if SB load fails with caution to avoid precipitating seizures.25
Magnesium has been recommended as well given its antiarrhythmic and antiepileptic
properties.26 Class 1a and class 1c agents should not be administered due to sodium
channel effects.
Benzodiazepines and propofol are treatments of choice for sedation and treatment
of seizures due to TCA -induced central g-aminobutyric acid (GABA)-A receptor inhi-
bition. Phenytoin should be avoided due to its sodium channel effect. Lacosamide is
avoided due to cardiac side effects.
Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake

Inhibitors, and Monoamine Oxidase Inhibitors
Pharmacology and use
Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake in-
hibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) are the major agents used
in outpatient treatment of depression.27 Antidepressant use increased from 10.6% to
13.8% between 2009 to 2010 and 2017 to 2018.28 During 2015% to 2018%, 13.2% of
adults in the United States used antidepressants in the past 30 days, with higher use in
women and older age groups, and more than 50,000 overdose cases were reported in
2016 with 102 fatalities.29 Clinical indications, mechanism of action, and pharma-
cology of SSRIs, SNRIs, and MAOIs are described in Table 2.
Toxicity
SSRIs are the first-line antidepressants prescribed most frequently due to decreased
toxicity compared with MAOIs and TCAs. The most common toxicity of SSRIs mani-
fests in autonomic instability leading in severe cases to serotonin syndrome (see
Table 3).30 Toxicity is enhanced when SSRIs are coingested with other drugs with
serotonergic effects. The prognosis generally is favorable, and long-term sequelae
rarely are observed in single-agent overdose.
Among the SSRIs, citalopram is associated with the greatest risk of cardiotoxicity
(QTc prolongation) and neurotoxicity (seizures); the most frequent symptoms of
toxicity are drowsiness, tachycardia, QTc prolongation, decreased level of conscious-
ness, coma, and seizures.31 Citalopram (>600 mg) and escitalopram (>300 mg) both
cause dose-dependent QT prolongation with high risk of torsades de pointes.32
Table 3
Comparison of the clinical features of serotonin syndrome, anticholinergic syndrome, neuroleptic malignant syndrome, and malignant hyperthermia
Neuroleptic Malignant
Condition Serotonin Syndrome Anticholinergic Syndrome Syndrome Malignant Hyperthermia
Exposure Serotonergics Anticholinergics Antipsychotics (dopamine Inhalational anesthetics,
(antidepressants, antagonists) and depolarizing muscle
fentanyl, tramadol, dopamine withdrawal blockers (succinylcholine)
linezolid, sumatriptan,
ondansetron)
Onset after exposure <12 h (25% of cases can <12 h 24–72 h 0.5–24 h
develop symptoms after
24 h)
Resolution after treatment Within 24 h Hours to days Up to 10 d 24–48 h
initiation
Temperature Hyperthermia (>41.1 C) Hyperthermia (<38.8 C) Hyperthermia (>41.1 C) Hyperthermia (up to 46 C)
Cardiorespiratory signs Hypertension, tachycardia, Hypertension (mild), Hypertension, tachycardia, Hypertension, tachycardia,
tachypnea tachycardia, tachypnea tachypnea tachypnea
Pupils Dilated Dilated Normal Normal
Neuromuscular signs Neuromuscular Normal muscle tone Neuromuscular Rigor mortis–like rigidity
hyperactivity, increased hypoactivity, diffuse
tone (lower rigidity (lead pipe–like),
limbs > upper limbs), bradykinesia
tremor, myoclonus
Reflexes Hyperreflexia, clonus Normal Bradyreflexia Hyporeflexia
Mental status Agitation, delirium, coma hypervigilance, agitation, Stupor, mutism, coma Agitation
delirium, hallucinations,
mumbling speech, coma
Mouth Sialorrhea Dry Sialorrhea Normal
Skin Sweaty Red, hot, dry Pale, sweaty Mottled, sweaty
GI signs Increased bowel sounds Decreased bowel sounds Normal or decreased bowel Decreased bowel sounds
sounds
523
524 Prisco et al
Most SNRIs are well tolerated in overdose and symptoms rarely are severe. Patients
may need intensive care unit (ICU) admission in cases of decreased level of con-
sciousness. Venlafaxine, in particular, is associated with increased reports of deaths,
dysrhythmias, and seizures compared with other SNRIs.33
MAOI toxicity presents as a syndrome of catecholamine excess followed by hypo-
tension, seizures, coma, and death.34 People taking MAOIs are instructed to avoid
excessive ingestion of foods and beverages containing tyramine (cheese, soy sauce,
and salami) due to potential of triggering a fatal hypertensive crisis. Use of MAOIs in
combination with SSRIs, TCAs, ecstasy, meperidine, tramadol, or dextromethorphan
can cause lethal reactions.
Management
The treatment of SSRI and SNRI intoxications is focused on supportive care, discon-
tinuation of all serotonergic agents, and continuous electrocardiogram (ECG) moni-
toring. Consensus-based guidelines have been developed to guide out-of-hospital
management of SSRI overdose.30,35 Patients with ingestions less than 5 times the
therapeutic dose can be monitored at home but patients with mixed overdoses or
ones involving greater than 5 times the therapeutic dose should be referred to the hos-
pital. Asymptomatic patients with a normal 12-lead ECG can be discharged after 6
hours to 12 hours of observation. Symptomatic patients with or without abnormal
ECG may need an additional 12 hours to 24 hours of monitoring. Several side effects
are transient but others may take a few weeks to resolve.
Benzodiazepines are the drugs of choice for management of seizures, agitation, and
muscle rigidity (diazepam or lorazepam, 0.1–0.2 mg/kg) associated with serotonin syn-
drome. Haloperidol and droperidol inhibit sweating and are contraindicated for agita-
tion. Severe toxicity may require aggressive support, including cooling, intubation,
ventilation, and neuromuscular paralysis.36 Muscle rigidity propagates hyperthermia,
and uncontrolled fever can trigger seizures and dehydration. Serotonin antagonists
like cyproheptadine or chlorpromazine for serotonin syndrome refractory to benzodiaz-
epines have minimal anecdotal evidence. Cyproheptadine, which is available only enter-
ally, is a first-generation antihistaminic with antiserotonergic effects and can be
considered for severe serotonin syndrome.35 Depolarizing muscle relaxants should be
avoided in patients with suspected rhabdomyolysis who need intubation and paralysis.
Short acting b-blockers can be used to treat hypertension and tachycardia but
should be avoided in cases of predominant MAOI overdose where unopposed a-adre-
noreceptor stimulation may exacerbate hypertension. Nitroglycerin and sodium nitro-
prusside are acceptable options for management of MAOI-related hypertension.
Patients who develop severe serotonin toxicity often require ICU admission.37 Pa-
tients with single-agent intoxication have a good prognosis and recover without com-
plications unless renal failure and refractory hypotension are present. Serotonin
syndromes involving MAOIs tend to produce the most severe and prolonged cases.
Other differential diagnoses to consider in cases without a clear-cut exposure to sero-
tonergic agents include neuroleptic malignant syndrome (NMS), malignant hyperther-
mia, anticholinergic toxicity, sympathomimetic toxicity, and infectious causes, such as
meningitis and encephalitis (see Table 3).
ANTIPSYCHOTICS
Pharmacology and Use
Antipsychotics or neuroleptic drugs are indicated in several neurologic and psychiatric
conditions (Table 4). Developed in the 1950s, this category accounts for approximately
30 currently available drugs with increasing use in younger age groups and decreasing
Table 4
Antipsychotics and mood stabilizers

Antipsychotics TAs Phenothiazines Dopamine receptor Prophylaxis of Time to onset: >1 wk (up to
(chlorpromazine, antagonists postoperative nausea 6 wk)
fluphenazine, and vomiting, Half-life: >100 h
perphenazine, schizophrenia, psychosis, Metabolism: high protein
thioridazine) Paranoid psychosis binding, hepatic
thioxanthenes metabolism and renal
(chlorprothixene) excretion
butyrophenones
(haloperidol)
diphenypbutylpiperidines
(pimozide)
Dihydroindolones
(molindone)
AAs Aripiprazole, clozapine, Acetylcholine receptor Schizophrenia, treatment Time to onset: < 1 wk
iloperidone, olanzapine, antagonist (muscarinic) of mania in bipolar Half-life: 7–12 h
paliperidone, quetiapine, Dopamine receptor disorder Metabolism: hepatic
risperidone, ziprasidone antagonists metabolism
77 Norepinephrine
reuptake inhibitor
(quetiapine)
Serotonin receptor
antagonists
H1 histamine receptor
antagonists
Mood stabilizers Anticonvulsants Carbamazepine, valproic Mechanisms of action are Epilepsy, neuropathic pain Time to onset: 4 h
acid, lamotrigine not completely (trigeminal neuralgia, Half-life: 12–30 h
elucidated peripheral neuropathy), Metabolism: hepatic
Sodium channel blocker resistant obsessive metabolism: some drugs
(lamotrigine) with disorders, migraine, are strong inducers of
suppression of glutamate cluster headaches, hepatic enzymes
and aspartate release affective disorders,
bipolar disorders,
schizophrenia,
borderline personality
disorders
525
(continued on next page)
526
Prisco et al
Table 4
(continued )
Mineral Lithium Decreases Bipolar disorders, Time to onset: 7–14 d
norepinephrine release depressive disorder Half-life: 18–36 h
Increases serotonin refractory to Metabolism: absorbed in
release antidepressants, the small intestine and
Interference with schizophrenic disorders renally excreted
dopamine signaling
Modulation of glutamate
levels
Increases levels of GABA
Inhibition of enzyme
inositol monophosphate
Interference with the
sodium-potassium pump
use in the elderly with dementia.38 The toxicity of these drugs is generally high and can
vary considerably although death from a pure neuroleptic ingestion is uncommon.39 An-
tipsychotics often are classified in 2 groups: typical antipsychotics (TAs), known as first-
generation drugs, and atypical antipsychotics (AAs) (see Table 4).
Toxicity
The most common side effects of antipsychotics include acute extrapyramidal symp-
toms, including dystonia, oculogyric crisis, torticollis, acute parkinsonism, akathisia,
and other movement disorders.40 AAs generally are preferred over TAs because of
less frequent extrapyramidal side effects, dyskinesia, and withdrawal but chronic
use of both AAs and TAs is associated with tardive dyskinesia, parkinsonism, and aka-
thisia. Additional adverse effects include anticholinergic symptoms similar to TCAs
(see Table 3), seizures, QT interval and QRS prolongation, orthostatic hypotension,
hypothermia, sedation, and respiratory depression.
Antipsychotics (TAs more frequently than AAs) also could lead to the development
of NMS, a life-threatening condition that affects multiple organ systems and results
in significant mortality (see Table 3).41 Patients may develop signs of serious toxicity
days after exposure with rigidity, fevers, possible dysrhythmias, status epilepticus,
autonomic instability, or coma and may present for intensive care management
despite no apparent antecedent exposure. Initiation of high-dose, high-potency an-
tipsychotics or a rapid increase in dose of previously well-tolerated doses can lead
to NMS. Although the incidence of NMS is less common with AA use, it can occur
when multiple agents are used even if smaller doses. Young men and postpartum
women have an unexplained predisposition to NMS. NMS is characterized by fever,
confusion, muscle rigidity, and autonomic instability similar to serotonin syndrome
and may have forme fruste presentations with delayed onset. Serotonergic agents,
carbamazepine, and mixed ingestions of serotonergics and antipsychotics also
can cause forme fruste presentations of NMS. Similar symptoms may occur with
rapid withdrawal of dopaminergic agents (eg, levodopa/carbidopa). Several clinical
decision tools have been proposed for NMS but no single one has gained wide-
spread use.42 Signs and symptoms of rhabdomyolysis and metabolic acidosis
may occur.
Management
The management of NMS centers on supportive care and cessation of the offending
agent. There is no specific antidote for antipsychotics. Activated charcoal may be
considered in recent acute ingestions, but ileus could hinder this method of GI decon-
tamination. Aggressive hydration with intravenous fluids is recommended in case of
hypotension, hyperthermia, or rhabdomyolysis. Norepinephrine is recommended in
cases of shock. Epinephrine and dopamine could induce paradoxic hypotension
due to simultaneous neuroleptic a-blockade and unopposed b-agonist peripheral
vasodilation. Benzodiazepines can be used for most seizures given they are self-
limited.43
Patients presenting with NMS and worsening hyperthermia must be treated
immediately with physical and pharmacologic cooling methods. In cases of severe
hyperthermia (core temperatures >40.6 C) and significant muscle rigidity, dantro-
lene, 1-mg/kg to 2.5-mg/kg initial dose, followed by 1-mg/kg infusion every 6 hours
(maximum 10 mg/kg/d) may be considered.41 Bromocriptine and amantadine are
central dopaminergic agonists only available in enteral formulations and can be
used to reverse the neuroleptic-induced dopaminergic blockade, although their ef-
fect has slow onset (eg, several days). Once NMS resolves, they should be tapered
528 Prisco et al
gradually to avoid rebound episodes of dopamine withdrawal mimicking NMS.

Parkinson patients or patients on long-term dopamine agonists (eg, metoclopra-
mide) could develop NMS on sudden withdrawal of their dopaminergic therapy.44
In these cases, levodopa/carbidopa, bromocriptine, and/or amantadine should be
supplemented urgently.45 Anecdotal reports of refractory NMS cases treated with
pulse steroid therapy have shown to reduce the illness duration and improve
symptoms.46
MOOD STABILIZERS
Mood stabilizers include some antipsychotics, anticonvulsants (lamotrigine, valproic
acid, and carbamazepine, which have similar toxicology profiles), and lithium (the
classic mood stabilizer).47 The mechanisms of action and therapeutic action are
reviewed in Table 4. Mood-stabilizers often are used in combination, and carbamaz-
epine cointoxication is more than 2-fold as fatal compared with lithium, which is
notable for its narrow therapeutic index. The safest and most efficient combination ap-
pears to be valproic acid plus lithium.48
Toxicity
Carbamazepine and lamotrigine have systemic and neurologic side effects. Systemic
effects include nausea, vomiting, diarrhea, hyponatremia, pruritis, and rash, whereas
the neurologic effects include headache, dizziness, blurry vision or diplopia, tremor,
stupor, and drowsiness. Acute valproate toxicity manifests with lethargy whereas
the chronic use of valproic acid causes weight gain, GI disturbances, alopecia, tremor,
and easy bruising. Approximately 5% to 10% of patients develop self-resolving trans-
aminitis. More severe forms of valproic acid toxicity include encephalopathy second-
ary to hyperammonemia, hepatotoxicity, and acute pancreatitis.49
Acute intoxication with lithium presents with GI symptoms (nausea, diarrhea, vom-
iting, and cramps), neuromuscular signs (tremor, dystonia, hyperreflexia, and ataxia),
and rarely cardiac effects, such as T-wave flattening, sinus node dysfunction, and QT
prolongation, which often are reversible.50 The therapeutic range of lithium concentra-
tion is 0.5 mmol/L to 1.0 mmol/L, and levels may increase in renal failure or elderly pa-
tients. Chronic intoxication is more challenging to treat and is precipitated by impaired
kidney function and hypovolemia. Symptoms are primarily neurologic (altered mental
status, coma, seizures), and severely intoxicated patients may present with the syn-
drome of irreversible lithium-effectuated neurotoxicity (SILENT), characterized by
cognitive dysfunction, cerebellar dysfunction, brainstem dysfunction, extrapyramidal
motor symptoms, myopathy, nystagmus, and sometimes loss of vision.51 This syn-
drome is a rare but important sequela of lithium toxicity that can persist despite
normalization of levels. Lithium is a potent renal toxin causing nephrogenic diabetes
insipidus, chronic tubulointerstitial nephritis, renal tubular acidosis, and nephrotic syn-
drome. Endocrine disorders, such as hypothyroidism and myxedema, can occur in
cases of chronic toxicity.52 It is important to recognize that acute on chronic toxicity
of lithium can develop in patients taking daily lithium in settings of dehydration, drug
interactions, or changes in renal function.53
Management
Management of carbamazepine toxicity includes supportive care, addressing airway
protection, and close cardiac monitoring.54 Activated charcoal (repeated dose of
1 g/kg each, every 2–4 hours) can be used if patients are able to protect their airway
with aspiration precautions. It can be given even after 2 hours if extended-release

preparations are ingested. Whole-bowel irrigation after ingestion of modified-release
carbamazepine may be considered (adults and adolescents, 1.5–2 L/ h, and small chil-
dren, 0.5 L/h, of polyethylene glycol electrolyte lavage solution), but evidence of
improved outcomes is lacking.
SB should be administered when the QRS complex is longer than 100 milliseconds.
Given the high fatality rate, up to 13%, an aggressive treatment plan may require char-
coal hemoperfusion, hemodialysis, intravenous lipid emulsion, and/or multiple doses
of activated charcoal.55 Seizures can be controlled with benzodiazepines or propofol,
depending on severity and patient’s intubation status.
Treatment of patients with valproic acid toxicity also mainly is supportive.56 Levo-
carnitine may be used for hyperammonemia by loading 100 mg/kg intravenously fol-
lowed by 50 mg/kg every 8 hours. Naloxone has been anecdotally reported to reverse
the CNS depression from valproate although the effect is not universal.57 Hemodialy-
sis and hemoperfusion may be indicated for severe cases with hyperammonemia.58
It is important to admit patients with suspected acute lithium intoxication with signifi-
cant symptoms regardless of the plasma levels of lithium. Lithium is an intracellular ion
similar to potassium so serum levels do not reflect the total body load. Because most
lithium formulations are sustained release, serial levels are necessary to assess for
ongoing absorption. The treatment of acute lithium toxicity may include GI decontamina-
tion with gastric lavage or whole-bowel irrigation if ingestion occurred within 1 hour. Acti-
vated charcoal does not adsorb lithium and is not recommended unless there is suspicion
of a mixed ingestion.59 Volume resuscitation is necessary in the management of lithium
intoxication with a goal to restore glomerular filtration rate, normalize urine output, and
enhance lithium clearance.60 Extracorporeal treatment is recommended in severe lithium
poisoning and in situations with lithium levels greater than 4.0 mEq/L with impaired renal
function or presence of neurologic or cardiac side effects irrespective of levels. Patients
who receive chronic lithium therapy should be admitted if plasma levels are higher than
2.0 mEq/L, and those who present with severe neurotoxicity require extracorporeal renal
support and ICU admission.61 The Extracorporeal Treatments In Poisoning workgroup
(https://www.extrip-workgroup.org) has specific recommendation on use of extracorpo-
real treatment in lithium poisoning. Extracorporeal treatment is continued for a minimum
of 6 hours until there is a clinical improvement or the lithium levels fall below 1.0 mEq/L,
with monitoring of serum levels every 12 hours for possibility of lithium rebound from
redistribution or ongoing absorption. Hemodialysis is the most efficient extracorporeal
treatment, but continuous renal replacement is an acceptable alternative.
HALLUCINOGENS
Hallucinogens comprise a unique group of substances that are used to induce hallu-
cinations and cause alteration of thought and emotion. Natural hallucinogens can be
found in plants and mushrooms and continue to be used worldwide for religious and
recreational purposes.
Hallucinogens can be classified according to chemical family (Table 5).62 Use of ke-
tamine as a dissociative hallucinogen also is increasing with illicit access being
sourced from veterinary offices.
Toxicity
Most patients presenting with hallucinogen intoxication have a history of recent expo-
sure, but mixed use of hallucinogens with drugs, such as acetaminophen, caffeine,
530
Prisco et al
Table 5
Hallucinogens

Psychedelics Tryptamines Serotonin receptor partial None Time to onset: 20–30 min
Psilocybin and psilocin agonist (5-HT2) Psilocybin and LSD have been Half-life: 1 h
(mushrooms), bufotenin investigated in the Metabolism: metabolized by
(toads), DMT (plants) treatment of cluster several pathways, including
headache monoamine oxidase,
limiting the oral
bioavailability of some
compounds
Ergolines Serotonin receptor agonist Time to onset: 3–4 h
LSD, lysergic acid amide Dopamine receptor partial (depending on the route of
(plants) agonist administration)
Norepinephrine receptor Half-life: 6–24 h
agonist Metabolism: extensively
metabolized by the liver,
predominantly via hydrolysis
Phenethylamines Serotonin receptor agonist Time to onset: >1 h (up to 24 h)
Mescaline (peyote cactus), 2C- Half-life: 5–10 min
series drugs (2C-B, 2C-I, 2C-C, Metabolism: urinary excretion
2C-T-7), 3C-E, 4-MTA, PMA, of the main metabolite,
DO-series drugs (DOC, DOB, phenylacetic acid
DOI, DOM)
Dissociative drugs Phencyclidine, NMDA receptor antagonist Anesthesia Time to onset: 2–60 min
dextromethorphan, Sigma-1 receptor agonist Half-life: 6 h – 3 d
ketamine Metabolism: complex active
metabolites
Deliriants Scopolamine and atropine Acetylcholine receptor Multiple legitimate uses Time to onset: 1–5 min
(plants), diphenhydramine, antagonist (muscarinic) (anesthesia, resuscitation, Half-life: 2–9.5 h
dimenhydrinate cardiology, ophthalmology, Metabolism: destroyed by
etc.) enzymatic hydrolysis,
particularly in the liver, with
13% to 50% excreted

unchanged in the urine

Salvinorin A (Salvia divinorum) Selective agonist of the Similar to some pain relief Time to onset: rapid when
kappa opioid receptor medications (pentazocine) smoked (40 s)
Half-life: 8 min
Metabolism: quick metabolism
in the GI tract
Muscimol (amanita muscaria) GABA-A agonist Research only Time to onset: 30–120 min
Half-life: 5–10 h
Metabolism: urinary excretion
531
532 Prisco et al
barbiturates, antipsychotics, or other pharmaceuticals is common.63 Although mush-

rooms containing psilocybin are recognizable, other hallucinogenic mushrooms
(Amanita muscaria) look similar to poisonous ones (Amanita phalloides) and may be
ingested by mistake causing severe hepatotoxicity.
Patients present with a wide range of behaviors that tend to fluctuate from a calm
euphoric state to one of extreme agitation and aggressiveness. An accurate history
may be difficult and often depends on circumstantial evidence.64 Delayed GI effects
(nausea and vomiting) can present after 6 hours from ingestion of hallucinogenic mush-
rooms. Most agents once ingested or inhaled have a predictable duration of effect. N,N-
Dimethyltryptamine (DMT) has onset of action in a few seconds and duration of effects
less than 60 minutes. The effects of methylenedioxy-methamphetamine last for 4 hours
to 8 hours, and LSD can be active for more than 12 hours. General features of halluci-
nogen intoxication include altered sensorium, tachypnea, tachycardia, and mild to mod-
erate hypertension. Hyperthermia is not a characteristic feature of mild toxicity with
single-substance hallucinogens; if present, fever should trigger suspicion of polysub-
stance intoxication, serotonin syndrome, or anticholinergic syndrome.65 Marked mydri-
asis is seen in tryptamine or LSD use. Phencyclidine and ketamine can produce
horizontal, vertical, or rotatory nystagmus. Muscle tremors and fasciculation are charac-
teristic of phenylethylamine use, whereas muscular rigidity, hyperreflexia of the lower ex-
tremities, and clonus are features of serotonin syndrome (LSD, psilocybin, and
mescaline).62 GI alterations are common with mescaline and DMT.
Management
Due to altered behavior, patients with acute hallucinogen intoxication should be placed
in a calm and relaxed environment. If this is not sufficient, physical restraints and sed-
atives may be required. Most patients who present without medical complications do
well with sedatives and reassurance.64 The first line of sedatives includes benzodiaze-
pines. Haloperidol or droperidol could be considered in addition to benzodiazepines but
can cause QT prolongation and torsades de pointes, seizures, or temperature dysregu-
lation.66 AAs are contraindicated because they can precipitate serotonin syndrome.
A thorough physical examination should pay attention to traumatic injuries, cardiac
dysrhythmias, and hyperthermia. Hyperthermia and agitation following ingestion of
hallucinogens are life-threatening emergencies and should be managed aggressively.
Phencyclidine and new hallucinogens also act as stimulants, causing severe hyper-
thermia and diffuse muscle fasciculations. Rapid cooling is recommended, and pa-
tients may require neuromuscular paralysis. Patients should be given intravenous
fluids and observed for the development of rhabdomyolysis.
OTHER COMMONLY USED LICIT PSYCHOACTIVE SUBSTANCES

Caffeine
Popular beverages, such as coffee, tea, soda, and energy drinks, contain caffeine. Ac-
cording to the Mayo Clinic, the maximum recommended amount of caffeine is 400 mg
per day for healthy adults (100 mg/d for adolescents and <200 mg/d for pregnant women).
The exact amount of caffeine that can lead to overdose is difficult to establish due to its
unpredictable half-life (Table 6).67 A caffeine overdose can be life-threatening, but most
people notice only some unpleasant symptoms that are self-resolving when the sub-
stance is metabolized. Diagnosis can be difficult. Symptoms of acute severe intoxication
include anxiety, hallucinations, irritability, uncontrollable muscle movements, vomiting
and diarrhea, seizures, and, in extreme cases, status epilepticus, chest pain, and dys-
rhythmias.67 Chronic use of high doses of caffeine could lead to hormonal imbalances.
Table 6
Other psychoactive drugs
Drug Mechanism of Action Medical Use Pharmacology

Caffeine Adenosine receptor Headache Time to onset:
(coffee, tea, antagonist 10 min
other plants) MAOI Half-life: from
1.5 h to 9.5 h
Metabolism:
metabolized by
the cytochrome
P450 enzyme
Nicotine (tobacco) Nicotinic Nicotine addiction Time to onset: 20 s
acetylcholine Half-life: 1–2 h
receptor agonist Metabolism:
metabolized to
N-oxide, product
of the hepatic
oxidation by
cytochrome P450
Cannabis Cannabinoid Chemotherapy- Time to onset:
(tetrahydrocannabinol) receptor partial induced nausea smoking onset in
agonist and vomiting, minutes, orally
neuropathic pain, slow onset
sleep disorders, Half-life: 12–36 h
epilepsy (longer for
frequent users)
Metabolism:
cytochrome
P450 enzyme
Nicotine
Nicotine poisoning is rare with traditional tobacco-containing cigarettes and cigars. It
has become more frequent in recent years due to increasing availability of alternative
products, such as e-cigarettes and pure liquid nicotine, that are more likely to cause
poisoning.68 There also is a worrisome increase in intoxications involving children.69
Consuming a few e-cigarettes at once could be fatal, given that 30 mg to 60 mg of
nicotine is considered lethal in adults.68 Adults who are not used to nicotine and try
vaping for the first time are at higher risk of poisoning compared with others who
have smoked cigarettes before. Rarely, exposure can occur from skin contact and
ingestion. Another population at risk includes workers involved with nicotine-based
products (tobacco plants and harvesting fields).
Nicotine primarily effects the heart and CNS, regardless of the amount ingested or
inhaled. Symptoms typically last an hour or 1 after a mild overdose and up to 24 hours
for severe poisoning and include dizziness, abdominal pain, sialorrhea, tachypnea,
tachycardia, hypertension, headache, and confusion. More severe symptoms include
diarrhea, hypoventilation, bradycardia, hypotension, stupor, weakness, uncontrollable
muscle movements, and seizures.70
Cannabis and Synthetic Cannabinoids

The easy availability of cannabis and synthetic cannabinoids and the associated
perception of a low risk of harm makes these among the most common substances
used by adolescents often with other substances. Cannabis and synthetic
534 Prisco et al
cannabinoids usually are smoked (inhaled). Ingestion of cannabis in health supple-

ments and edible forms is increasing.
Approximately 6% of the world population uses cannabis with reported incidence of
15.3% use in the United States, making it the most common PAD.71,72 Legalization
of cannabis for recreational use has caused a noteworthy decline in the amount of
cannabis herb seized globally.8,73
All synthetic cannabinoids can cause severe agitation, hallucinations, delusions,
paranoia, and schizophrenic behaviors. In severe intoxication, patients can show se-
vere agitation, panic attacks, tremor, seizures, and tachycardia. Cannabinoids adul-
terated with brodifacoum may present with signs and symptoms of coagulopathy.74
Diagnosis of intoxication usually is made using urine drug screens for cannabis but
synthetic cannabinoids are not detected.75
Management
Treatment of caffeine intoxication focuses on increasing elimination from the blood
while preventing or treating dysrhythmias. If patients present within an hour of
ingestion, activated charcoal can be used. Continuous cardiac monitoring and
ongoing neurologic assessment are required. The treatment of cannabis or syn-
thetic cannabinoid intoxication may include the use of benzodiazepines for seda-
tion as well as ventilator support in case of respiratory depression or decreased
level of consciousness.
Fig. 1. NPSs by effect group, up to December 2019. (Adapted from World Drug Report 2020
(United Nations publication, Sales No. E.20.XI.6).8) Permission to share content from UNODC
documents (from United Nations publication, Sales No. E.20.XI.68): “This publication may be
reproduced in whole or in part and in any form for educational or non-profit purposes
without special permission from the copyright holder, provided acknowledgment of the
source is made. The United Nations Office on Drugs and Crime (UNODC) would appreciate
receiving a copy of any publication that uses this publication as a source”
Table 7
Toxicology and management strategies for neurologic symptoms
Drug Class Neurologic Symptoms of Toxicity Management Strategies Focused on Neurologic Symptoms
TCAs Agitation, confusion, memory impairment, and anxiety Increasing arterial pH to 7.45 with SB
CNS depression with reduced level of consciousness, Lipid emulsion in refractory cases
hypoventilation, coma and seizures Benzodiazepines and propofol for seizures; avoid phenytoin
and lacosamide
SSRIs, SNRIs, and MAOIs Neuromuscular excitation, autonomic instability–Hunter Muscle relaxants to target rigidity and hyperthermia
criteria Benzodiazepines for management of seizures, agitation and
Altered level of consciousness and coma muscle rigidity (diazepam or lorazepam, 0.1–0.2 mg/kg)
Serotonin syndrome in case of serotonergic agents Butyrophenones (eg, haloperidol) and droperidol worsen
Fatal hypertensive crisis in adrenergic agents hyperthermia and are contraindicated
Cyproheptadine or chlorpromazine may be considered for
symptoms refractory to benzodiazepines
Avoid depolarizing muscle relaxant drugs
Antipsychotics Acute extrapyramidal symptoms Benzodiazepines (eg, lorazepam, midazolam) for treatment
Seizures and status epilepticus of seizures
Tardive dyskinesia NMS–dantrolene sodium (1–10 mg/kg) for muscle rigidity
NMS and fever in severe cases
Bromocriptine and amantadine for less severe cases
Pulse steroid therapy for refractory cases
Carbamazepine and Headache, dizziness, blurry vision or diplopia, tremor, Charcoal hemoperfusion, hemodialysis, intravenous lipid
lamotrigine stupor, drowsiness, seizures emulsion and multiple doses activated charcoal
Benzodiazepine for seizure control
Valproate Tremors, agitation, miosis L-carnitine for hyperammonemia
Hyperammonemia causing stupor, coma, or death Hemodialysis and hemoperfusion for refractory cases
Lithium Tremor, dystonia, hyperreflexia, ataxia, confusion, lethargy, Intravenous fluids to restore renal perfusion
seizure Hemodialysis for removing lithium
SILENT
Hallucinogens Altered sensorium Benzodiazepines for agitation and seizures
Marked mydriasis in tryptamine or lysergic acid use Avoid AAs
(continued on next page)
535
536
Prisco et al
Table 7
(continued )
Drug Class Neurologic Symptoms of Toxicity Management Strategies Focused on Neurologic Symptoms
Horizontal, vertical, or rotatory nystagmus with Aggressive cooling
phencyclidine
Life-threatening hyperthermia and agitation
Caffeine Anxiety, hallucinations, irritability, uncontrollable muscle Supportive care
movements Benzodiazepines for agitation and seizures
Seizures and status epilepticus
Nicotine Headache, confusion, stupor Supportive care
Weakness, uncontrollable muscle movements Benzodiazepines for agitation and seizures
Seizures
Cannabis Severe agitation, hallucinations, delusions, paranoia, Benzodiazepines for agitation and seizures
schizophrenic behaviors
NPSs Seizures, agitation, aggressiveness, and acute psychosis Supportive care
Benzodiazepines for agitation and seizures
NEW PSYCHOACTIVE SUBSTANCES
New psychoactive substances (NPSs), also known as legal highs, bath salts, or
research chemicals, have been synthesized for decades but are increasingly pop-
ular in the illicit drug market, with more than 500 NPS formulations identified on
the market each year. A majority of NPSs identified by United Nations Office on
Drugs and Crime monitors are stimulants, cannabinoid receptor agonists, and
classic hallucinogens (Fig. 1).8 NPSs in general have not replaced traditional
drugs on a larger scale but NPSs with opioid-like effects have been associated
with fatalities, and injectable NPSs have been associated with high-risk adminis-
tration practices.76
Globally, the large number of emerging NPSs poses a significant risk to public
health and a challenge to drug policy processes. NPS users frequently are hospi-
talized with severe intoxications. Safety data on many NPSs are limited, and details
on long-term adverse effects and risks still are unknown, making both prevention
and treatment challenging. Known side effects of NPSs include seizures, agitation,
aggressiveness, and acute psychosis. Additionally, impurities or compounds added
to stabilize formulations may have high risk of complex and unpredictable severe
side effects. Deaths associated with NPSs often are caused by polysubstance
use.76 Table 7 summarizes the neurologic toxicity and targeted management for
PADs and NPSs.
DISCUSSION
In recent years, there have been important changes in the PAD markets. There is
increased production and use of NPSs, ongoing use of available PADs, and a rise in
the nonmedical use of prescription drugs obtained from licit channels or illegally man-
ufactured. In addition, many substances sold as alleged medicines are being directed
for nonmedical use through illicit channels.
Similar to the 2008 economic crisis, reports suggest that the COVID-19 pandemic is
shifting trends in PAD trafficking, consumption patterns, and shift in preferred sub-
stance of abuse based on accessibility and availability.8,77 Cannabis use may have
increased since the first lockdown measures.8 Monitoring, reporting, information
sharing, early warning, and risk awareness are essential to prepare the response to
the emerging health threat associated with PAD use.
CLINICS CARE POINTS
SB is the mainstay of therapy for severe TCA toxicity by alkalinization effect as well sodium
load to reverse the sodium channel blocking effect of TCAs.
Benzodiazepines are the mainstay of seizure management in most overdose-related seizures
due to psychoactive substances.
Early recognition, discontinuation of drugs, and supportive care are central to managing
serotonin syndrome and NMS. Dantrolene should be considered in hyperthermia related
to NMS.
Extracorporeal treatments should be considered in lithium toxicity and severe valproate
toxicity
Symptomatic management of agitation in most hallucinogen ingestions involves careful use
of sedatives.
538 Prisco et al
DISCLOSURE
Lara Prisco is a Doctoral Research Fellow (NIHR300741) funded by the National Insti-
tute for Health Research (NIHR). The views expressed in this publication are those of
the author(s) and not necessarily those of the NIHR, NHS or the UK Department of
Health and Social Care.
REFERENCES
1. Rhee TG, Olfson M, Nierenberg AA, et al. 20-year trends in the pharmacologic
treatment of bipolar disorder by psychiatrists in outpatient care settings. Am J
Psychiatry 2020;177(8):706–15.
2. Yu Z, Zhang J, Zheng Y, et al. Trends in antidepressant use and expenditure in six
major cities in China from 2013 to 2018. Front Psychiatry 2020;11:551.
3. Wesselhoeft R, Jensen PB, Talati A, et al. Trends in antidepressant use among
children and adolescents: a Scandinavian drug utilization study. Acta Psychiatr
Scand 2020;141(1):34–42.
4. Madras BK. The growing problem of new psychoactive substances (NPS). Curr
Topbehav Neurosci 2017;32:1–18.
5. Lloyd SL, Striley CW. Marijuana use among adults 50 years or older in the 21st
Century. Gerontol Geriatr Med 2018;4. 2333721418781668.
6. Carrasco-Garrido P, Jiménez-Trujillo I, Hernández-Barrera V, et al. Gender differ-
ences in the nonmedical use of psychoactive medications in the school popula-
tion- national trends and related factors. BMC Pediatr 2019;19(1):362.
7. Ait-Daoud N, Blevins D, Khanna S, et al. Women and addiction: an update. Med
Clin North Am 2019;103(4):699–711.
8. World drug report 2020. United Nations. 2020. Available at: https://wdr.unodc.
org/wdr2020/. Accessed Jan 21,2021.
9. NIDA. Sex and gender differences in substance use. National Institute on Drug
Abuse website; 2020. Available at: https://www.drugabuse.gov/publications/
research-reports/substance-use-in-women/sex-gender-differences-in-substance-
use. Accessed February 9, 2021.
10. Treatment Episode Data Set (TEDS): 2004-2014, National admissions to sub-
stance abuse treatment Services. U.S. Department Health & Human Services.
Substance Abuse and Mental Health Services Administration, Center for Behav-
ioral Health Statistics and Quality. 2016. Available at: https://www.samhsa.gov/
data/report/treatment-episode-data-set-teds-2004-2014-national-admissions-
substance-abuse-treatment. Accessed January 21, 2021.
11. Women and depression: Discovering Hope. National Institute of Mental Health
Science Writing, Press & Dissemination Branch. Available at: http://www.nimh.
nih.gov. Accessed Date Jan 21, 2020.
12. Lipari RN. Understanding adolescent inhalant use. In: Center for behavioral
health Statistics and Quality SAaMHSA. The CBHSQ report. 2017.
13. Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons aged 12 and over:
United States, 2005-2008. In: NCHS data brief. 2011. p. 76.
14. Gummin DD, Mowry JB, Beuhler MC, et al. 2019 Annual report of the American
association of poison control centers’ national poison data system (NPDS):
37th annual report. Clin Toxicol 2020;58(12):1360–541.
15. Methling M, Krumbiegel F, Hartwig S, et al. Toxicological findings in suicides - fre-
quency of antidepressant and antipsychotic substances. Forensic Sci Med
Pathol 2019;15(1):23–30.
16. Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interac-
tions updated. Br J Pharmacol 2007;151(6):737–48.
17. Schatzberg AF, Nemeroff CB, editors. The American psychiatric publishing Text-
book of psychopharmacology. 5th edition. Washington, DC: American Psychiatric
Association Publishing; 2017.
18. Jarvis MR. Clinical pharmacokinetics of tricyclic antidepressant overdose. Psy-
chopharmacol Bull 1991;27(4):541–50.
19. Schulz M1, Schmoldt A. Therapeutic and toxic blood concentrations of more than
800 drugs and other xenobiotics. Die Pharmazie 2003;58(7):447–74.
20. Hill T, Coupland C, Morriss R, et al. Antidepressant use and risk of epilepsy and
seizures in people aged 20 to 64 years: cohort study using a primary care data-
base. BMC Psychiatry 2015;15(1):315.
21. Judge BS, Rentmeester LL. Antidepressant overdose-induced seizures. Neurol
Clin 2011;29(3):565–80.
22. Body R, Bartram T, Azam F, et al. Guidelines in Emergency Medicine Network
(GEMNet): guideline for the management of tricyclic antidepressant overdose.
Emerg Med J 2011;28(4):347–68.
23. Pierog JE, Kane KE, Kane BG, et al. Tricyclic antidepressant toxicity treated with
massive sodium bicarbonate. Am J Emerg Med 2009;27(9):1168.e3.
24. McKinney PE, Rasmussen R. Reversal of severe tricyclic antidepressant-induced
cardiotoxicity with intravenous hypertonic saline solution. Ann Emerg Med 2003;
42(1):20–4.
25. Yekehtaz H, Farokhnia M, Akhondzadeh S. Cardiovascular considerations in antide-
pressant therapy: an evidence-based review. J Tehran Heart Cent 2013;8(4):169–76.
26. Emamhadi M, Mostafazadeh B, Hassanijirdehi M. Tricyclic antidepressant
poisoning treated by magnesium sulfate: a randomized, clinical trial. Drug
Chem Toxicol 2012;35(3):300–3.
27. Linde K, Kriston L, Rücker G, et al. Efficacy and acceptability of pharmacological
treatments for depressive disorders in primary care: systematic review and
network meta-analysis. Ann Fam Med 2015;13(1):69–79.
28. Brody DJGQ. Antidepressant use among adults: United States, 2015–2018. In:
NCHS data brief. 2020.
29. Gummin DD, Mowry JB, Spyker DA, et al. 2016 Annual report of the American as-
sociation of poison control centers’ national poison data system (NPDS): 34th
annual report. Clin Toxicol 2017;55(10):1072–252.
30. Nelson LS, Erdman AR, Booze LL, et al. Selective serotonin reuptake inhibitor
poisoning: an evidence-based consensus guideline for out-of-hospital manage-
ment. Clin Toxicol 2007;45(4):315–32.
31. Jimmink A, Caminada K, Hunfeld NG, et al. Clinical toxicology of citalopram after
acute intoxication with the sole drug or in combination with other drugs: overview
of 26 cases. Ther Drug Monit 2008;30(3):365–71.
32. van Gorp F, Whyte IM, Isbister GK. Clinical and ECG effects of escitalopram over-
dose. Ann Emerg Med 2009;54(3):404–8.
33. Vo KT, Merriman AJ, Wang RC. Seizure in venlafaxine overdose: a 10-year retrospec-
tive review of the California poison control system. Clin Toxicol 2020;58(10):984–90.
34. Nelson JC, Spyker DA. Morbidity and mortality associated with medications used
in the treatment of depression: an analysis of cases reported to U.S. poison con-
trol centers, 2000-2014. Am J Psychiatry 2017;174(5):438–50.
35. Wang RZ, Vashistha V, Kaur S, et al. Serotonin syndrome: preventing, recog-
nizing, and treating it. Clevel Clin J Med 2016;83(11):810–6.
540 Prisco et al
36. Eyer F, Zilker T. Bench-to-bedside review: mechanisms and management of hy-

perthermia due to toxicity. Crit Care 2007;11:236.
37. Pedavally S, Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care
unit: clinical presentations and precipitating medications. Neurocrit Care 2014;
21(1):108–13.
38. Højlund M, Pottegård A, Johnsen E, et al. Trends in utilization and dosing of anti-
psychotic drugs in Scandinavia: comparison of 2006 and 2016. Br J Clin Pharma-
col 2019;85(7):1598–606.
39. Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsy-
chotics on metabolic function in patients with schizophrenia, predictors of meta-
bolic dysregulation, and association with psychopathology: a systematic review
and network meta-analysis. Lancet Psychiatry 2020;7(1):64–77.
40. Stroup TS, Gray N. Management of common adverse effects of antipsychotic
medications. World Psychiatry 2018;17(3):341–56.
41. Oruch R, Pryme IF, Engelsen BA, et al. Neuroleptic malignant syndrome: an easily
overlooked neurologic emergency. Neuropsychiatr Dis Treat 2017;13:161–75.
42. Tse L, Barr AM, Scarapicchia V, et al. Neuroleptic malignant syndrome: a review
from a clinically oriented perspective. Curr Neuropharmacol 2015;13(3):395–406.
43. Cobaugh DJ, Erdman AR, Booze LL, et al. Atypical antipsychotic medication
poisoning: an evidence-based consensus guideline for out-of-hospital manage-
ment. Clin Toxicol 2007;45(8):918–42.
44. Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists.
Neurohospitalist 2011;1(1):41–7.
45. Frucht SJ. Treatment of movement disorder emergencies. Neurotherapeutics
2014;11(1):208–12.
46. Sato Y, Asoh T, Metoki N, et al. Efficacy of methylprednisolone pulse therapy on
neuroleptic malignant syndrome in Parkinson’s disease. J Neurol Neurosurg Psy-
chiatry 2003;74(5):574–6.
47. Hawton AEF, Galit G, Deborah C, et al. Relative toxicity of mood stabilisers and
antipsychotics: case fatality and fatal toxicity associated with self-poisoning.
BMC Psychiatry 2018;18(1):1–8.
48. Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and effi-
cacy. Am J Psychiatry 1998;155(1):12–21.
49. Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin
Toxicol 2002;40(6):789–801.
50. Oruch R, Elderbi MA, Khattab HA, et al. Lithium: a review of pharmacology, clin-
ical uses, and toxicity. Eur J Pharmacol 2014;740:464–73.
51. Adityanjee, Munshi KR, Thampy A. The syndrome of irreversible lithium-
effectuated neurotoxicity. Clin Neuropharmacol 2005;28(1):38–49.
52. Ng YW, Tiu SC, Choi KL, et al. Use of lithium in the treatment of thyrotoxicosis.
Hong Kong Med J 2006;12(4):254–9.
53. Baird-Gunning J, Lea-Henry T, Hoegberg LCG, et al. Lithium poisoning.
J Intensive Care Med 2017;32(4):249–63.
54. Spiller HA. Management of carbamazepine overdose. Pediatr Emerg care 2001;
17(6):452–6.
55. Ghannoum M, Yates C, Galvao TF, et al. Extracorporeal treatment for carbamaz-
epine poisoning: systematic review and recommendations from the EXTRIP work-
group. Clin Toxicol 2014;52(10):993–1004.
56. Manoguerra AS, Erdman AR, Woolf AD, et al. Valproic acid poisoning: an
evidence-based consensus guideline for out-of-hospital management. Clin Toxi-
col 2008;46(7):661–76.
57. Thanacoody HKR. Chronic valproic acid intoxication: reversal by naloxone.

Emerg Med J 2007;24(9):677–8.
58. Ghannoum M, Laliberté M, Nolin TD, et al. Extracorporeal treatment for valproic
acid poisoning: systematic review and recommendations from the EXTRIP work-
group. Clin Toxicol 2015;53(5):454–65.
59. Bretaudeau Deguigne M, Hamel JF, Boels D, et al. Lithium poisoning: the value of
early digestive tract decontamination. Clin Toxicol 2013;51(4):243–8.
60. McKnight RF, Adida M, Budge K, et al. Lithium toxicity profile: a systematic review
and meta-analysis. Lancet 2012;379(9817):721–8.
61. Decker BS, Goldfarb DS, Dargan PI, et al. Extracorporeal treatment for lithium
poisoning: systematic review and recommendations from the EXTRIP Workgroup.
Clin J Am Soc Nephrol 2015;10(5):875–87, 64.
62. Hill SL, Thomas SH. Clinical toxicology of newer recreational drugs. Clinl Toxicol
2011;49(8):705–19.
63. Hardaway R, Schweitzer J, Suzuki J. Hallucinogen use disorders. Child Adolesc
Psychiatr Clin N Am 2016;25(3):489–96.
64. Hantson, Frédéric J, Karim J, et al. Management of pharmaceutical and recrea-
tional drug poisoning. Ann Intensive Care 2020;10(1):1–30.
65. Simon LV, Keenaghan M. Serotonin syndrome. In: StatPearls. . Treasure Island,
FL: StatPearls Publishing; 2020.
66. Ghuran A, Nolan J. Recreational drug misuse: issues for the cardiologist. Heart
2000;83(6):627–33.
67. Murray A, Traylor J. Caffeine toxicity. In: StatPearls. . Treasure Island, FL: Stat-
Pearls Publishing; 2020.
68. Mayer B. How much nicotine kills a human? Tracing back the generally accepted
lethal dose to dubious self-experiments in the nineteenth century. Arch Toxicol
2014;88(1):5–7.
69. Quail MT. Nicotine toxicity: protecting children from e-cigarette exposure. Nursing
2020;50(1):44–8.
70. Shao XM, Fang ZT. Severe acute toxicity of inhaled nicotine and e-cigarettes: sei-
zures and cardiac arrhythmia. Chest 2020;157(3):506–8.
71. World drug report 2020. United Nations office on drugs and Crime. https://www.
unodc.org/. Accessed January 18, 2021.
72. Gummin DD, Mowry JB, Spyker DA, et al. 2018 Annual report of the American as-
sociation of poison control centers’ national poison data system (NPDS): 36th
annual report. Clin Toxicol 2019;57(12):1220–413.
73. Lewis B, Fleeger T, Judge B, et al. Acute toxicity associated with cannabis edi-
bles following decriminalization of marijuana in Michigan. Am J Emerg Med 2020.
74. Chan A, Adashek M, Kang J, et al. Disseminated intravascular coagulopathy sec-
ondary to unintentional brodifacoum poisoning via synthetic marijuana. J Hematol
2019;8(1):40–3.
75. Schmid Y, Scholz I, Mueller L, et al. Emergency department presentations related
to acute toxicity following recreational use of cannabis products in Switzerland.
Drug Alcohol Depend 2020;206:107726. https://doi.org/10.1016/j.drugalcdep.
2019.107726.
76. Shafi A, Berry AJ, Sumnall H, et al. New psychoactive substances: a review and
updates. Ther Adv Psychopharmacol 2020;10. 2045125320967197.
77. Vittadini G, Beghi M, Mezzanzanica M, et al. Use of psychotropic drugs in Lom-
bardy in time of economic crisis (2007-2011): a population-based study of adult
employees. Psychiatry Res 2014;220(1–2):615–22.

Psychoactive Sustances 2021

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Psychoactive Sustances 2021

Uploaded by

Copyright:

Available Formats

Tox i c o l o g y o f P s y c h o a c t i v e

Crit Care Clin 37 (2021) 517–541

Neurotransmitter Effects Substances

EPIDEMIOLOGY OF PSYCHOACTIVE SUBSTANCES

Class Drugs Mechanism of Action Medical Use Pharmacology

fluvoxamine, paroxetine, inhibitors panic disorders, anxiety, 1–2 wk

neurologic toxicity to guide proper management while addressing immediate resusci-

Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake

Class Drugs Mechanism of Action Medical Use Pharmacology

gradually to avoid rebound episodes of dopamine withdrawal mimicking NMS.

with aspiration precautions. It can be given even after 2 hours if extended-release

Class Drugs Mechanism of Action Medical Use Pharmacology

13% to 50% excreted

unchanged in the urine

barbiturates, antipsychotics, or other pharmaceuticals is common.63 Although mush-

OTHER COMMONLY USED LICIT PSYCHOACTIVE SUBSTANCES

Drug Mechanism of Action Medical Use Pharmacology

Cannabis and Synthetic Cannabinoids

cannabinoids usually are smoked (inhaled). Ingestion of cannabis in health supple-

Toxicology and management strategies for neurologic symptoms

(continued on next page)

NEW PSYCHOACTIVE SUBSTANCES

CLINICS CARE POINTS

36. Eyer F, Zilker T. Bench-to-bedside review: mechanisms and management of hy-

57. Thanacoody HKR. Chronic valproic acid intoxication: reversal by naloxone.

You might also like