Download “Signs, Symptoms and Treatment of Synthetic Marijuana Abuse

“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
OBJECTIVES
(1) Compare/contrast cannabimimetic agents in regards
to mechanisms, signs and symptoms and methods of
detection
(2) Describe treatment modalities available and
indications for patients with synthetic marijuana
poisoning
(3) Identify candidates for treatment of cannabis
substance use disorders and discuss treatment
modalities available
POFPS 40th Annual CME Symposium
August 7-9, 2015
1
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
THE EPIDEMIOLOGY
OF CANNABINOID USE
DRUG USE REPORTED DURING PAST YEAR FOR
8TH AND 12TH GRADERS (50,000 SURVEYED/YR)
SOURCE: University of Michigan (2013) Monitoring the Future Study
AFTER HIGH SCHOOL, MARIJUANA CONTINUES
TO BE THE MOST COMMONLY ABUSED ILLICIT
DRUG; SOME STATES ALLOW USE IN CERTAIN
CIRCUMSTANCES
POFPS 40th Annual CME Symposium
August 7-9, 2015
2
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
CANNABIS SATIVA
 >60 cannabinoids
synthesized by plant
 Main psychoactive
constituent: Δ9tetrahydrocannabinol
 Most commonly used drug
in US
 Potency has increased
dramatically
Helping Patients Learn the Metric System
SOURCE: Compton (1991) J of Pharmacology and Experimental Therapeutics, Fattore (2001) Frontiers in Behavioral Neuroscience,
Forrester (2012) Human Experimental Toxicology, Greineisen (2010) International Immunopharmacology, Martin (1991) Pharm
Biochemistry and Behavior, Harris (2012) J Emergency Medicine, Pamplona (2011) J of Psychopharmacology
POFPS 40th Annual CME Symposium
August 7-9, 2015
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“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
CANNABIS: CB1 AND CB2 RECEPTOR AGONIST
CB1
CB2
Impaired short-term memory
Emesis
Decreased ability for complex tasks
Anti-inflammatory and immune
modulation
Impaired balance and stability
Delayed reaction time
Appetite stimulation
Analgesia
Tachycardia
Vasodilation of scleral and
conjunctival vessels
SOURCE: Compton (1991) J of Pharmacology and Experimental Therapeutics, Fattore (2001) Frontiers in Behavioral Neuroscience,
Forrester (2012) Human Experimental Toxicology, Greineisen (2010) International Immunopharmacology, Martin (1991) Pharm
Biochemistry and Behavior, Harris (2012) J Emergency Medicine, Pamplona (2011) J of Psychopharmacology
THE TETRAD OF CANNABINOID EFFECTS
CANNABIS: COMMON EFFECTS
ALTERED PERCEPTION OF
TIME
 Euphoria
 Relaxation
 Heightened sensory
perception
 Laughter
 Increased appetite
18
SOURCE: NIDA. (2010). NIDA DrugFacts: Marijuana.
POFPS 40th Annual CME Symposium
August 7-9, 2015
4
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
LONG TERM EFFECTS MAY BE A FUNCTION OF
SEVERITY AND CHRONICITY OF USE
CANNABIS INCREASES RISK FOR SCHIZOPHRENIA, PSYCHOSIS,
ANXIETY, DEPRESSION AND AMOTIVATIONAL SYNDROME
ADVERSE EFFECTS

Tachyarrhythmias

Myocardial infarction

Chronic cough +/bronchitis

Anxiety

Fear, distrust +/- panic

Severe mental health
problems

Hyperemesis syndrome
R U D Y E U G E N E , T H E “ M I A M I
Z O M B I E ” C O U L D H A V E H A D
S U B S T A N C E I N D U C E D
P S Y C H O S I S
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SOURCE: NIDA. (2010). NIDA DrugFacts: Marijuana.
SUBSTANCE INDUCED PSYCHOSIS
THE USUAL SUSPECTS:
Substances with dopaminergic
effects
May be a function of the severity
and chronicity of use
Delayed onset
Duration can be permanent
depending on the extent of
neurologic toxicity (e.g.
methamphetamine)
Can be difficult to differentiate
from primary psychosis
Amphetamines
Cannabis
Cocaine
Ketamine
PCP
SOURCE: Fiorentini (2011) Clinical Psychiatry
POFPS 40th Annual CME Symposium
August 7-9, 2015
5
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
TOLERANCE DEVELOPS RAPIDLY AND SOME
EFFECTS ARE POORLY UNDERSTOOD
E FFE C T S D E MONST RATING
RAPID TOLERANCE
E FFE C T S FLU C T UAT I NG
OVER TIME
Hypothermia
Antiemetic-emetic
CANNABINOID HYPEREMESIS SYNDROME
Chronic use over 1 year
Cyclic nausea and
vomiting
Sometimes with
abdominal pain
Symptoms improve
during hot showers
and after drug
cessation (~48hrs)
Treatment with
dopamine
antagonists and
benzodiazepines
SOURCE: Sung and Zimmerman (2013) Hosp Pharm, Galli et al (2011) Curr Drug Abuse Rev,
DSM-5 CANNABIS WITHDRAWAL SYNDROME
DEVELOPING >=3 S/SX
DAYS AFT E R C E SSAT I ON
 Irritability or anger
 Nervousness
 Insomnia
 Decreased appetite
 Restlessness
 Depressed mood
 Abdominal cramps
 Tremors
 Diaphoresis
 Fever
 Chills
 Headache
POFPS 40th Annual CME Symposium
August 7-9, 2015
6
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
PEAK SYMPTOMS AT ABSTINENT DAY 10
Figure 2.
Resolution: standard
SOURCE: Hesse and Thyistrup. Time-course of the DSM-5 cannabis withdrawal symptoms in poly-substance abusers. BMC Psychiatry 2013
Symptom severity for overall cannabis withdrawal syndrome as a function of time since last cannabis use. Left-hand panel: when assessed at week 1. Right-hand panel: when assessed
at week 2.
Hesse and Thylstrup BMC Psychiatry 2013 13:258
Download authors' original image
doi:10.1186/1471-244X-13-258
DELAYED
RESOLUTION: IRRITABILITY & VIVID DREAMS
Figure 3.
Resolution: standard / high
SOURCE: Hesse and Thyistrup. Time-course of the DSM-5 cannabis withdrawal symptoms in poly-substance abusers. BMC Psychiatry 2013
MEDICATIONS FOR TREATMENT OF CANNABIS ABUSE
CANNABINOID AGONISTS
AND ANTAGONISTS
NON-CANNABINOID
PHARMACOTHERAPIES
Dronabinol 40-120 mg/day
Gabapentin 1200 mg/day
Nabilone
NAC 1200 mg bid
Rimonabant
Clonidine
Trazodone
SOURCE: Martinex and Trifilieff. Review of Potential Pharmacologic Treatments for Cannabis Abuse. Education & Training 2015
POFPS 40th Annual CME Symposium
August 7-9, 2015
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“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
20 MG DRONABINOL BID DECREASED WITHDRAWAL
SYMPTOMS AND INCREASED 2 WEEK TREATMENT
RETENTION COMPARED TO PLACEBO
SOURCE: Levin et al. Dronabinol for the Treatment of Cannabis Dependence: A Randomized, Double-Blind, Placebo-Controlled Trial. Drug Alcohol Depend. 2011
SCB WERE CREATED BY
RESEARCH SCIENTISTS
 JWH - John W
Huffman
(Clemson U)
 AM - Alexandros
Makriyannis
(Northeastern U)
 HU - Raphael
Mechoulam
(Hebrew U)
POFPS 40th Annual CME Symposium
August 7-9, 2015
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“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
SCB ARE APPLIED ONTO FINELY CUT PLANT MATERIAL
AND LABELED “NOT FOR HUMAN CONSUMPTION” TO
MINIMIZE REGULATION
DECLARED INGREDIENTS
Z OR NI A L AT I FOL I A
 Pedicularis densiflora
 Nymphacea caerulea
 Leonatis leonurus
 Leonurus sibiricus
 Carnavalia maritima
 Zornia latifolia
PRESENTED IN COLORFUL AND PROFESSIONALLY
DESIGNED PACKETS
AT T R ACTIVE PSYC H E DEL IC
PACKAGING
 Marketed as “safe”
alternatives to
marijuana
 May be found for
sale on the internet
or in head shops
(depending on legal
status)
SOURCE: NIDA. (2012). NIDA DrugFacts: Spice (Synthetic Marijuana).
WIDE VARIETY OF HERBAL MIXTURES WITH CHEMICAL
ADDITIVES AND POOR QUALITY CONTROL
SCB HERBAL MIXTURES
 Tested samples have
had inconsistent
chemical analysis
 Characteristics depend
on potency and
stereoselectivity for the
CB1R and CB2Rs
 Compared to Δ9-THC,
JWH cannabinoids
usually have higher
affinity for CB1Rs
SOURCE: Compton (1991) J of Pharmacology and Experimental Therapeutics, Fattore (2001) Frontiers in Behavioral Neuroscience,
Forrester (2012) Human Experimental Toxicology, Greineisen (2010) International Immunopharmacology, Martin (1991) Pharm
Biochemistry and Behavior, Harris (2012) J Emergency Medicine, Pamplona (2011) J of Psychopharmacology
POFPS 40th Annual CME Symposium
August 7-9, 2015
9
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
CANNABIMIMETICS: TIMELINE
SOURCE: Fattore & Fratta. (2011). Frontiers in Behavioral Neuroscience, 5(60), 1-12.
SYNTHETIC DRUGS IN CENTRAL PA
MM/YY
3/15
4/15
5/15
6/15
Synthetic drug cases
(N)
1
51
25
8
Inpatient length of stay: 46 hrs (median 26, range 10-233)
SYNTHETIC CANNABINOID (SCB) USE IN
CENTRAL PA (OVER 100 USERS IN 4 MONTHS)
• Users in all age groups but ages 20-40 most
commonly presented with toxicity
• Male>>female
• Halfway house residents
• Individuals desiring a high with low risk for
detection
• Accidental?
POFPS 40th Annual CME Symposium
August 7-9, 2015
10
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
STEREOSELECTIVITY FOR CB1 RECEPTOR PREDICTS
GREATER ABUSE POTENTIAL
Compound
CB1 (nM)
CB2 (nM)
THC
40.7
36.4
CB1/CB2
1.1
HU-210
0.061
0.52
8.5
6.8
WIN 55
1.9
(21xTHC)
0.3
(121xTHC)
JWH 018
9
2.9
3.1
JWH 073
8.9
38
0.2
AM-2201
1
2.6
2.6
UR-144
29
4.5
6.4
XLR-11
24
2.1
11.4
AB-FUBINACA
0.9
-
-
SOURCE: Compton (1991) J of Pharmacology and Experimental Therapeutics, Fattore (2001) Frontiers in Behavioral Neuroscience,
Forrester (2012) Human Experimental Toxicology, Greineisen (2010) International Immunopharmacology, Martin (1991) Pharm
Biochemistry and Behavior, Harris (2012) J Emergency Medicine, Pamplona (2011) J of Psychopharmacology
COMPARISON OF SCB POTENCY (MICE)
SCB
Cataplexy
(ED50)
Antinociception
(ED50)
Hypothermia
(ED50)
Immobility
(ED50)
Average
Potency
THC
0.92
2.7
2.5
-
2
WIN 55
0.19
1.4
1.5
-
1
JWH-018
0.44
0.09
1.7
3.9
0.7
JWH 073
0.34
1.3
3.3
-
1.6
UR-144
1
2.6
0.6
1
1.3
XLR-11
0.9
3.3
0.6
0.6
1.4
COMPARISON OF CANNABINOID EXPOSURES (PCCs)
Common Adverse Effect
Tachycardia
SCB
No. (%)
Marijuana
No. (%)
RR
95% CI
153 (36.6%)
13 (13.1%)
2.79
1.58-5.36
1.15-5.68
Agitation/irritability
80 (19.1%)
8 (8.1%)
2.37
Drowsiness/lethargy
73 (17.5%)
14 (14.1%)
1.23
0.69-2.37
Vomiting
62 (14.8%)
8 (8.1%)
1.84
0.88-4.44
Hallucinations/delusions
47 (11.2%)
2 (2%)
5.57
1.46-47.30
Hypertension
40 (9.6%)
3 (3%)
3.16
1.01-15.96
Nausea
39 (9.3%)
3 (3%)
3.08
0.98-15.57
Confusion
37 (8.9%)
7 (7.1%)
1.25
0.55-3.33
Dizziness/vertigo
37 (8.9%)
3 (3%)
2.92
0.93-14.81
Chest pain
29 (6.9%)
9 (9.1%)
0.76
0.35-1.83
418
99
Total
SOURCE: Compton (1991) J of Pharmacology and Experimental Therapeutics, Fattore (2001) Frontiers in Behavioral Neuroscience,
Forrester (2012) Human Experimental Toxicology, Greineisen (2010) International Immunopharmacology, Martin (1991) Pharm
Biochemistry and Behavior, Harris (2012) J Emergency Medicine, Pamplona (2011) J of Psychopharmacology
POFPS 40th Annual CME Symposium
August 7-9, 2015
11
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
COMPARISON OF CANNABINOID EXPOSURES
FROM CLINICAL CASE REPORTS AND SERIES
• Most symptoms are
similar to cannabis
intoxication:
• Symptoms not
typically seen after
cannabis intoxication:
– Tachycardia
– Reddened eyes
– Anxiousness
– Mild sedation
– Hallucinations
– Acute psychosis
– Memory deficits
– Seizures
– Hypokalemia
– Hypertension
– Nausea/vomiting
– Agitation
– Violent behavior
– Coma
– Rhabdomyolysis
– Death
SOURCES: Hermanns-Clausen et al. (In Press), Addiction; Rosenbaum et al. (2012). Journal of Medical Toxicology;
Forrester et al. (2011). Journal of Addictive Disease; Schneir et al. (2011). Journal of Emergency Medicine.
DEATHS REPORTED WITH SCB PRODUCT USE
DEATHS REPORTED WITH SCB PRODUCT USE
POFPS 40th Annual CME Symposium
August 7-9, 2015
12
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
URINE DRUG SCREENS (COMMON)
Detect the classical
cannabinoids
Marijuana
usage
Approximate
Detection
Period
Detection is dependent
on usage patterns
and time of last use
single use
3d
long term use
4w
SOURCE: Levine 2011 Chest Medicine
BECAUSE OF CONSTANT EVOLUTION, SCB ARE
MORE DIFFICULT TO DETECT WITH UDS
Aminoalkylindoles:
Naphtoylindoles
Nonclassical cannabinoids:
Cyclohexylphenoles
Aminoalkylindoles:
Phenylacetylindoles
Classical cannabinoid
SOURCE: United Nations Office on Drugs and Crime “Synthetic cannabinoids in herbal products.” Agudelo et al. (2012).
Effects of Synthetic Cannabinoids on the Blood Brain Barrier, Presented at 74th Annual CPDD.
DESIGNER DRUGS IDENTIFIED BY U.S. TOX LABS
(2005-2012)
SOURCE: U.S. DEA, Office of Diversion Control, NFLIS data analysis by J.C. Maxwell.
POFPS 40th Annual CME Symposium
August 7-9, 2015
13
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
SCB PRODUCTS CONTINUE TO EMERGE AND ARE
USED FOR 12-24 MONTHS BEFORE BEING
REPLACED BY THE NEXT WAVE
2010
2012
2011
SOURCE: U.S. DEA, Office of Diversion Control, NFLIS data, 2010 and 2011, Logan, B.K. (2012). Testing Strategies to
Monitor Novel/Emerging/Designer Drug Use in At-Risk Populations, Presented at 74th Annual CPDD
SYNTHETIC DRUGS DETECTED IN CENTRAL PA
D R U G S D E T E C T E D A N D
C O N F I R M E D W H E N P A T I E N T S
R E P O R T S M O K I N G S P I C E O R K 2
S Y N T HE T I C C A N N A B I N O I D
T R E N D S N A T I O N A L L Y A N D MA Y
B E MI S S E D I N C E N T R A L PA
• Cocaine
CHMINACA Species
• PCP
• Cathinones:
• Ethylone
• Cannabinoids:
• THC and XLR-11
TREATMENT: CHEMICAL SEDATION BEST
http://www.freedomsphoenix.com/Uploads/Graphics/171/01/1710111083804-hannibal-the-cannibal-mask.jpg
http://i1.mirror.co.uk/incoming/article864742.ece/ALTERNATES/s615
/Former%20Bath%20Salts%20addict%20Freddy%20Sharp-864742
EMMC (2012) –
ambulances deliver
agitated patients to side
door in ED, paralyze and
intubate
Mid Coast – lobster nets to
restrain agitated
patients
POFPS 40th Annual CME Symposium
August 7-9, 2015
14
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
TREATMENT
Agitation: benzodiazepines and antipsychotics
Hypoxia: oxygen
Hypotension: IV fluids
Elevate head of bed
End tidal CO2 monitor if concerns about respirations
Neurochecks (Riker sedation analgesia score)
Avoid endotracheal intubation
BENZODIAZEPINES
Midazolam
Diazepam
Lorazepam
Formulations
IV, IM
IV, PO
IV, IM, PO
Onset (min)
1-5, 15
2-5, 30
5-10, 20-30
Peak (min)
30-60
8, 60
15-20, 160, 60
T1/2 (hr)
9
72
10-20
Metabolism
CYP3A4 to OHmidazolam
CYP2C19 & 3A4 to Conjugation to
temazepam &
glucuronide
oxazepam
Equipotent
dose (mg)
25
100
20
Dose
2-5 mg IV
10 mg q5 mins
2-10 mg IV
SOURCE: Micromedex
ANTIPSYCHOTICS: BUTYROPHENONES
Haloperidol
Formulations
IV, IM,PO
Onset
<1 hr
Peak
2-6 hrs
T1/2
IV 14 hr, IM 3
wks
Metabolism
Hepatic
Dose
1-10 mg q 3045 mins
Mechanism
 competitive blockade D2
receptor
 alpha-1 adrenergic
 5HT2 receptor
Adverse Reactions
 QTc prolongation
 Movement disorders with
oral formulation
SOURCE: Micromedex
POFPS 40th Annual CME Symposium
August 7-9, 2015
15
“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
ATYPICAL ANTIPSYCHOTICS
SOURCE: Murasaki (2008) J Clin Psychopharmacol
SYNTHETIC DRUGS IN CENTRAL PA
MM/YY
ED
OBS
Inpt
Total
Synthetic drug
cases (N)
38
33
23
94
Hours to
discharge: M,
Mdn (range)
7, 5.5
(1-18)
12.5, 13
(4.5-26)
46, 26
(9.5233)
23.5, 13
(1-233)
SCB WITHDRAWAL IS SIMILAR TO CANNABIS
WITHDRAWAL SYNDROME
WITHIN HOURS AND UP
TO ONE DAY:
Irritability, emotionally
uneasy, anxiety,
insomnia, productive
cough (pulmonary
exam normal)
Anorexia, agitation, chills,
mood swings, muscle
pain
SOURCE: Gurney. Pharmacology, toxicology, and adverse effects of SCB. Forensic Sci Rev 2014
POFPS 40th Annual CME Symposium
August 7-9, 2015
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“Signs, Symptoms and Treatment of Synthetic Marijuana Abuse”
Philip W. Moore, D.O.
RESOURCES
• SAMHSA: https://findtreatment.samhsa.gov
• Erowid: www.erowid.org
• DEA: www.dea.usdoj.gov
• National Institute on Drug Abuse: www.nida.nih.gov
• Office of National Drug Control Policy:
www.ondcp.org
• Street drug prices: streetrx.com
61
QUESTIONS?
[email protected]
POFPS 40th Annual CME Symposium
August 7-9, 2015
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