Understanding Stimulant Use and Use Disorders in a New Era

Corresponding Author: Daniel Ciccarone, Justine Miner Endowed Professor of Addiction, Medicine Department of Family and Community, Medicine, University of California, San Francisco, MU3-E, Box 900, 500 Parnassus Avenue, San Francisco, CA 94143-0900, USA Tel +1 415 514-0275, ude.fscu@enoraccic.leinad, Steve Shoptaw, Department of Family Medicine, 10880 Wilshire Blvd, Suite 1800, Los Angeles, CA 90024, Tel: +1 310 794 6206, ude.alcu.tendem@watpohss

Abstract

Extending from the ‘triple wave epidemic’ of opioid-related overdose deaths, a ‘fourth wave’ of high mortality involving methamphetamine and cocaine use has been gathering force. This paper provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, and medical and behavioral treatments

Keywords: cocaine, methamphetamine, fentanyl, mortality, overdose, epidemiology, pharmacology, neurobiology, medical consequences, psychiatric consequences, medical treatment, behavioral treatment

Epidemiology

The US is in an era of unprecedented levels of drug-related mortality, evidenced by an exponential increase in deaths over a recent 38-year period. 1 The recent drivers of overdose deaths are illicit opioids; mortality from which has been described as a triple wave phenomenon. 2–4 Most recently, illicit stimulant (including psychostimulants, predominantly methamphetamine, as well as cocaine) use and medical consequences, including overdose, are rising. This paper provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, medical and behavioral treatments.

National surveys reveal increased methamphetamine use prevalence 2016–19, 5 but with considerable regional and demographic variation. 6 The national prevalence of past-year cocaine use in 2019 is estimated at 5.5 million, increasing since 2011. 5 Illicit supplies are growing as well as shifting. Seizures of methamphetamine, a proxy for supply, have risen in all US census regions including those in which supply was historically low. 7 Correspondingly, for example, methamphetamine use is rising in Massachusetts, a state where its use was uncommon in the past. 8 According to US DEA data, cocaine production estimates and US border seizures are at 10-year high levels as of 2019. 9

Extending from the ‘triple wave epidemic’ of opioid-related overdose deaths, a ‘fourth wave’ of high mortality involving methamphetamine and cocaine use has been gathering force. 10 From 2012–18 psychostimulant-related mortality has risen five-fold (from 0.8 to 3.9/100,000) and cocaine-related mortality 3-fold (from 1.4 to 4.5/100,000 pop.). 11 Rates for methamphetamine-involved deaths are higher among men and non- Hispanic American Indian or Alaska Native and non-Hispanic White individuals. 12

The current rise in stimulant-related deaths, while poorly understood, appears entwined with the ongoing opioid epidemic. 6,13–16 Polydrug use, e.g. the co-use of stimulants and opioids, may partially explain the rise in stimulant-related deaths; this is increasingly common, 6 e.g., the 3-fold increase nationally, 2015–17, in methamphetamine use among those reporting past-month heroin use. 17 Nationally, in 2019, 76% of cocaine-related overdose deaths also involved an opioid; for psychostimulant-related deaths 54% also involved an opioid; with co-involvement increasing over time 16 . Co-use of stimulants with high-potency synthetic opioids, e.g. fentanyl and fentanyl analogs, is particularly concerning. Synthetic opioids are involved in deaths attributable to psychostimulants (14%) and cocaine (40%). 14 The reasons for co-use of stimulants, particularly methamphetamine, with synthetic opioids requires exploration.

In addition to the above illicit stimulants there are rising numbers of novel psychoactive substances (NPS) - including novel stimulants such as substituted cathinones. Eutylone and N-ethylpentylone are among the two most common NPS stimulants according to recent US DEA seizure data, 9 toxicological surveillance 18 and wastewater analyses. 19

Prevalence of use data is scarce and a recent estimate using multiple sources indicated that under 3% of US adults have used any NPS in the past 12 months; estimates for younger persons were higher. 20 An estimated 5.8 percent of young adults aged 18 to 25, reported past year misuse of prescription stimulants in 2019; declining from 7.3 percent in 2015. 5

Pharmacology

Methamphetamine supply, purity and potency have increased nationally to historically high levels following shifts in source and chemical production. 9 Methamphetamine purity and potency now exceed 90% following several changes: decline in US domestic production and rise in Mexico-based production; 21 historic shift from ephedrine-based to several variants of phenyl-2-propanone (P2P)-based chemical production; 22 and increases in d-isomer to l-isomer ratio (i.e. potency is defined by the proportion of d- isomer). 22 Methamphetamine typically exists in a racemic mixture of these two stereo- isomers which have some known physiological differences: l-methamphetamine has strong peripheral a-adrenergic activity, while d-methamphetamine has 3 to 5 times the central nervous system activity (e.g. increased euphoria as well as mental health problems and addiction liability). 23 The broad clinical implications of increasing availability and use of potent d-methamphetamine need explication.

Illicit or street methamphetamine comes in liquid (rarely used on the street), powder, crystalline and pill (sometimes prescription mimics) forms. 9 Powder methamphetamine (e.g. Meth; Speed; Crank) is the HCL salt of racemic methamphetamine; crystal methamphetamine (e.g. Crystal, Ice, Tina) tends to be a purer form of d-methamphetamine and is more smokable as such. 23,24 Intake can be through oral ingestion, nasal insufflation (IN) (i.e. snorting), vapor inhalation (i.e. smoking, including “hot railing”), insertion per rectum (i.e. “booty bumping”), and injecting (IV) (i.e.“slamming”). 25 The plasma half-life following intake is 9 – 11 hours depending on route. Intravenous and intra-nasal routes lead to peak effects within 15 minutes; while smoking and oral routes take longer. Bioavailability is 100% for IV and 60–80% for other routes. Following use, approximately 70% of a dose is excreted in the urine within 24 hours. 26

Cocaine (benzoylmethylecgonine) is a naturally occurring alkaloid extracted from the leaves of the Erthroxylon coca plant, indigenous to the Andean region of South America. The powder form of cocaine (e.g. Coke, Blow, Snow, etc.) is the hydrochloride salt, which is water soluble and consumable by IN and IV routes. The basic or bicarbonate form is well known as “crack”; this is typically smoked/inhaled unless converted by acidification to a more soluble, and thus injectable, form. Cocaine HCL is typically not smoked as its vaporization temp is too high. 23 Inhaled (smoked) cocaine has the fastest onset of action (3–5 seconds) followed by IV (1–3 minutes) and IN (>10 minutes). Inhaled cocaine leads to rapid cycling of use given its immediate effect and short duration of action. Half-life is 0.7 to 1.5 hours with rapid metabolism by the liver and excretion in the urine. 27,28

Cocaine is often consumed along with heroin, a combination known as a “speedball”. 23 The expected effects are to boost the euphoria from heroin; this is more common once physical dependence to heroin sets in. The combination of methamphetamine and strong opioids, e.g. heroin or fentanyl, is known as a “goofball.” This was historically less common than the cocaine and heroin speedball but appears to be getting more common. 6,29 The combinations of stimulants and synthetic opioids appears to be driving the recent mortality wave. 16

Synthetic cathinones are a class of NPS structurally similar to cathinone, a naturally occurring chemical derived from the khat plant (Catha edulis), native to East Africa and the Arabian Peninsula. Cathinones are the chemical analogues of amphetamine and were once marketed as “bath salts” or “legal highs” to avoid regulation, and often sold as counterfeit MDMA (aka Ecstasy). Synthetic cathinones are usually consumed in pill or capsule form, but smoking and insufflation, and more rarely injection, routes are options. There is a range of dosing (1–300 mg), onset of action (2–120 minutes), and duration of effect (.25–6 hours) depending on the substance; many have unknown pharmacokinetics. Regulation, beginning in 2011 in the US, led to a decline in some of the initial products, however a diversity of cathinones has sprung up since. 30

Neurobiology

The neurobiology of methamphetamine has been well described in several excellent reviews. 31,32 In brief, methamphetamine is a potent indirect agonist at noradrenaline, dopamine and serotonin receptors and thus stimulates releases of these monoamines in the central and peripheral nervous system. Mechanisms which combine to enhance neurotransmitter release include: redistribution from neuron synapse storage vesicles to the cytosol; increased (reversed) transport from cytosol to synapse; blockade as well as decreased expression of membrane transporters; inhibition of monoamine oxidase (metabolism); and increasing the activity of tyrosine hydroxylase (increasing dopamine production). 33 Methamphetamine is twice as potent at releasing noradrenaline than dopamine and 60-fold more effective at releasing serotonin. 26

Methamphetamine acts on the major CNS dopaminergic, noradrenergic and serotonergic pathways. 34 Dopaminergic circuits, mediating reward and reinforcement processes, include mesolimbic, mesocortical circuit and nigrostriatal pathways. Noradrenergic regions include the prefrontal cortex (cognitive processes), hippocampus (memory consolidation) and medial basal forebrain (arousal). The serotonergic system is diffuse and includes regulation of diverse functions e.g. those involving pain perception, reward, satiety and impulsivity, among others. The opioidergic pathways are also affected; with intertwined effects on drug reinforcement and craving. 34

CNS effects of acute methamphetamine use include arousal, euphoria, positive mood, improvements in cognitive function, as well as anxiety. Use over time leads to down regulation of receptors and depletion of monoamine stores. It is increasingly evident that chronic methamphetamine use is involved in neuroinflammation and degeneration processes. Three molecular cascades are being investigated: oxidative stress, neurotoxic and neuroinflammation. These neurobiological cascades are associated with altered brain metabolism and parallels in chronic dysfunction similar to other degenerative CNS diseases. 33

Cocaine also boosts postsynaptic monoamine levels, not through the mechanisms outlined above for methamphetamine leading to greater release of neurotransmitters, but through presynaptic reuptake blockade. 27 In addition to boosting the dopaminergic reward pathways, repeated cocaine exposure leads to significant neuroadaptations in the excitatory neurotransmitter glutamate 35 as well as brain pathways that respond to stress. Cocaine use disorders frequently co-occur with stress- related disorders and stress can contribute to recurrence of use. 36

Similar to methamphetamine and cocaine, synthetic cathinones are psychomotor stimulants that exert their effects by impairing monoamine transporter function. Ring- substituted cathinones, e.g. mephedrone, promote neurotransmitter release (like methamphetamine) while pyrrolidine-containing cathinones (e.g. 3,4- methylenedioxypyrovalerone (MDPV)) act through reuptake blockage (like cocaine). 30

Medical and Psychiatric Complications

The medical complications of stimulant use are diverse and occur in many organ systems ( Table 1 ). Major mechanisms of organ injury include ischemia, excess central and peripheral nervous system stimulation and direct toxicity 23 . Etiology of methamphetamine-related mortality is multifaceted including e.g. cardiovascular (common), pulmonary, CNS and renal systems; in addition, intentional and unintentional fatal injuries stemming from use, are common. 26

Table 1

Medical complications of stimulant use

Abbreviations: CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; LH, luteinizing hormone

The most serious medical complications, leading to the most mortality, are cardiovascular and cerebrovascular. 33 Psychostimulants cause harm in these systems through excessive sympathetic nervous system stimulation; cocaine has an additional pro-thrombotic effect. 37 In the acute setting, chest pain is a more common presentation from cocaine than methamphetamine use. Chest pain is the most common complaint of persons using cocaine presenting to the emergency department, 38 however only a minority of patients have evidence of ischemia (10%) or acute myocardial infarction (6%). 39 Acute coronary syndrome is more likely due to vasospasm over plaque rupture. 40,41 Myocardial infarction due to plaque rupture is seen in a minority of cases and more likely stemming from cocaine use due to its prothrombic effect. Hypertension can be acute or chronic. 37 Cardiac arrythmias can develop in persons using high dose psychostimulants. Long term use leads to chronic HTN, cardiomegaly, congestive heart failure and myocardial ischemia. Myocarditis is considered a precursor to the development of dilated cardiomyopathy, a significant clinical problem among persons using psychostimulants. 42,43 Hypertensive, or hypertrophic, cardiomyopathy is less common; this resulting from profound chronic hypertension. 37 Injury to the cerebrovascular system also occurs due to persistent hypertension. Stoke, particularly hemorrhagic stroke, is found at higher rates among psychostimulant users. 44,45

There is mounting evidence that chronic methamphetamine use leads to neurodegeneration, cognitive impairment, psychiatric and psychomotor syndromes. 33 Cognitive impairment stemming from methamphetamine use is across multiple domains including executive function, memory, learning and processing speed, and motor and language skills. 46 Cocaine use is associated with milder or more transient deficits. 45 Premorbid impairments may account for some of these findings. Psychotic symptoms are common stemming from occasional use and become more frequent with regular, high-dose, or high-potency (e.g. d-methamphetamine) use. Psychotic symptom expression among persons who use methamphetamine may indicate an underlying vulnerability to schizophrenia, 45 although there are important differences: persons with methamphetamine induced psychotic symptoms had less “negative” symptoms (i.e. blunted affect, disorganization, social withdrawal) and similar levels of “positive” symptoms (i.e., grandiosity, hallucinations, paranoia) compared with individuals with schizophrenia. 32 Co-morbid mood disorders are also common among those meeting criteria for methamphetamine use disorder. 47 Abnormal psychomotor symptoms include tremors, dyskinesia, akathisia, etc., as well as repetitive and compulsive behaviors e.g. “tweaking” (due to tactile hallucinations i.e. formication). 23 Neurodegeneration of dopaminergic CNS pathways, secondary to chronic methamphetamine use, may lead to premature development of Parkinson’s disease and parkinsonism. 45 It is important to recognize that premorbid conditions, e.g. genetics, family history, childhood trauma or isolation, can led to both substance use disorders and psychiatric syndromes. 33,45

Nationwide, HIV diagnoses are edging up among persons who inject drugs (PWID); this increase is more profound among White PWID. 48,49 Recent outbreaks of HIV discovered among PWID in several US states accentuate this trend along with rising viral hepatitis infection rates. 50–53 Injection stimulant use, both of cocaine and methamphetamine, has been associated with HIV seroconversion, whether through injection practices or high risk sexual behavior, often in patterns of polydrug use. 6,54–56 Methamphetamine also incurs increased physiological risk of HIV acquisition 57 and is associated with lower rates of viral suppression among people living with HIV and therefore enhanced risk of transmission. 58

Long-term use of stimulants is frequently preformed in cycles of binging and abstinence. 23 Cohort studies estimate that following initiation of cocaine use 7% meet criteria for cocaine use disorder at 1-year; with a 15% cumulative probability of cocaine use disorder after 10 years. 59 Stimulant use disorder is a chronic relapsing condition. Criteria for meeting the diagnosis come from the Diagnostic and Statistical Manual, Fifth Edition (DSM-5) published by the American Psychiatric Association. 60 Eleven criteria are detailed including for example: craving; failure to satisfy important school, home, or work obligations; consistent desire to control use; and continued use despite psychological or physical difficulties. Three levels of severity of illness are diagnosed based on number of criteria met within a 12-month period: mild disorder (2–3 criteria); moderate disorder (4–5 criteria); or severe disorder (6 or more). Development of stimulant use disorder is strongly influenced by early childhood adversity. A recent national study found a statistically significant relationship between the number of self-reported adverse childhood experiences (ACEs) and stimulant use and use disorders among adult respondents. 61

Management of Stimulant Withdrawal Symptoms

Abstinence following prolonged use can produce withdrawal symptoms defined by DSM-5 that include trouble sleeping, trouble concentrating, tiredness/fatigue, irritability, agitation, anxiety, sadness, depression and inability to do normal activities. 60

In the inpatient and emergency department settings, patients with stimulant-related agitation are usually managed with antipsychotics 62 though these medications show no efficacy for sustaining abstinence after discharge. In outpatient settings, withdrawal symptoms are usually mild-to-moderate in severity; most are short-lived 63 and mostly absent after five weeks. On the other hand, craving for stimulants, diminishes slowly contributing to continued use or recurrence of use in the first weeks and months of abstinence. 63 Longer-term abstinence from stimulants leads some to attribute decreases in cognitive abilities, especially in settings of continued episodic use, as protracted withdrawal. 64 As no medications show consistent effects in treating stimulant withdrawal, 65 treatments are largely behavioral (e.g., cognitive-behavioral therapies, behavioral activation, 12-step facilitation and contingency management) – all of which require patients to allot cognitive resources to sustain abstinence -- resources that may be diminished from direct effects of the stimulants themselves and of the effects of stimulant withdrawal symptoms. In addition, patients who experience repeated use and recurrence of use as a consequence of failures of treatments to successfully resolve withdrawal can lose motivation to remain in treatment. There are some innovations, however. One new approach that enhances cognitive reserve is repetitive transcranial magnetic stimulation. A pilot study showed superiority in reducing methamphetamine withdrawal symptoms compared to a sham condition in a small study of men acutely abstinent from methamphetamine use disorder. 66

Medication Treatments for Stimulant Use Disorder

Evidence-based treatments, whether pharmacological or behavioral, can be considered for use to the extent they show superiority over placebo or other comparisons along defined targets ( Table 2 ). While there are no FDA-approved medications for cocaine or methamphetamine use disorders, clinical research shows some medications show statistically significant and clinically relevant outcomes over placebo. A small number of medications have data in placebo-controlled trials showing measurable reductions in stimulant use. The point worth remembering is that this benefit is due to a medication or medications, a benefit to patients that occurs directly related to the medication – and a benefit that accrues to the patient without needing to allot psychological energy or motivational resources regarding their stimulant use (or non-use).

Table 2

What would effective medication and behavioral treatments for stimulant use disorder do? a