Methamphetamine Use and Affective Disorders
Larissa Mooney, MD
UCLA ISAP, UCLA Division of Addiction Psychiatry
Tuesday, October 12th, 2021
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Methamphetamine Use and Affective Disorders
Larissa Mooney, MDAssociate Clinical Professor of Psychiatry, UCLA
Director, UCLA Division of Addiction Psychiatry
October 12th, 2021
Disclosures
There are no relevant financial relationships with
ACCME-defined commercial interests for anyone who
was in control of the content of this activity.
Outline
• Methamphetamine Use Epidemiology and Clinical Effects
• Behavioral and Medication Treatments (off-label) for MUD
• Mood D/O Comorbidity:
– Bipolar Spectrum D/O and SUDs
– Major Depressive D/O and SUDs
• Concluding thoughts
7
Amphetamine-Type Stimulants
Amphetamine
―Powder, Tablets, Liquid
―Routes of administration: oral, inhalation, injection, smoking
Methamphetamine (more potent)
―Powder: inhaled, smoked, injected
―Crystal/Ice: smoked
―Tablets: oral, crushed and inhaled, smoked, injected
Approximately 40-60 million users worldwide
“Crystal Meth” or “Ice”
• Most potent, pure and distilled type of meth
– More intense physiologic and behavioral effects
– Greater dopamine release than powdered meth
• More addictive potential
• Shaped in the form of crystalline rocks
– Commonly smoked but can be injected too
• “Ice” turns to liquid once heated
• Most illicit methamphetamine used in the U.S. is crystal meth
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Methamphetamine Use Among Treatment-Seeking Opioid Users
Ellis, Kasper & Cicero, 2018, Drug Alcohol Depend.
U.S. Stimulant Overdoses
From 2009-2018 there was an 8x increase in the
overdose death rate involving psychostimulants
(from 0.5 to 3.9 per 100,000)
Methamphetamine: chemical structure
• Exists as 2 enantiomers: levo (L) and dextro (D)
• Methamphetamine proper refers to racemic form (equal
amounts)
• Potency refers to % of drug that is the D-isomer 13
Early 2000s methamphetamine
• At its height in the 2000s, meth was primarily being made in home labs using the OTC nasal decongestant ingredient pseudoephedrine
14
• Subsequently laws were enacted to limit sale of pseudoephedrine
The P2P Method
• Manufacturers/chemists begin using different formula to make meth without pseudoephedrine
– 1-phenyl-2-propanone (P2P)
– Altered ratio of L- to D-meth
15
• DEA profiling program:
In 2010 43% seized meth
made using P2P
In 2011 79%
In 2013 95%
Methamphetamine seizures
16
Today U.S. border agents are seizing 10-
20x the amount of meth they did in 2010
Stoddard M and Alamdari N. “As nation faces opioid epidemic, in Nebraska and Iowa, meth is still the “No 1 threat.” Omaha World Herald. Oct 9, 2017. Accessed 10/16/2019.
Available at: https://www.omaha.com/news/crime/as-nation-faces-opioid-epidemic-in-nebraska-and-iowa-meth/article_87acfe3a-4708-5207-9271-3a158dc66ece.html
Purity of Mexican-produced meth has surged from 39% in 2007 to 97% today
17The Economist. Amid the opioid crisis, a different drug comes roaring back. March 9, 2019. Accessed October 11, 2019. Available at:
https://www.economist.com/united-states/2019/03/09/amid-the-opioid-crisis-a-different-drug-comes-roaring-back
Meth 2.0
Methamphetamine Mechanism of Action
•synthetic
•high lasts 8-24 hours
•T ½: 12 hours
•mechanism: increased catecholamines, DA
•limited medical uses
•Desoxyn
•neurotoxicity
(A)↓Dopamine transporters:
↓Ability to respond to non-drug rewards,
↑impulsivity, favor immediate > delayed reward
Volkow ND, Am J Psychiatry. 2001;158(3):377-382. © Copyright AAAP 2021
22
Stimulant use associated with
dysfunction in brain dopamine and
glutamate systems
Nora D. Volkow et al. J. Neurosci. 2001;21:9414-9418
©2001 by Society for Neuroscience
23
Recovery of Dopamine Transporters
with Abstinence
Clinical effects: short term
• Euphoria and “rush”
• Increased arousal
– ↑attention, ↑activity, ↑wakefulness, ↓fatigue, ↑libido
• Appetite suppression
• Autonomic and cardiovascular activation
– ↑respiration, ↑HR, ↑BP, arrhythmias, hyperthermia
• Psychiatric symptoms
– Psychosis, mood disturbances, anxiety24
Psychiatric effects of methamphetamine use
• Transient psychosis (up to 40%)
– Paranoia
– Delusions
– Visual, tactile, auditory hallucinations
– Ideas of reference
• Mood disturbances
– Depression, suicidality
– Hypomanic sx’s (e.g. racing thoughts, impulsivity)
• Anxiety, irritability
• Agitation, aggressive behavior
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Co-occurring disorders: common and complex
Primary Psychiatric Disorder
+Methamphetamine Use Disorder
Methamphetamine-induced psychiatric disorder
Psychiatric and Substance Use Disorder (SUD) Comorbidity• Individuals with lifetime mood or anxiety
disorder
– Approximately 20% with SUD
• Individuals with lifetime SUD
– 41% with mood disorder
– 30% with anxiety disorder
• Comorbidity rates higher in women with SUDs despite lower rates of SUDs than men
27Source: NESARC 2001-2002
Comorbidity Continued...
• 56% of patients with bipolar disorder (BP), and 46% of patients with schizophrenia have SUD compared to 15% of the general population.
– Higher for Bipolar I than Bipolar II
– Mixed episodes, rapid cycling subtypes more common
• 60+% of psychiatric inpatients have a current or previous SUD
• Estimated that up to 50% of patients with SUD may have a treatable psychiatric disorder.
28Source: SAMHSA, 2007
Challenges for Dually Diagnosed
• Patients with both mental illness and SUD are more likely to have
– greater illness severity
– poorer treatment (tx) adherence
than those with mental illness alone.1
• Due to complexities in patient populations, there is little consensus in the scientific literature on the best treatments.
– Co-occurring disorders often excluded from medication trials
• Ex: antidepressants have been associated with mixed substance use outcomes in those with depression in clinical trials.2,3
29Sources: 1. SAMHSA, 2007; 2. Agabio, Trogu & Pani, 2018 Cochrane Review; 3. Torrens et al., 2005
BEHAVIORAL TREATMENT INTERVENTIONS
Current Status of Treatment Approaches for Stimulant Use Disorder
• Contingency management unanimously supported in reviews (7 recent systematic reviews and meta-analyses) found to have best evidence of effectiveness.
• Including for stimulant use reduction in patients on medications for OUD
• Other approaches with less but clear evidence of support: Cognitive Behavioral Therapy (CBT) and Community Reinforcement Approach (CRA).
• Approach with evidence for treatment of a broad variety of SUD: Motivational Interviewing (MI).
• Approach with recent studies showing benefit to stimulant users: Physical Exercise (PE).
Source: AshaRani, PV, et al. 2020; Bolivar, et al., 2021; Rawson et al., 2015; Trivedi et al.,
Contingency Management
• A technique employing the systematic delivery of positive reinforcement for desired behaviors.
• In the treatment of stimulant use disorder, vouchers or gift cards can be “earned” for submission of methamphetamine-free urine samples or other behaviors that promote recovery (e.g., attendance at treatment sessions).
• Implementation examples: VA system, dHealth (app-based) platforms (e.g. reSET, Dynamicare)
PHARMACOTHERAPY
Medications for MUD - 1
Positive Signals• Bupropion (better in low severity users)1
• Mirtazapine2
• Naltrexone3,8
• Methylphenidate4
• d-amphetamine (craving/WD)5
• Topiramate (better if abstinent at tx entry)6
• Modafinil (better in hi-severity users)7
1Elkashef et al. 2008, Shoptaw et al., 2008; Heinzerling et al., 2014; Anderson et al., 2015; 2Colfax et al., 2012;
Coffin et al., 2020; 3Jayaram-Linstrom et al., 2008; 4Tiihonen et al., 2007; Ling et al., 2014; 5Galloway et al., 2011; 6Elkashef et al., 2011; 7Heinzerling et al., 2010; Anderson et al., 2012.8 8Trivedi et al., 2021
Medications for MUD - 2
Summary of Evidence – Methamphetamine •Underpowered studies, high attrition•Bupropion (300 mg/day) may be more effective in individuals
with lower use disorder severity •May be better in individuals with depression, males
• Low strength evidence that methylphenidate and topiramate may facilitate reduction in use • Topiramate better if negative urine screen at baseline• Standard dosing ranges generally studied •More recent evidence: mirtazapine (2nd trial), and combination
XR-NTX + bupropion XL
Chan B, Kondo K, et al., 2018. VA ESP Project #05-225.; Coffin et al., 2019; Trivedi et al., 2021 NEJM
Bipolar D/O and Substance Use Disorders
Bipolar D/O and SUDs
• High co-morbidity rates: comorbidity of SUD up to 60% in BP D/O (AUD 45%)
– greater severity of mood symptoms
• Rapid cycling
– increased suicide risk
– worse tx adherence
– greater EtOH withdrawal
– higher rates of hospitalization
• Recovery of SUD associated with improved mood sx’s and outcomes.
38Source: Camacho & Akiskal, 2005; Farren et al., 2012; Levin & Hennesey, 2004
Psychosocial Tx
Integrated group therapy (IGT) best studied and effective for tx of co-occurring SUD + BP Disorder (developed by Weiss and colleagues)
39Source: Gold et al., 2018
Evidence for Comorbidity Tx…
• Randomized, double blind trial of pts with stimulant use d/o and BP d/o (N=80), quetiapine vs. risperidone.
– Both associated with reduced mood sx’s and cravings, and this was associated with reduced stim use
• Open label study (N=15) cocaine use d/o w/ BP d/o, therapeutic doses of VPA associated with reduced cocaine use
40Sources: Salloum et al., 2007; Nejtek et al., 2008 Journal of Clin Psychiatry; Coles, Sasiadek & George, 2019 review
Depression and SUDs
Treatment of Depression in Patients with Alcohol or Other SUD (Meta-Analysis)
• 14 randomized, double-blind, placebo-controlled trials
– Participants with unipolar depression & SUD
• 8 studies alcohol, 4 studies OUD/methadone, 2 cocaine
• 5 studies of tricyclic antidepressants, 7 of SSRIs, 2 others
• N=848 participants
42Source: Nunes & Levin, JAMA 2004
Results:
• Antidepressant medication modestly effective for treatment of depressive disorders among patients with SUD
• Improvement in depressive sx’s is associated with reductions in substance use
– Studies with greater depression effect sizes showed reduced substance use
– Studies with lower depression effect sizes showed no reduction in substance use
• Diagnosis of depression after one week of abstinence was associated with greater antidepressant effect
43Source: Nunes & Levin, 2004
Depression and SUDs
Current recommendations that alcohol and SUD not be a barrier to treatment of depression
44Source: Agabio, Trogu & Pani, 2018 Cochrane Review
• Care is needed in diagnosis of depression: period of abstinence is preferred but not required
• Antidepressant treatment may have limited impact on alcohol and drug use (reduced amount vs. abstinence)
• Specific psychosocial or pharmacological interventions for addictive disorders will be necessary
Emerging Evidence for Repetitive Transcranial Magnetic Stimulation (rTMS) for Addiction
• rTMS of frontal brain regions produces a selective stimulation of hippocampal dopamine (DA) release
– Positioning DA as a key candidate neurotransmitter system directly and selectively modulated by rTMS
• Long-term neurophysiological changes induced by rTMS have the potential to affect behaviors relating to drug craving, and relapse.
• Innovative, safe and cost-effective for some SUDs
45Source: Diana et al., 2017
Effects of rTMS on Craving and Substance Consumption (Review and Meta-analysis)
• rTMS has been studied for substance cravings and use outcomes (mostly nicotine, some cocaine, EtOH).
– 26 RCTs
– N=748 patients
• rTMS appeared to have an acute effect on reducing craving and substance consumption in patients with SUD.
– Anti-craving effect may be associated with stimulation dose.
46Source: Zhang et al., 2019
Concluding Thoughts
47
Importance of good psychiatric
history and interview for
clinical symptoms, medication
history.
Psychosocial treatments/
adjuvant medications to target SUD are important in
those with CODs.
Evidence for BP d/o, ADHD, PTSD is
strongest —treatment of the
underlying psychiatric illness will improve the
SUD, even if active.
Integratedtreatment for
CODs preferred.
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Thank you! Larissa Mooney, MD
All photos: Photograph © 2003 by Alan Nyiri, courtesy of the Atkinson Photographic Archive
Questions?
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