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Again another alcohol related death : Preventable…

 

Verne Troyer’s death ruled a suicide caused by alcohol abuse: L.A. coroner

When Verne Troyer died unexpectedly in April, there was speculation it was a suicide — and now the L.A. coroner’s report confirms it.

The case is officially closed on the death of the actor who was Mini-Me in the Austin Powers films with the report listing the manner of death as “suicide” and the cause being “sequelae of alcohol intoxication,” which is better described as alcohol abuse. (“Sequelae” means “a condition that is the consequence of a previous disease or injury.”) When the 49-year-old was taken from his North Hollywood home to the hospital, it was reported that he had very high alcohol levels in his body, leading to alcohol poisoning.

 

The death of “Austin Powers” actor Verne Troyer has been certified as a suicide, the Los Angeles County Medical Examiner-Coroner’s office said Wednesday.

According to the coroner’s office, Troyer died in April from sequelae of alcohol intoxication. Sequelae refers to a condition that was the consequence of a previous disease or injury.

Troyer died after being taken by paramedics from his North Hollywood, California home to a hospital in Van Nuys for reported alcohol intoxication. He was 49.

“Verne was also a fighter when it came to his own battles. Over the years he’s struggled and won, struggled and won, struggled and fought some more, but unfortunately this time was too much,” read the statement. “Depression and Suicide are very serious issues. You never know what kind of battle someone is going through inside. Be kind to one another. And always know, it’s never too late to reach out to someone for help.”

The actor was hospitalized earlier that week after emergency personnel responded to a call at his residence. A spokesperson for the Los Angeles Police Department told TheWrap that there was a call regarding a medical emergency, resulting in Troyer being transported to a local hospital.

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The pros and cons of ketamine

Geuris “Jerry” Rivas, a native of New York, was diagnosed with severe obsessive-compulsive disorder when he was 15. Obsessions with organizing and reorganizing the belongings in his bedroom — posters, comic books, videos — took over most of his life.

Forced by germ obsessions to compulsively wash and rewash his hands, he started wearing gloves all day to both protect him from the germs and stop him from washing his hands raw. Now, at 36, OCD symptoms continue to cost him jobs and relationships. He’s managed to turn his organizational skills into a profession — he’s a home organizer and house cleaner — but still he struggles daily with his obsessions.

“It’s caused me a great deal of suffering,” Rivas says. “I’ve tried many, many medications. I’ve wasted so much of my life.”

In 2012, running out of answers, Rivas took part in the first clinical trial to test ketamine as a treatment for OCD. While ketamine is approved by the U.S. Food and Drug Administration as an anesthetic, it is also an illicit party drug known as “Special K,” with hallucinogenic effects and the potential for abuse. Over the past 10 years, dozens of small studies of ketamine’s ability to treat a variety of mood and anxiety disorders have reported remarkable results — including the sudden alleviation of treatment-resistant depression, bipolar disorder and post-traumatic stress disorder. And these effects lasted days, sometimes weeks, after the hallucinogenic effects of the drug wore off.

With a single infusion of the drug, Rivas experienced for two weeks what it was like to live without the compulsions and obsessions that had for years controlled his life.

“I felt like, for the first time, I was able to function like a regular person,” he says.

Illustration of a giant K being painted by a man in a white coat

Pros and cons

Ketamine has brought hope to a psychiatric field desperate to find new treatments for severe OCD, a chronic condition marked by debilitating obsessions and repetitive behaviors. Current treatments, which include antidepressants such as Prozac, can take months to have any effect on the disease, if they work at all.

“Severe OCD takes such a toll on patients,” says Carolyn Rodriguez, MD, PhD, who as a researcher at Columbia University ran the OCD trial. Now an assistant professor of psychiatry and behavioral sciences at Stanford, she has continued to explore the pros and cons of using ketamine to treat OCD. “The constant, intrusive thoughts that something is contaminated, the checking and rechecking, the repetitive behaviors. It interferes with your life, your jobs, your relationships.”

Ketamine was developed in the 1960s and has been used for decades as an anesthetic during surgery. It remains a mystery just how the drug works in the brain, and there are safety concerns. There is evidence from people who take the drug routinely — in much higher doses — that chronic, high-frequency ketamine use may be associated with increased risk of bladder inflammation and cognitive impairment, Rodriguez says. And if taken regularly, it can lead to dependence.

But researchers like Rodriguez are intrigued about the drug’s potential to help them identify a whole new line of medicines for fast-acting treatment of mental health disorders.

“What most excites me about ketamine is that it works in a different way than traditional antidepressants,” Rodriguez says. “Using ketamine, we hope to understand the neurobiology that could lead to safe, fast-acting treatments. I feel that is part of my mission as a physician and researcher.”

‘Right out of a movie’

Rodriguez’s interest in ketamine as a treatment for OCD was sparked about a decade ago when she was starting out as a research scientist at Columbia. A small, placebo-controlled study published in 2006 by a mentor of hers, Carlos Zarate, MD, now chief of the section on neurobiology and treatment of mood disorders at the National Institute of Mental Health, had shown that ketamine induced dramatic improvement in treatment-resistant depression within two hours of infusion. It was a landmark study, drawing attention among the psychiatric community and launching a new field of research into the use of ketamine to treat various mood and anxiety disorders.

“What most excites me about ketamine is that it works in a different way than traditional antidepressants.”

Rodriguez, intent on searching for better, faster treatments for her patients like Rivas with OCD, took note. There was an emerging theory that ketamine affects the levels of the neurotransmitter glutamate in the brain and increasing evidence that glutamate plays a role in OCD symptoms, she says. Perhaps ketamine could help regulate OCD symptoms as well as depression.

In 2013, Rodriguez and colleagues published their results from that first clinical trial of ketamine in OCD patients. The trial randomized 15 patients with OCD to ketamine or placebo.

In those patients who were given ketamine, the effect was immediate. Patients reported dramatic decreases in their obsessive-compulsive symptoms midway through the 40-minute infusion, according to the study. The diminished symptoms lasted throughout the following week in half of the patients. Most striking were comments by the patients quoted in the study: “I tried to have OCD thoughts, but I couldn’t,” said one. Another said, “I feel as if the weight of OCD has been lifted.” A third said, “I don’t have any intrusive thoughts. … This is amazing, unbelievable. This is right out of a movie.” And while nearly all initially had dissociative effects like feelings of unreality, distortions of time or hallucinations, they were gone within two hours after the start of the infusion.

“Carolyn’s study was quite exciting,” Zarate says, adding that there were a number of similar, small but rigorous studies following his 2006 study that found fast-acting results using ketamine to treat bipolar disorder and post-traumatic stress disorder.

“We had no reason to believe that ketamine could wipe out any symptoms of these disorders within hours or days,” he says.

So how does it work?

Virtually all of the antidepressants used in the past 60 years work the same way: by raising levels of serotonin or one or two other neurotransmitters. Ketamine, however, doesn’t affect serotonin levels. Exactly what it does remains unclear.

“There’s a recognition that people like me and others are using the drug to treat patients now. There’s an incredible need for something.”

Since coming to Stanford in 2015, Rodriguez has been funded by the National Institute of Mental Health for a large clinical trial of ketamine’s effects on OCD. This five-year trial aims to follow 90 OCD patients for as long as six months after they’ve been given a dose of ketamine or an alternative drug. Rodriguez and her research team want to observe how ketamine changes participants’ brains, as well as test for side effects.

Ultimately, Rodriguez says, she hopes the study will lead to the discovery of other fast-acting drugs that work in the brain like ketamine but without its addictive potential.

Recent research in the field indicates that the glutamate hypothesis that triggered her pilot study might be further refined.

“Ketamine is a complicated drug that works on many different receptor sites,” she says. “Researchers have fixated on the NMDA receptor, one of the glutamate-type receptors, but it might not be the only receptor bringing benefit.”

In May 2016, researchers from NIMH and the University of Maryland — Zarate among them — published a study conducted in mice showing that a chemical byproduct, or metabolite, created as the body breaks down ketamine might hold the secret to its rapid antidepressant actions. This metabolite, hydroxynorketamine, reversed depressionlike symptoms in mice without triggering any of the anesthetic, dissociative or addictive side effects associated with ketamine, Zarate says.

“Ideally, we’d like to test hydroxynorketamine and possibly other drugs that act on glutamate pathways without ketamine-like side effects as possible alternatives to ketamine in OCD,” Rodriguez says.

Beyond the clubs

Meanwhile, dozens of commercial ketamine clinics have popped up across the country, making treatments available to patients who are searching for help to stop their suffering now. Medical insurance companies usually cover ketamine’s FDA-approved use as an anesthetic but won’t cover its use for other purposes, such as mental health disorders. So patients who have run out of treatment options are paying hundreds of dollars a dose for repeated ketamine infusions.

“The fact that these clinics exist is due to the desperation of patients,” says Rodriguez.

She and other researchers are calling for guidelines to protect patients and more research to learn how to use the drug safely.

“I think it’s a game changer, and it’s here to stay,” says David Feifel, MD, PhD, professor emeritus of psychiatry at UC-San Diego, who studies the effect of ketamine on clinical depression. Feifel began prescribing the drug for patients with treatment-resistant depression in 2010.

“I’ve found it to be very safe,” Feifel says, adding that the American Psychiatric Association this year issued safety guidelines on how to use ketamine clinically for treatment of depression.

“There’s a recognition that people like me and others are using the drug to treat patients now,” he says. “There’s an incredible need for something.”

The drug hasn’t worked for everyone he’s treated, Feifel says, but for many it’s been “life-changing.”

Rodriguez says she understands what motivates the clinicians to prescribe the drug now to patients in dire straits — those who are suicidal or who have tried every possible medication and therapeutic option and continue to suffer each day.

“I see it as a way to treat people whose OCD is very, very severe,” she says. “People who can’t come out of the house, who are suicidal, who have no other options.

“I just don’t like the idea of people being in pain,” Rodriguez adds. “I want to see science translated into treatments now.”

Meanwhile, researchers are learning more about the drug. Janssen Pharmaceutical is testing the efficacy of a version of ketamine, known as esketamine, as a therapy for treatment-resistant depression and for major depressive disorder with imminent risk for suicide. The FDA has fast-tracked both investigations. At Stanford, Alan Schatzberg, MD, a professor of psychiatry and behavioral sciences, along with other faculty including Rodriguez, is studying the mechanism of action for ketamine in treating depression.

Rodriguez is also interested in using ketamine to kick-start a type of cognitive behavioral therapy called exposure and response prevention, an evidence-based psychological treatment designed to help patients overcome OCD. The therapy involves teaching patients with OCD to face anxieties by refraining from ritualizing behaviors, then progressing to more challenging anxieties as they experience success.

Relaxation and other techniques also help patients tolerate their anxiety — for example, postponing the compulsion to wash their hands for at least 30 minutes, then extending that time period.

“My goal isn’t to have people taking ketamine for long periods of time,” Rodriguez says. But perhaps a short-term course of ketamine could provide its own kind of exposure and response prevention by allowing patients to experience that it is possible not to be controlled by their OCD, she says.

Rivas well remembers that infusion of ketamine he received during Rodriguez’s first clinical trial to test the drug. The rush made him feel “like Superman.”

“I felt like my body was bigger, that I was more muscular, that I could tackle anything,” he says. But that feeling only lasted the duration of the 40-minute infusion. His OCD symptoms disappeared immediately and were still gone for two weeks after.

“I was amazed that something like that would work and work so fast,” he says. His OCD symptoms today are still intrusive, but he manages to keep them under control by taking antidepressants and seeing a therapist. Still, each day when he comes home from work, he has to put gloves on before he enters his apartment building, and as soon as he enters his apartment, he must wash his hands.

“It’s a ritual now,” he says. “There has never been a time that I haven’t done that, except those two weeks after the ketamine.”

When he heard that certain private ketamine clinics are now offering the drug as treatment for OCD, he said he understands why patients take the risks and pay the high prices. As more research has become available, he’s begun considering it himself.

“I’ve been suffering through my OCD for so long, I’ve gotten to the point where I’d try anything,” he says.

USING KETAMINE TO TREAT SEVERE MENTAL ILLNESS conversation with Stanford psychiatrist Carolyn Rodriguez, MD, PhD, about how she got interested in the use of ketamine to treat obsessive-compulsive disorder and how she is determined to find out why, in studies, the drug has provided relief from symptoms.

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While America wages war on opioids, meth makes its comeback – CNN

 

(CNN)For Capt. Mark Wollmershauser Jr. and the Tulsa Police Department, the late-2000s and early 2010s were an extremely dangerous time.

In Oklahoma, a state that is no stranger to the scourge of methamphetamine addiction, those years were the heyday of the “shake and bake” method — a rudimentary way of making meth using just cold medicine, some toxic chemicals and an empty two-liter bottle.
The technique is simple enough that many addicts can cook their own meth, but with one tiny misstep, the chemical reaction that occurs inside can cause deadly explosions.
By 2011, Wollmershauser and his narcotics unit were finding and dismantling hundreds of these vessels in meth labs around the city.

A display of items used in the &quot;shake-and-bake&quot; method of manufacturing methamphetamine is shown in Oklahoma City. The items shown were purchased for display purposes.

“People were not just burning themselves while cooking meth but were causing damage to other residents that had nothing to do with methamphetamine,” he said. “It was a really horrible time.”
When new laws were enacted to limit access to pseudoephedrine — an allergy drug used in making meth — the proliferation of these mobile labs waned. After responding to a high of 431 meth labs in 2011, his department encountered just 19 last year.
But Wollmershauser said that didn’t spell the end of Tulsa’s meth problem. In fact, officials across the state say they are seizing meth that is purer, cheaper and in greater quantities than ever before, with most of it coming from south of the border.
And while much of America is focused on combating the devastating impacts of opioid addiction, some states like Oklahoma are struggling to fight a new battle against an old foe.

The role of Mexican ‘superlabs’

Richard Salter has been with the Drug Enforcement Administration for 27 years, most recently as the special agent in charge for the state of Oklahoma.
He said the meth problem in Oklahoma is getting worse, and points to Mexican cartels — in particular, the powerful Sinaloa cartel — as the reason.
As it became more difficult and dangerous to produce meth in the United States, cartels recognized an opportunity to fill the void.
“They came in with much purer, much cheaper meth and just flooded this region of the country,” Salter said.

A Mexican Army expert stands near containers with crystal meth paste at a clandestine laboratory in Mexico&#39;s Baja California state. &quot;Superlabs&quot; like this one can produce hundreds of pounds of crystal meth daily.

Salter said in 2012, the DEA was buying meth undercover off the streets for $1,100 an ounce. Today, his agents are regularly getting ounces for just $250 to $450.
“That’s as cheap as I have ever seen methamphetamine my entire career,” he said.
The reason for the drop in prices is the scale of production that the Mexican cartels have achieved. Whereas “shake and bake” labs could turn out lots of small batches, so-called “superlabs” in Mexico produce hundreds of pounds daily.
Salter said most of the meth his agents seize first comes across the US-Mexico border in California or Arizona, before making its way through the interstate highway system and temporary stash houses on its way to Oklahoma.
Along the border, officials with US Customs and Border Protection also report a steep increase in the amount of meth they are seizing.
Anne Maricich, deputy director of field operations for the agency’s San Diego ports of entry, said her field office has seen a 50% increase in the amount of meth seized compared to this time last year.
“The other hard narcotics like cocaine, heroin and fentanyl, we see them — they’re prevalent at our border crossings, but nowhere near the quantities that we see of meth,” she said.
On the streets of Oklahoma, this influx of cheap and powerful meth has had deadly consequences.
The number of lethal meth overdoses in the state has more than doubled in recent years, rising from 140 in 2012 to 335 deaths in 2016. In 2017, there were 327 meth overdose deaths, but that tally is incomplete and the actual number is likely higher, according to Mark Woodward, spokesman with the Oklahoma Bureau of Narcotics.
“There’s so much attention — not just in Oklahoma, but nationwide — on the opioid crisis,” said Woodward. “But our single most deadly individual drug is methamphetamine.”
Perhaps no city has been hit harder by this latest meth epidemic than Tulsa.
In just the first six months of 2018, Wollmershauser said his Special Investigations Division has already surpassed the amount of meth they seized in all of 2017 by 30 pounds.
He can’t explain why the problem is more severe here than in other parts of the state, but he doesn’t think incarceration is the solution.
Wollmershauser said his department is trying to use more “front end diversion” tactics to help addicts get treatment without getting the criminal justice system involved, while also aggressively pursuing the cartels and other large-scale distributors.
While the amount of meth his officers has seized has risen, he said his department is on track to reduce the number of arrests by 40% this year.
“I think we’re definitely targeting the right folks that are taking advantage of our city and citizens, but the addiction is strong and it’s difficult,” Wollmershauser said.

How meth fueled a crisis behind bars

Lindsay McAteer’s struggles with anxiety and depression led her to self-medicate as a teenager.
At age 14, her boyfriend at the time introduced her to meth.
“I immediately liked it,” McAteer said. “It gave me a false sense of identity and a false sense of accomplishment.”
It was the beginning of a 20-year struggle with the drug that nearly ended with a life sentence.
After using meth for several years, she said she stopped for a brief period, but after she was laid off from work and had her house foreclosed on, her addiction spiraled out of control.
“I had nothing,” McAteer said. “I was losing everything, and meth was able to make me feel like everything was OK, despite the fact that nothing was OK.”
In addition to using meth, McAteer began selling the drug. She was eventually arrested for trafficking and found herself staring at a possible sentence of 12 years to life.
Mass incarceration is also an issue in Oklahoma — particularly among women — and lengthy sentences for drug offenses are a major contributing factor, according to analysis by Reveal from The Center for Investigative Reporting. The state has the nation’s highest female incarceration rate, with 149 out of every 100,000 women locked up, more than double the national average.

The total chaos of meth addiction

But even for those like McAteer who face time in prison, there are sometimes alternatives to a life behind bars. Women in Recovery, or WIR, is an intensive program for women who are looking at lengthy sentences for drug offenses in Tulsa County.
With the door of a prison cell the only other option that was open to her, McAteer entered WIR in August 2014.
Mimi Tarrasch, the executive senior director for WIR, said that many of the program’s participants are multi-substance users, but at least 60% have seen their addictions lead them to meth.
“Early on, because it’s a stimulant, they feel wonderful and it makes them productive and motivated,” said Roxanne Hinther, clinical director for WIR. “But ultimately, they can’t take care of their children and they lose everything they have.”
Tarrasch said that most of the women in her program have been battling addiction for 13 to 15 years, which takes a huge toll on their health and wellness, and that of their family. Many have also experienced traumatic events, from childhood abuse to sexual assaults and domestic violence.
Using a range of treatments, training and education, the program gives women who would be spending time behind bars a second chance at a productive and fulfilling life.
McAteer graduated from WIR in 2016 and has now been in active recovery for more than four years. Today, she works as a housing compliance specialist for the Mental Health Association Oklahoma.
Since Women in Recovery began in 2009, 390 women have graduated, with 6.7% of graduates relapsing or falling back into criminal activity.
“I can say that recovery is definitely possible, and I can say that treatment is the answer versus punishment,” McAteer said. “It’s not foolproof — I can’t say that everyone is able to use this [program] the way it’s designed to work, but the vast majority of us do.”
______________________________________________________________________________
Treatment of Methamphetamine use:
Abstract
Copyright © 2016, Zahedan University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Background
2. Objectives
3. Patients and Methods
4. Results
5. Discussion
Acknowledgements
Footnote
References
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Current Research on Methamphetamine: Epidemiology, Medical and Psychiatric Effects, Treatment, and Harm Reduction Efforts

Abstract

Background

Methamphetamine (MA) which is known as “shisheh” in Iran is a drug that widely is used in many parts of the world and it is near to a decade that is available for the most drug users and has a considerable prevalence of use. Due to high abuse prevalence and very new challenging phenomenon, it is very important that researchers and treatment providers become more familiar with different aspects of MA.

Discussion

It has multiple neurobiological impacts on the nervous system, some of which are transitory and some longer lasting. MA activates the reward system of the brain and produces effects that are highly reinforcing, which can lead to abuse and dependence. Routes of administration that produce rapid onset of the drug’s effects (i.e., smoking and injection) are likely to lead to more rapid addiction and more medical and psychiatric effects. No effective pharmacotherapies have been developed for the treatment of MA dependence; although, this is an area of very active research. Several behavioral treatments have been shown to reduce MA use, but better treatments are needed.

Conclusion

Harm reduction strategies for non-treatment seeking MA users are needed to reduce the risk of human immunodeficiency virus and other medical risks. The research agenda for MA is substantial, with development of effective pharmacotherapies as one of the most important priorities. Appropriate and effective response for prevention, treatment and harm reduction services due to increasing problems regarding MA in Iran and some other countries in the region.

Keywords: Methamphetamine, Epidemiology, Side-effects, Treatment, Harm reduction, Iran

Introduction

Worldwide, as many as 52 million individuals aged 15-64 are estimated to have used amphetamine-type stimulants for non-medical purposes at least once in the past year. Methamphetamine (MA) is the second most widely abused illicit drug in the world (following cannabis); its users nearly outnumber heroin and cocaine users combined. About two-thirds of the world’s MA/amphetamine users reside in East and Southeast Asia, followed by approximately one-fifth in the Americas (specifically the United States and Northern Mexico).

Iran has a special situation in Asia and Middle East, with regard to amphetamine type stimulants (ATS) availability and use. Prior to 2004, there were no reported seizures of ATS in Iran. The first reported of ATS seizure was in 2005, followed by an increasing number of seizures, year by year. The amount of MA seized qualified Iran for ranking 5th in ATS seizures in 2010 and 2011., There was a 400% increase in the amount of ATS seized in Iran between 2010 and 2011, this 1 year rate of increase compares to increases of 238% in Mexico 166% in Thailand, 153% in USA and 140% in China, put Iran in 1st ranking for an increase in seizure.

Discussion

Pharmacology of MA

MA increases activation of the dopamine, norepinephrine, and serotonin systems. MA use causes the release of dopamine into the synaptic cleft, increasing dopamine concentration. Furthermore, MA inhibits transport of dopamine into the storage vesicles, thus increasing the synaptic dopamine concentration. This abnormally high concentration of dopamine contributes to the severe neurotoxicity of MA. Heavy daily MA use and high dosages over a long duration result in neurobiological deficits that do not resolve until many months following cessation of use.

Besides the acute dopaminergic stimulation, MA produces norepinephrine effects such as mild elevation of pulse and blood pressure and cutaneous vasoconstriction, but it is important to know that some chronic users shows a unpredictable hypotension during general anesthesia in operation rooms, which one of the possible cause is down-regulation of endogenous catecholamine receptors.

Higher doses increase central nervous system stimulation, manifested as increased alertness and compulsive or repetitive behavior. MA users have increased sympathomimetic effects such as dizziness, tremor, hyperreflexia, pyrexia, mydriasis, diaphoresis, tachypnea, tachycardia, and hypertension. The drug has a prolonged half-life (10-12 h) and long duration of action. Elevated levels of dopamine in the central nervous system are associated with the reinforcing and highly addictive properties of MA.

Route of administration

MA can be used orally or intranasal, or it can be smoked or injected intravenously. Injection and smoked administration of MA carry higher risk for acute toxicity as well as greater potential for the development of addiction. In general, the rapid onset of euphoria provided by these routes of administration provides a powerful stimulus for re-administration of the drug to maintain the euphoria. When injected intravenously, MA reaches cerebral circulation in 10-15 s. When smoked, it reaches the brain in 6-8 s; smoking can achieve blood levels comparable to those reached through intravenous injection., These routes also have the most potential for toxicity due to rapid dose escalation. Intranasal insufflation (snorting) of MA produces euphoria in 3-5 min. Absorption of orally administered MA occurs more slowly from the intestines, with peak plasma levels being reached 180 min after dosing. Clinical reports recount dependence-level users taking 50 to 1000 mg of MA daily.

MA injection in Iran is reporting recently in different cities with high rate of injection and shared injection both in closed and open setting, which is an alarming sign for human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) prevention programs in Iran.

Symptoms of MA use, misuse, and dependence

MA use increases blood pressure, body temperature, heart rate, and breathing rate. Continued use is common because of rewarding effects such as euphoria, reduced fatigue, reduced hunger, increased energy, increased sex drive, and increased self-confidence. Negative acute effects include abdominal cramps, shaking, high body temperature, bruxism (teeth grinding), stroke, and cardiac arrhythmia, as well as increased anxiety, insomnia, aggressive tendencies, paranoia, and hallucinations.

The acute subjective effects of MA use depend on the amount used and route of administration. The effects of injection and smoking are rapid and intense, often described as a “rush,” followed by euphoria and a sense of increased energy, wakefulness, alertness, and increased libido. Heart rate, blood pressure, and breathing rate increase and many users will grind their teeth and pick at their skin. Effects of MA can last up to 12 h. Due to the development of tolerance, chronic MA users repeat dosing every few hours in “binging” episodes, which can result in paranoia, hallucinations, delusions, mood disturbance, and formication (tactile hallucination of bugs crawling on the skin).

After prolonged or heavy use of MA, a withdrawal syndrome may emerge characterized by dysphoric mood, anhedonia, fatigue, increased appetite, sleep disturbance, and slowing, or acceleration of psychomotor activity. The severity of withdrawal is related to the duration and intensity of recent MA use. MA-dependent individuals have reported remission of the most severe withdrawal symptoms within several days to 3 weeks; although, there have been numerous clinical observations of more subtle symptoms (i.e., anhedonia) lasting for several months., Apathy has been reported more frequently than depressed mood, suggesting that anhedonia may be more problematic than major depressive disorder following cessation of MA use.

Psychiatric considerations

MA-associated psychiatric impairment may occur in several domains: cognitive, intellectual, or affective. The drug’s contribution to impairment may be acute, delayed, or cumulative/residual. Psychiatric impairment appears to correlate with duration of use as well as total and peak amounts of MA absorbed. Neurocognitive deficits associated with chronic MA use include impairments in episodic memory, executive functions, and psychomotor tasks related to frontostriatal and limbic circuits. MA use may also be associated with deficits in attention, memory, and language. Neurocognitive impairment may persist for 9 months or longer following cessation of MA use, but recovery in DAT activity and improvement in cognitive functioning is possible with sustained abstinence.

Psychiatric symptoms have been well-documented in MA users. Anxiety, depression, insomnia, and psychosis are among the most commonly reported symptoms associated with MA dependence, and individuals presenting to the emergency department in the context of MA intoxication may be agitated, violent, or suicidal., Though minor agitation may be treated by placing the individual in a quiet, less stimulating environment, benzodiazepines, or neuroleptics may be required for more severe MA-related agitation or psychosis.

Psychiatric symptoms may vary as a result of individual differences in sensitivity to MA, amount and/or frequency of use, and route of administration. Individuals who use intravenously and who have a family history of psychotic symptoms are at heightened risk for the development of MA-related psychosis, which may mimic schizophrenia. Clinical symptoms of MA-induced psychosis include paranoia, delusions, and hallucinations., Psychosis occurs at least intermittently in a significant proportion of MA users, with wide variation in the severity and clinical course of symptoms.

Although the majority of MA-related psychiatric symptoms typically remit within a week of abstinence,a subset of MA users experience prolonged psychiatric symptomatology, even in the absence of a prior reported history of mental illness., Although MA is one of the most famous drugs in a drug-induced psychosis, but recent studies finding suggest that designer drugs may have severe side-effects in this domain than MA.

Medical considerations

Chronic use of MA results in a variety of medical consequences, including cardiovascular disease, pulmonary problems, neurological problems, and dental disease. Long-term MA use is associated with elevated rates of infectious diseases, including HIV, hepatitis B and C, and endocarditis. Factors mediating the relationship between MA use and infectious diseases include increased risky sexual behaviors occurring in the context of MA intoxication, as well as injection drug use and associated risk behaviors (e.g., needle sharing).

Clinical considerations

The groups disproportionately impacted by MA have been women and men who have sex with men (MSM). Unlike with cocaine and heroin, where a very high proportion of users are male, women use MA at rates almost equal to men. Surveys among women suggest that they are more likely than men to be attracted to MA for weight loss and to control symptoms of depression. Over 70% of MA-dependent women report histories of physical and sexual abuse and are more likely than men to present for treatment with greater psychological distress. MA has been a popular drug among MSM since the 1980s. MSM report using MA to combat feelings of loneliness and isolation and to promote sexual desire and sexual behavior., In addition to the appeal of its sexual effects, MA serves as a coping tool for many MSM with HIV or AIDS. MSM with HIV report using MA to manage symptoms of HIV disease, such as fatigue, or to remedy HIV-related “burn out” and depression.

MA’s dramatic effect on sexual desire and sexual behavior has been a major public health concern, as it has been associated with increasing risk for transmission of HIV., Sexual practices associated with MA use include increased numbers of casual and anonymous sexual partners, increased anal intercourse, decreased condom use, sex trading, group sex, and more frequent and longer episodes of sexual activity. The multicenter AIDS cohort study and several other studies found a high correlation between MA use and HIV seroconversion and other sexually transmitted infections, such as syphilis, gonorrhea, and hepatitis. Treatment of MA dependence may be one of the most effective strategies in reducing the spread of HIV and other associated sexually transmitted infections.

Pharmacotherapy treatments

Until date, there is limited literature on evidence-based pharmacological treatment approaches for MA withdrawal. Antidepressants and anxiolytics may be used to ameliorate depressive and anxiety symptoms, though research suggests only limited benefits of antidepressants in reducing withdrawal symptoms.Neuroleptics may be used to treat MA-induced psychotic symptoms in the context of intoxication or recent use, and a recent study demonstrated the equivalent efficacy of Olanzapine (Zyprexa), an atypical neuroleptic, and haloperidol (Haldol), atypical neuroleptic, in improving psychotic symptoms related to amphetamine use.

The research literature lacks substantiation of efficacy of any medication as a treatment for MA dependence. Past work has failed to determine the efficacy of compounds such as selegiline (Eldepryl), sertraline (Zoloft), gabapentin (Neurontin), rivastigmine (Exelon), risperidone (Risperdal), ondansetron (Zofran), and Abilify (Aripiprazole) as potential treatments for MA dependence.

Medication development for MA addiction generally strives to address deficits caused by MA use or associated with withdrawal. The target of therapeutic development has focused on initiation of abstinence and prevention of relapse. Bupropion (Wellbutrin), modafinil (Provigil), naltrexone, mirtazapine (Remeron), and baclofen (Lioresal) have exhibited limited utility in treating MA addiction, especially in conjunction with behavioral therapy. Other medications (e.g., lobeline, vigabatrin) are under consideration, but evidence for efficacy is lacking and the scant data that do exist contain no information regarding the suitability for various populations. Also of interest is a “replacement” or “substitution” approach with other stimulants such as methylphenidate,, akin to methadone for opioid addiction. As with methadone, however, such a pharmacotherapy enables the patient to rehabilitate in other life areas, but does not lead to near-term abstinence from stimulants. There is at least one clinical trial in Iran, which recently compared aripiprazole with risperidone for treatment of MA induced psychosis, based on findings of this study risperidone is better choice for patients with positive psychosis symptoms and vice versa aripiprazole is better for patients with negative psychosis symptoms.

Matrix model of cognitive behavioral therapy (CBT): The matrix model incorporates principles of CBT in individual and group settings, family education, motivational interviewing, and behavioral therapy that employ CBT principles. This manualized therapy has been proven effective in reducing MA use during the 16-week application of the intervention, in comparison to a “treatment as usual” condition. The matrix model has been evaluated as a stand-alone treatment for subgroups of MA abusers (e.g., gay and bisexual men and heterosexuals) and as the behavioral treatment platform in pharmacotherapy trials for MA dependence.

Contingency management (CM) therapy for treatment of stimulant use disorders employs principles of reinforcement for demonstration of desired behaviors. Drug use can be brought under control if desired behaviors that replace or compete with drug use are followed by rewards to increase the frequency of these behaviors. Thus, CM combined with a pharmacotherapy, such as modafinil that potentially enhances cognition or restores memory/learning processes impacted by MA dependence could be a potent approach. CM and CBT have been assessed for comparative effectiveness in treating stimulant dependence with a group of cocaine- and MA-dependent individuals-participants who received CM were retained in treatment significantly longer than those who received only CBT and they provided more stimulant-negative urine samples.

Another approach is empowering patients and their families by empower based interventions which could be effective for Iranian patients.

Harm reduction

Some MA users who do not want treatment and cannot stop using MA should be considered as a target group of harm reduction services. Harms of MA use includes:

  • Direct medical harms such as cardiovascular disease, pulmonary problems, liver disease, strokes, pregnancy complications, neurological/mental complications, and dental complications.
  • Indirect medical harms such as HIV and hepatitis B and/or C because increase in high risk sex behaviors and sharing behaviors. Even in non-injecting MA users we can see an increase in the rate of hepatitis C because of pipe sharing.
  • Indirect social harms such as increase in minor and major crimes, and violence.,

Current harm reduction strategies have been established in the context of heroin injecting drug users (IDUs) and have been shown to be effective for controlling HIV epidemic among these opiate using IDUs. Many of the harm reduction strategies developed for IDUs are likely to be useful for injecting MA users. Needle exchange has been shown to be an effective harm reduction strategy with opiate injectors, but there is evidence that MA injectors prefer to take, but avoid engagement with service providers resulting in less opportunity for patient education. Establishment of harm reduction facilities that are accepting, non-stigmatizing and provide food, and support services could be useful for engaging MA users into a safe environment. Furthermore, there is some evidence that the availability of smoking equipment such as pipes may provide some benefit in reducing injection use.

MA use increases sexual risk behaviors61 Condom promotion programs as well as safer sex education and safer sex negotiation for both male and female MA users can be part of harm reduction activities for MA users. In countries such as Iran that already have established harm reduction strategies for IDUs, MA harm reduction activities should be integrated with current activities to expand the impact of the programs. Consideration should be given to employing communication tools including mobile phones, virtual social networks, and text messaging to expand outreach activities.

Conclusion

MA, a drug that is widely used in many parts of the world, produces significant acute and chronic medical and psychiatric conditions. Currently, there are no medications that have shown evidence of efficacy in the treatment of MA dependence. Several behavioral treatments have been shown to reduce MA use, but additional treatments are needed to provide a sufficient set of clinical tools to adequately treat the majority of MA-dependent individuals. The development of effective treatments that can reduce the use of MA as well as its consequent medical and psychiatric comorbidities is an important priority for future research. Integration of MA harm reduction strategies in current harm reduction programs as well as tailoring new innovative methods for better access to harm reduction assistance for both injecting and non-injecting MA users should be considered as a priority. Iran and many other developing countries in the region are newly facing problems with MA, rapidly and widely, it is highly recommended that responsible authorities and scientific communities try to establish appropriate and effective response for prevention, treatment and harm reduction services, which specially should be tailored considering local resources and characteristics.

Acknowledgments

Dr. Radfar was supported by the IAS-NIDA fellowship grant in 2012. Dr. Rawson was supported by the NIH Fogarty Grant D43-TW009102. The authors would like to thank Kris Langabeer for her editorial assistance with the manuscript.

Footnotes

Conflicts of Interest

The Authors have no conflict of interest.

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Bupropion for the Treatment of Methamphetamine
Dependence

 

Bupropion_for_the_Treatment_of_Methamphe

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This
was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse
treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV
diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and
79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments,
urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a
methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant (p ¼ 0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline (po0.0001). Comorbid depression and attention-deficit/ hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition.
Neuropsychopharmacology (2008) 33, 1162–1170; doi:10.1038/

_________________________________________________________________________

Chronic Methamphetamine Effects on Brain Structure and Function in Rats

Methamphetamine (MA) is a widely abused drug with devastating health effects [1]. MA increases extracellular concentrations of dopamine (DA), norepinephrine (NE) and serotonin (5HT) by acting on the transporter of each neurotransmitter [24] and by reversing neurotransmitter transport direction [5]. Chronic abuse of MA has been associated with damage to DA and 5HT terminals [57].

Additionally MA is rapidly taken by various organs in the body, including the lungs, brain, liver, pancreas, stomach, and kidneys, where it clears slowly [8], which could explain the association between MA and pulmonary hypertension [9] and kidney damage [10] among others. However, most MA studies have focused on the central nervous system. Studies in humans and non-human primates using magnetic resonance imaging (MRI) have shown structural abnormalities in the brain of MA users, including lower gray matter volumes [11], increased white matter volumes [11], enlarged striatal volumes [1217] and larger volumes of the parietal cortex [14]. This increased brain volume in MA users has been hypothesized to reflect inflammatory changes in these brain regions, including microglial activation, and has been positively correlated with deterioration of performance in reversal learning [17]. Still, volumetric increases in the striatum of MA users have also been positively correlated with novelty seeking [15] and with improved cognitive performance [1316], which suggests that increased striatal volume after MA use may also reflect compensatory changes in response to MA-induced neurotoxicity.

Using positron emission tomography (PET) and the glucose analog fluorodeoxyglucose (FDG), regional brain glucose metabolism (BGluM) has been assessed in MA users. In detoxified MA users, metabolic activity was increased in the parietal cortex and decreased in the thalamus and striatum [1819], although some recovery of function was seen in the thalamus after protracted abstinence [19]. Other studies have reported increased metabolism in the parietal cortex [20], increased metabolism in the cingulate, amygdala, ventral striatum, and cerebellum, but decreased metabolism in the insular and orbitofrontal area in abstinent MA users [21]. In addition PET studies have reported a downregulation of DA transporters (DAT) [22] and of DA D2 receptors in the striatum of MA abusers [23] with evidence of some recovery in DAT levels after protracted detoxification [2425]. Finally PET studies using [11C]PK 11195, which serves as a marker of microglia activation have also provided evidence of neuroinflammatory changes in the brain of MA users [26].

Together, these studies show that chronic MA use can lead to structural and functional brain deficits, although the possibility of pre-existing vulnerabilities in the brain of human MA users cannot be excluded. To further characterize the effects of long term MA use, the present study examined in rodents, the structural changes using magnetic resonance imaging (MRI), functional changes using PET to measure regional BGluM, and microglial activation with in vitro [3H]PK 11195 autoradiography. We hypothesized that chronic MA treatment would result in structural and functional deficits throughout the brain and that these effects would be potentiated in regions linked to the dopaminergic system, including the striatum and the nucleus accumbens. Furthermore, [3H]PK 11195 autoradiography would allow us to assess if MA-induced structural and functional changes in the brain were associated with neuroinflammation.

_______________________________________________________________________________________

Pharmacological treatments for methamphetamine addiction current status and future directions

ABSTRACT
Introduction: Methamphetamine (MA) abuse remains a global health challenge despite intense research interest in the development of pharmacological treatments. This review provides a summary of clinical trials and human studies on the pharmacotherapy of methamphetamine use disorder (MUD).

Areas covered: We summarize published clinical trials that tested candidate medications for MUD and
also conducted PubMed and Google Scholar searches to identify recently completed clinical trials using the keywords ‘methamphetamine’ ‘addiction’ ‘pharmacotherapy’ and ‘clinical trial.’ To determine the status of ongoing clinical trials targeting MUD, we also searched the ClinicalTrials.gov online database.
We conclude this review with a discussion of current research gaps and future directions.

Expert commentary: Clinical trials examining the potential for pharmacotherapies of MUD have largely
been negative. Future studies need to address several limitations to reduce the possibility of Type II errors: small sample sizes, high dropout rates or multiple comorbidities. Additionally, new treatment targets, such as MA-induced disruptions in cognition and in the neuroimmune system, merit trials with agents that selectively modulate these processes.

Pharmacotherapeutic agents in the treatment of methamphetamine dependence

 

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 PART II:    Methamphetamine Treatment

2.2. Consequences of MA use

2.2.1. Neurotoxicity

Clinical evidence using positron emission tomography (PET), magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS) provide support for prolonged neurotoxicity, including structural and metabolic changes, following extended use of moderate-to-large doses of MA.

PET studies have consistently observed reduced levels of DAT availability (from 11% to 28%) in abstinent MA users relative to nonusers in brain regions that include the dorsolateral prefrontal cortex, orbitofrontal cortex, amygdala, and striatum [12London EDKohno MMorales AM, et al. Chronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging. Brain Res. 2015;1628(Pt A):174185.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Chronic use of high doses can lead to downregulation of DAT that does not recover until many months of abstinence. One study has demonstrated a 38% DAT recovery within 2 weeks of abstinence [13Chou YHHuang WSSu TP, et al. Dopamine transporters and cognitive function in methamphetamine abuser after a short abstinence: A spect study. Eur Neuropsychopharmacol. 2007;17(1):4652.[Crossref][PubMed][Web of Science ®][Google Scholar]], while another reported a 16–19% increase only after protracted abstinence (12–17 months) [14Volkow NDChang LWang GJ, et al. Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci. 2001;21(23):94149418.[PubMed][Web of Science ®][Google Scholar]]. Downregulation in dopamine D2-type receptor availability has also been observed in the striatum of abstinent MA users [15Ballard MEMandelkern MAMonterosso JR, et al. Low dopamine d2/d3 receptor availability is associated with steep discounting of delayed rewards in methamphetamine dependence. Int J Neuropsychopharmacol. 2015;18(7):pyu119.[Crossref][PubMed][Web of Science ®][Google Scholar],16Volkow NDChang LWang GJ, et al. Low level of brain dopamine d2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry. 2001;158(12):20152021.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Finally, reduced levels of the 5-HT transporter (SERT) have been observed in cortical and subcortical brain regions in MA users abstinent for <12 months relative to controls [17Sekine YOuchi YTakei N, et al. Brain serotonin transporter density and aggression in abstinent methamphetamine abusers. Arch Gen Psychiatry. 2006;63(1):90100.[Crossref][PubMed][Web of Science ®][Google Scholar]] and reductions in VMAT-2 density of up to 10% have also been reported in chronic MA users following at least 3 months of abstinence [18Johanson CEFrey KALundahl LH, et al. Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers. Psychopharmacology (Berl). 2006;185(3):327338.[Crossref][PubMed][Web of Science ®][Google Scholar]].

Evidence from structural MRI studies has demonstrated cortical and striatal gray and white matter abnormalities in chronic MA users relative to controls. Reduced cortical gray matter volume has been observed following brief abstinence in the prefrontal cortex [19Daumann JKoester PBecker B, et al. Medial prefrontal gray matter volume reductions in users of amphetamine-type stimulants revealed by combined tract-based spatial statistics and voxel-based morphometry. Neuroimage. 2011;54(2):794801.[Crossref][PubMed][Web of Science ®][Google Scholar]], anterior cingulate cortex, and limbic cortex [20Thompson PMHayashi KMSimon SL, et al. Structural abnormalities in the brains of human subjects who use methamphetamine. J Neurosci. 2004;24(26):60286036.[Crossref][PubMed][Web of Science ®][Google Scholar]] while larger striatal volumes have been reported following 3–4 months of abstinence, possibly due to a compensatory effect [21Jernigan TLGamst ACArchibald SL, et al. Effects of methamphetamine dependence and hiv infection on cerebral morphology. Am J Psychiatry. 2005;162(8):14611472.[Crossref][PubMed][Web of Science ®][Google Scholar]]. White matter abnormalities underlying and interconnecting prefrontal cortex and the hippocampus have also been reported in chronic MA users [22Tobias MCO’Neill JHudkins M, et al. White-matter abnormalities in brain during early abstinence from methamphetamine abuse. Psychopharmacology (Berl). 2010;209(1):1324.[Crossref][PubMed][Web of Science ®][Google Scholar]].

Alterations in neuronal integrity and neuronal inflammation have also been observed in MA users relative to ‘never-used’ controls. MRS studies have found reduced concentration of N-acetyl-aspartate in basal ganglia and frontal white matter and reduced total creatine in the basal ganglia in chronic users [23Ernst TChang LLeonido-Yee M, et al. Evidence for long-term neurotoxicity associated with methamphetamine abuse: A 1h mrs study. Neurology. 2000;54(6):13441349.[Crossref][PubMed][Web of Science ®][Google Scholar]]. PET studies have observed increased PK 11195 binding, a marker for neuroinflammation, in several brain regions of abstinent MA users including the striatum, thalamus, insular, and orbitofrontal cortex [24Sekine YOuchi YSugihara G, et al. Methamphetamine causes microglial activation in the brains of human abusers. J Neurosci. 2008;28(22):57565761.[Crossref][PubMed][Web of Science ®][Google Scholar]].

2.2.2. Neurocognitive and psychiatric consequences

Chronic MA use has been demonstrated to be associated with neuropsychological impairment [12London EDKohno MMorales AM, et al. Chronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging. Brain Res. 2015;1628(Pt A):174185.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Significant deficits in cognitive processes contingent upon fronto-striatal and limbic circuits such as executive function, episodic memory, processing speed, and psychomotor tasks have consistently been reported with medium effect sizes, with smaller effects observed for attention and language tasks [25Iudicello JEWoods SPVigil O, et al. Longer term improvement in neurocognitive functioning and affective distress among methamphetamine users who achieve stable abstinence. J Clin Exp Neuropsychol. 2010;32(7):704718.[Taylor & Francis Online][Web of Science ®][Google Scholar]27Woods SPRippeth JDConover E, et al. Deficient strategic control of verbal encoding and retrieval in individuals with methamphetamine dependence. Neuropsychology. 2005;19(1):3543.[Crossref][PubMed][Web of Science ®][Google Scholar]]. These impairments are generally observed during the first 3 months of abstinence with some impairments improving following protracted sustained abstinence [25Iudicello JEWoods SPVigil O, et al. Longer term improvement in neurocognitive functioning and affective distress among methamphetamine users who achieve stable abstinence. J Clin Exp Neuropsychol. 2010;32(7):704718.[Taylor & Francis Online][Web of Science ®][Google Scholar]].

MA can lead to a range of psychiatric sequelae following acute use, withdrawal, and chronic extended use. Psychotic symptoms can be difficult to distinguish from schizophrenia and include persecutory delusions, auditory hallucinations, and loss of insight [28McKetin RDawe SBurns RA, et al. The profile of psychiatric symptoms exacerbated by methamphetamine use. Drug Alcohol Depend. 2016;161:104109.[Crossref][PubMed][Web of Science ®][Google Scholar]]. MA-induced acute withdrawal symptoms include negative affect, psychosis, anxiety, and fatigue [29Zorick TNestor LMiotto K, et al. Withdrawal symptoms in abstinent methamphetamine-dependent subjects. Addiction. 2010;105(10):18091818.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Chronic MA users report higher rates of anxiety, depression, psychotic states, impulsivity, and aggression [30Rusyniak DE. Neurologic manifestations of chronic methamphetamine abuse. Psychiatr Clin North Am. 2013;36(2):261275.[Crossref][PubMed][Web of Science ®][Google Scholar]]. These symptoms can subside with protracted abstinence but some persist long term [31Harro JNeuropsychiatric adverse effects of amphetamine and methamphetamine. Int Rev Neurobiol. 2015;120:179204.[Crossref][PubMed][Google Scholar]]. It has been reported that transient psychotic symptoms are related to earlier onset MA use while persistent psychotic symptoms are associated with a family history of psychosis and depression [32McKetin RGardner JBaker AL, et al. Correlates of transient versus persistent psychotic symptoms among dependent methamphetamine users. Psychiatry Res. 2016;238:166171.[Crossref][PubMed][Web of Science ®][Google Scholar]]. The prevalence of comorbidity between mental health disorders and substance use is well documented and results in poorer treatment course and outcomes.

Long term neuropsychiatric changes in MA users have been correlated with markers of long-term neurotoxicity. For example, low D2 receptor striatal availability has also been associated with greater impulsivity in MA users [15Ballard MEMandelkern MAMonterosso JR, et al. Low dopamine d2/d3 receptor availability is associated with steep discounting of delayed rewards in methamphetamine dependence. Int J Neuropsychopharmacol. 2015;18(7):pyu119.[Crossref][PubMed][Web of Science ®][Google Scholar]], memory deficits have been associated with reduced DAT site density [33Volkow NDChang LWang GJ, et al. Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry. 2001;158(3):377382.[Crossref][PubMed][Web of Science ®][Google Scholar]], and reduced levels of SERT density in the orbitofrontal, temporal, and anterior cingulate cortices have been observed to be associated with higher levels of aggression [17Sekine YOuchi YTakei N, et al. Brain serotonin transporter density and aggression in abstinent methamphetamine abusers. Arch Gen Psychiatry. 2006;63(1):90100.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Furthermore, reduced white matter integrity has been found to correlate with depression severity [22Tobias MCO’Neill JHudkins M, et al. White-matter abnormalities in brain during early abstinence from methamphetamine abuse. Psychopharmacology (Berl). 2010;209(1):1324.[Crossref][PubMed][Web of Science ®][Google Scholar]], reduced hippocampal volumes have been associated with poorer memory performance [20Thompson PMHayashi KMSimon SL, et al. Structural abnormalities in the brains of human subjects who use methamphetamine. J Neurosci. 2004;24(26):60286036.[Crossref][PubMed][Web of Science ®][Google Scholar]], and cognitive impairment has been found to be associated with several neuroinflammatory markers [34Loftis JMChoi DHoffman W, et al. Methamphetamine causes persistent immune dysregulation: A cross-species, translational report. Neurotox Res. 2011;20(1):5968.[Crossref][PubMed][Web of Science ®][Google Scholar]].

It has been questioned whether the degree to which the observed neurocognitive changes in MA users are clinically meaningful and also whether they are directly a result of MA-induced neurotoxicity or preexisting factors [35Hart CLMarvin CBSilver R, et al. Is cognitive functioning impaired in methamphetamine users? A critical review. Neuropsychopharmacology. 2012;37(3):586608.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Given the absence of prospective longitudinal studies, it is still possible that MA users have preexisting alterations in transporter densities and neurocognitive abnormalities. Nonetheless, systematic evaluations of the literature conclude that MA can induce clinically significant impairments but only in some users [36Dean ACGroman SMMorales AM, et al. An evaluation of the evidence that methamphetamine abuse causes cognitive decline in humans. Neuropsychopharmacology. 2013;38(2):259274.[Crossref][PubMed][Web of Science ®][Google Scholar]], whereby deficits may be moderated by individual factors such as age and genotypic variability in the metabolic clearance of MA via cytochrome p450-2D6 activity [37Cherner MBousman CEverall I, et al. Cytochrome p450-2d6 extensive metabolizers are more vulnerable to methamphetamine-associated neurocognitive impairment: preliminary findings. J Int Neuropsychol Soc. 2010;16(5):890901.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Finally, from a therapeutic perspective, it seems that markers of neurotoxicity are clinically important given that high striatal D2 receptor availability in MA users at baseline predicts relapse [38Wang GJSmith LVolkow ND, et al. Decreased dopamine activity predicts relapse in methamphetamine abusers. Mol Psychiatry. 2012;17(9):918925.[Crossref][PubMed][Web of Science ®][Google Scholar]] and DAT recovery with abstinence is correlated with recovery of executive function [13Chou YHHuang WSSu TP, et al. Dopamine transporters and cognitive function in methamphetamine abuser after a short abstinence: A spect study. Eur Neuropsychopharmacol. 2007;17(1):4652.[Crossref][PubMed][Web of Science ®][Google Scholar]].

3. Potential pharmacotherapies for MA dependence

The complex mechanism of action of MA produced by repeated MA use opens several potential neuropharmacological angles regarding targets for management. Pharmacotherapies investigated for the management of MA have different underlying mechanisms that may (1) modulate the mesolimbic dopamine system either directly or indirectly to alter the experience of reward (e.g. GABA, glutamate, opioid, peptide hormones); (2) recover alterations in dopaminergic homeostasis through acting on the membrane protein (e.g. DAT, DA receptor partial agonists) to potentially improve neurocognitive deficits or psychiatric symptoms and attenuate negative reinforcing effects of withdrawal (and potentially promote treatment engagement); (3) reduce neurotoxicity using anti-inflammatory agents; and (4) modulate the pharmacokinetics of MA to reduce the amount of drug entering the brain (via immunotherapy).

3.1. Preclinical studies

Preclinical studies are an important step in the discovery of new pharmacotherapies. When investigating complex disorders, such as drug addiction, there are obvious limitations for the translation from rodent models to the human condition (species differences, simple models, greater homogeneity); however, they do provide the building blocks for understanding how chronic drug use affects brain function to suggest targets for drug development. Moreover, in comparison to other disorders, drug addiction has a known etiology, which can be more easily modeled in preclinical experiments through repeated drug administration.

It is important here to make the distinction between preclinical models that investigate drug reward or acute reinforcement and those that elucidate changes associated with repeated drug use and relapse. The former is problematic as therapies that are aimed at effective reduction of drug reinforcement are also likely to affect natural reinforcers, limiting their therapeutic potential. The latter have greater validity for promoting abstinence in users, particularly those that assess potential for relapse reduction. There are a number of models that investigate the enduring neurobiological changes associated with repeated MA abuse and addiction: the expression of behavioral sensitization [39Scofield MDHeinsbroek JAGipson CD, et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev. 2016;68(3):816871.[Crossref][PubMed][Web of Science ®][Google Scholar]], conditioned place preference (CPP) [39Scofield MDHeinsbroek JAGipson CD, et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev. 2016;68(3):816871.[Crossref][PubMed][Web of Science ®][Google Scholar],40Napier TCHerrold AADe Wit HUsing conditioned place preference to identify relapse prevention medications. Neurosci Biobehav Rev. 2013;37(9 Pt A):20812086.[Crossref][PubMed][Web of Science ®][Google Scholar]], and intravenous self-administration reinstatement models [39Scofield MDHeinsbroek JAGipson CD, et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev. 2016;68(3):816871.[Crossref][PubMed][Web of Science ®][Google Scholar]]. The following pharmacotherapies have shown some promise for alleviating MA addiction in preclinical models.

The atypical antipsychotic aripiprazole, which is a partial dopamine receptor agonist with serotonergic actions, has shown some efficacy for MA treatment in preclinical studies. Aripiprazole effectively attenuated MA self-administration in rats [41Wee SWang ZWoolverton WL, et al. Effect of aripiprazole, a partial dopamine d2 receptor agonist, on increased rate of methamphetamine self-administration in rats with prolonged session duration. Neuropsychopharmacology. 2007;32(10):22382247.[Crossref][PubMed][Web of Science ®][Google Scholar]] and had greater efficacy in reducing the motivation to administer MA in rats exposed to long-access (6 h/day) compared to short-access (1 h/day) regimes [41Wee SWang ZWoolverton WL, et al. Effect of aripiprazole, a partial dopamine d2 receptor agonist, on increased rate of methamphetamine self-administration in rats with prolonged session duration. Neuropsychopharmacology. 2007;32(10):22382247.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Repeated aripiprazole treatment also reduced the expression of behavioral sensitization to repeated MA use when given daily for 5 days during the withdrawal period in mice [42Futamura TAkiyama SSugino H, et al. Aripiprazole attenuates established behavioral sensitization induced by methamphetamine. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(6):11151119.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Using an acute MA model, aripiprazole treatment also reduced MA-induced stereotypy in a dose-dependent manner in both pre- or posttreatment for MA use [43Kitanaka NKitanaka JHall FS, et al. Pretreatment or posttreatment with aripiprazole attenuates methamphetamine-induced stereotyped behavior in mice. J Exp Neurosci. 2015;9(Suppl 1):110.[Crossref][PubMed][Google Scholar]]. Together, these data indicate that aripiprazole may have therapeutic potential, not only to reduce drug intake and relapse but also to reverse MA overdose.

Reichel and See have demonstrated that chronic administration of the weak dopamine reuptake inhibitor, modafinil, reduces conditioned cue-induced and MA-primed reinstatement, an effect which remains 2 weeks following treatment cessation [44Reichel CMSee REChronic modafinil effects on drug-seeking following methamphetamine self-administration in rats. Int J Neuropsychopharmacol. 2012;15(7):919929.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In addition to reducing MA relapse, this group has shown that modafinil may enable adaptive behaviors in MA-experienced rats by enhancing cognition, measured by restoration of spatial memory [45Reichel CMGilstrap MGRamsey LA, et al. Modafinil restores methamphetamine induced object-in-place memory deficits in rats independent of glutamate n-methyl-d-aspartate receptor expression. Drug Alcohol Depend. 2014;134:115122.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Similar effects have been measured for modafinil in MA-experienced mice for reversing deficits in object recognition [46Gonzalez BRaineri MCadet JL, et al. Modafinil improves methamphetamine-induced object recognition deficits and restores prefrontal cortex erk signaling in mice. Neuropharmacology. 2014;87:188197.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Modafinil also works as a neuroprotectant and significantly reduced the neurotoxicity and inflammation induced by MA administration [47Raineri MGonzalez BGoitia B, et al. Modafinil abrogates methamphetamine-induced neuroinflammation and apoptotic effects in the mouse striatum. Plos One. 2012;7(10):e46599.[Crossref][PubMed][Web of Science ®][Google Scholar]], providing a promising avenue for therapeutic investigation. New analogs of modafinil have recently been developed [48Cao JSlack RDBakare OM, et al. Novel and high affinity 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues as atypical dopamine transporter inhibitors. J Med Chem. 2016;59(23):1067610691.[Crossref][PubMed][Web of Science ®][Google Scholar]]. However, it should be noted that some studies [49Soeiro Ada CMoreira KDAbrahao KP, et al. Individual differences are critical in determining modafinil-induced behavioral sensitization and cross-sensitization with methamphetamine in mice. Behav Brain Res. 2012;233(2):367374.[Crossref][PubMed][Web of Science ®][Google Scholar]], but not others [50Holtz NALozama APrisinzano TE, et al. Reinstatement of methamphetamine seeking in male and female rats treated with modafinil and allopregnanolone. Drug Alcohol Depend. 2012;120(1–3):233237.[Crossref][PubMed][Web of Science ®][Google Scholar]], have indicated that modafinil may have reinforcing properties or enhance the effect of MA.

Evidence indicates that dopamine D3 receptors may have a key role in mediating substance abuse. The administration of a novel D3 receptor antagonist, YQA14, inhibited rat MA self-administration [51Chen YSong RYang RF, et al. A novel dopamine d3 receptor antagonist yqa14 inhibits methamphetamine self-administration and relapse to drug-seeking behaviour in rats. Eur J Pharmacol. 2014;743:126132.[Crossref][PubMed][Web of Science ®][Google Scholar]], facilitated extinction and decreased reinstatement to MA-induced MA-seeking behavior via CPP [52Sun LSong RChen Y, et al. A selective d3 receptor antagonist yqa14 attenuates methamphetamine-induced behavioral sensitization and conditioned place preference in mice. Acta Pharmacol Sin. 2016;37(2):157165.[Crossref][PubMed][Web of Science ®][Google Scholar]]. These results indicate some promise for D3 selective antagonists as treatment for relapse to MA use. Gong et al. [53Gong XYue KMa B, et al. Levo-tetrahydropalmatine, a natural, mixed dopamine receptor antagonist, inhibits methamphetamine self-administration and methamphetamine-induced reinstatement. Pharmacol Biochem Behav. 2016;144:6772.[Crossref][PubMed][Web of Science ®][Google Scholar]] observed that levo-tetrahydropalmatine (L-THP), a mixed receptor antagonist, blocked self-administration and reinstatement of MA-seeking behavior. They concluded that L-THP may be useful for the treatment of MA addiction and has a better safety profile with fewer side effects than other DA receptor antagonists. Mi et al. [54Mi GGao YYan H, et al. L-scoulerine attenuates behavioural changes induced by methamphetamine in zebrafish and mice. Behav Brain Res. 2016;298(Pt A):97104.[Crossref][PubMed][Web of Science ®][Google Scholar]] demonstrated that I-Scoulerine, which is a tetrahydroprotoberberine (THPB) alkaloid, blocked the expression of MA-induced CPP. THPBs represent a series of compounds extracted from the Chinese herb Corydalis ambigua and various species of Stephania and are a category of dopamine receptor ligands [55Mo JGuo YYang YS, et al. Recent developments in studies of l-stepholidine and its analogs: chemistry, pharmacology and clinical implications. Curr Med Chem. 2007;14(28):29963002.[Crossref][PubMed][Web of Science ®][Google Scholar]].

Mirtazapine is an atypical antidepressant that primarily acts on both norepinephrinergic and serotonergic systems, through the antagonism of their autoreceptors,α2 adrenoreceptor and 5HT2 receptor, respectively [56De Boer TThe pharmacologic profile of mirtazapine. J Clin Psychiatry. 1996;57(Suppl 4):1925.[PubMed][Web of Science ®][Google Scholar]]. Activity at 5HT1A receptors by mirtazapine also enhances dopamine neurotransmission, notably in the prefrontal cortex [57Nakayama KSakurai TKatsu HMirtazapine increases dopamine release in prefrontal cortex by 5-ht1a receptor activation. Brain Res Bull. 2004;63(3):237241.[Crossref][PubMed][Web of Science ®][Google Scholar]], and it has been reported to have inverse agonist activity at 5HT2C receptors [58Chanrion BMannoury La Cour CGavarini S, et al. Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2c receptors: differential modulation of cell surface expression and signal transduction. Mol Pharmacol. 2008;73(3):748757.[Crossref][PubMed][Web of Science ®][Google Scholar]]. One research group has shown treatment with mirtazapine to be effective in reducing several preclinical indicators of MA addiction in rats – the expression of behavioral sensitization [59McDaid JTedford CEMackie AR, et al. Nullifying drug-induced sensitization: behavioral and electrophysiological evaluations of dopaminergic and serotonergic ligands in methamphetamine-sensitized rats. Drug Alcohol Depend. 2007;86(1):5566.[Crossref][PubMed][Web of Science ®][Google Scholar]] and CPP [60Voigt RMNapier TCContext-dependent effects of a single administration of mirtazapine on the expression of methamphetamine-induced conditioned place preference. Front Behav Neurosci. 2011;5:92.[PubMed][Web of Science ®][Google Scholar]] including a reversal of CPP when treatment occurred during withdrawal [61Herrold AAShen FGraham MP, et al. Mirtazapine treatment after conditioning with methamphetamine alters subsequent expression of place preference. Drug Alcohol Depend. 2009;99(1–3):231239.[Crossref][PubMed][Web of Science ®][Google Scholar],62Voigt RMMickiewicz ALNapier TCRepeated mirtazapine nullifies the maintenance of previously established methamphetamine-induced conditioned place preference in rats. Behav Brain Res. 2011;225(1):9196.[Crossref][PubMed][Web of Science ®][Google Scholar]], and reinstatement of MA seeking triggered by cue reexposure [63Graves SMNapier TCMirtazapine alters cue-associated methamphetamine seeking in rats. Biol Psychiatry. 2011;69(3):275281.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Another study failed to see an effect of mirtazapine on MA sensitization in rats when used in combination with the dopamine and serotonin receptor agonist pergolide [64Bhatia KSSzabo STFowler JC, et al. Reversal of long-term methamphetamine sensitization by combination of pergolide with ondansetron or ketanserin, but not mirtazapine. Behav Brain Res. 2011;223(1):227232.[Crossref][PubMed][Web of Science ®][Google Scholar]]. However, the treatment dose and period was almost half used in the mirtazapine treatment regime of McDaid et al. [59McDaid JTedford CEMackie AR, et al. Nullifying drug-induced sensitization: behavioral and electrophysiological evaluations of dopaminergic and serotonergic ligands in methamphetamine-sensitized rats. Drug Alcohol Depend. 2007;86(1):5566.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Together, these data suggest that mirtazapine or pharmacologically related compounds [65Graves SMNapier TCSb 206553, a putative 5-ht2c inverse agonist, attenuates methamphetamine-seeking in rats. BMC Neurosci. 2012;13:65.[Web of Science ®][Google Scholar]] are strong candidates for clinical investigation.

Bupropion is also an atypical antidepressant and acts as a norepinephrine and dopamine reuptake inhibitor [66Ascher JACole JOColin JN, et al. Bupropion: A review of its mechanism of antidepressant activity. J Clin Psychiatry. 1995;56(9):395401.[PubMed][Web of Science ®][Google Scholar]]. In preclinical models of MA self-administration, bupropion has reduced drug intake rats [67Reichel CMMurray JEGrant KM, et al. Bupropion attenuates methamphetamine self-administration in adult male rats. Drug Alcohol Depend. 2009;100(1–2):5462.[Crossref][PubMed][Web of Science ®][Google Scholar]]; however, no research has been conducted in preclinical relapse models. It is proposed that bupropion would be used as ‘agonist’ or replacement therapy in MA users, and although it shows locomotor and sensitized behavior similar to MA administration [68Mori TShibasaki MOgawa Y, et al. Comparison of the behavioral effects of bupropion and psychostimulants. Eur J Pharmacol. 2013;718(1–3):370375.[Crossref][PubMed][Web of Science ®][Google Scholar]], the effect was at 15-fold higher doses. This suggests, together with the reduction in MA self-administration behavior, that bupropion has low abuse potential at low–moderate doses [68Mori TShibasaki MOgawa Y, et al. Comparison of the behavioral effects of bupropion and psychostimulants. Eur J Pharmacol. 2013;718(1–3):370375.[Crossref][PubMed][Web of Science ®][Google Scholar]].

Other potential ‘agonist therapies’ for stimulant dependence are treatment with methylphenidate or d-amphetamine, which work to either block or reverse DAT and NET, respectively [69Heal DJCheetham SCSmith SLThe neuropharmacology of adhd drugs in vivo: insights on efficacy and safety. Neuropharmacology. 2009;57(7–8):608618.[Crossref][PubMed][Web of Science ®][Google Scholar]], similar to MA. There have been a number of preclinical studies that have investigated the behavioral effects of either of these compounds; however, very few have investigated their effect on MA self-administration or relapse studies. In one study using rhesus monkeys, methylphenidate administration did not affect the intake of MA [70Schindler CWGilman JPPanlilio LV, et al. Comparison of the effects of methamphetamine, bupropion, and methylphenidate on the self-administration of methamphetamine by rhesus monkeys. Exp Clin Psychopharmacol. 2011;19(1):110.[Crossref][PubMed][Web of Science ®][Google Scholar]], and it has also shown significant reinforcing effects on its own to the point of dysfunctional intake in rats [71Marusich JABeckmann JSGipson CD, et al. Methylphenidate as a reinforcer for rats: contingent delivery and intake escalation. Exp Clin Psychopharmacol. 2010;18(3):257266.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In contrast, d-amphetamine showed significantly less reinforcing effects when compared to MA administration in rhesus monkeys trained to self-administer cocaine [72Lile JACharnigo RJNader MAThe relative reinforcing strength of methamphetamine and d-amphetamine in monkeys self-administering cocaine. Behav Pharmacol. 2013;24(5–6):482485.[Crossref][PubMed][Web of Science ®][Google Scholar]], suggesting a realistic alternative for MA replacement therapy.

Growing evidence supports a role for trace amine associated-receptor 1 (TAAR1) in the functional regulation of monoamine transporters and neuronal mechanisms that modulate dopaminergic activity, providing a potential avenue for drug development to treat psychostimulant addiction [73Miller GMAvenues for the development of therapeutics that target trace amine associated receptor 1 (taar1). J Med Chem. 2012;55(5):18091814.[Crossref][PubMed][Web of Science ®][Google Scholar]]. MA is a full agonist of the TAAR1 [74Reese EABunzow JRArttamangkul S, et al. Trace amine-associated receptor 1 displays species-dependent stereoselectivity for isomers of methamphetamine, amphetamine, and para-hydroxyamphetamine. J Pharmacol Exp Ther. 2007;321(1):178186.[Crossref][PubMed][Web of Science ®][Google Scholar]] and indeed, modulation of TAAR1 with the partial TAAR1 agonist RO5263397 has been reported to attenuate MA cue and drug-induced reinstatement and behavioral sensitization [75Jing LZhang YLi JXEffects of the trace amine associated receptor 1 agonist ro5263397 on abuse-related behavioral indices of methamphetamine in rats. Int J Neuropsychopharmacol. 2014;18(4): pyu060.[PubMed][Web of Science ®][Google Scholar]]. In addition, TAAR1knockout mice displayed decreased acquisition of MA-induced CPP and increased retention compared with wild-type mice [76Achat-Mendes CLynch LJSullivan KA, et al. Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1. Pharmacol Biochem Behav. 2012;101(2):201207.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Taken together, these studies suggest that compounds aimed at TAAR1 regulation may be promising therapeutic targets for reducing MA addiction.

The administration of compounds targeting GABA and glutamatergic systems has also been suggested as important therapeutic directions for MA addiction. Treatment with the GABAB receptor agonist, baclofen, facilitated the extinction of MA-induced CPP [77Voigt RMHerrold AANapier TCBaclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats. Behav Neurosci. 2011;125(2):261267.[Crossref][PubMed][Web of Science ®][Google Scholar]] and pretreatment with baclofen dose dependently inhibited the development and expression of MA-induced CPP [78Li SMYin LLRen YH, et al. Gaba(b) receptor agonist baclofen attenuates the development and expression of d-methamphetamine-induced place preference in rats. Life Sci. 2001;70(3):349356.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Baclofen treatment also reduced the motivation to lever press for MA intake [79Ranaldi RPoeggel KBaclofen decreases methamphetamine self-administration in rats. Neuroreport. 2002;13(9):11071110.[Crossref][PubMed][Web of Science ®][Google Scholar]], suggesting that enhancing GABA neurotransmission may reduce MA addiction. The molecular structure of the anticonvulsant gabapentin was modeled off GABA; however, its mechanism of action is not yet fully understood. It is thought that gabapentin may act to antagonize voltage-gated calcium channels to inhibit neural activity. Through this mechanism, gabapentin treatment has prevented the development of sensitization or CPP to MA [80Kurokawa KShibasaki MMizuno K, et al. Gabapentin blocks methamphetamine-induced sensitization and conditioned place preference via inhibition of alpha(2)/delta-1 subunits of the voltage-gated calcium channels. Neuroscience. 2011;176:328335.[Crossref][PubMed][Web of Science ®][Google Scholar]]; however, no preclinical data yet exist to suggest that gabapentin treatment can reduce relapse to MA addiction. Topiramate is another anticonvulsant drug and has mixed effects on calcium channels, sodium channels, GABAA receptors, and AMPA/Kainate glutamate receptors; yet, no preclinical data exist on the therapeutic potential of this drug on MA addiction. Similarly, while it is known that glutamate systems are important mediators of MA relapse [39Scofield MDHeinsbroek JAGipson CD, et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev. 2016;68(3):816871.[Crossref][PubMed][Web of Science ®][Google Scholar]], there has been little preclinical studies on potential treatments in this domain. Pretreatment with CSB6B, a vesicular glutamate transporter inhibitor, has been reported to suppress the acquisition of MA-induced CPP [81He ZChen YDong H, et al. Inhibition of vesicular glutamate transporters contributes to attenuate methamphetamine-induced conditioned place preference in rats. Behav Brain Res. 2014;267:15.[Crossref][PubMed][Web of Science ®][Google Scholar]]; however, the effect on MA relapse has not been conducted. The potential anti-addiction effects of N-acetylcysteine (NAC), which has multiple actions on glutamate neurotransmission [82McKetin RDean OMBaker AL, et al. A potential role for n-acetylcysteine in the management of methamphetamine dependence. Drug Alcohol Rev. 2016;36(2):153159.[Crossref][PubMed][Web of Science ®][Google Scholar]], have been well described in models of preclinical cocaine addiction [39Scofield MDHeinsbroek JAGipson CD, et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol Rev. 2016;68(3):816871.[Crossref][PubMed][Web of Science ®][Google Scholar]]; however, less has been shown in MA models. Treatment with NAC has shown potential to reverse neurotoxicity produced by MA abuse [83Hashimoto KTsukada HNishiyama S, et al. Effects of n-acetyl-l-cysteine on the reduction of brain dopamine transporters in monkey treated with methamphetamine. Ann N Y Acad Sci. 2004;1025:231235.[Crossref][PubMed][Web of Science ®][Google Scholar]] and also reduced the expression of behavioral sensitization to MA [84Fukami GHashimoto KKoike K, et al. Effect of antioxidant n-acetyl-l-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine. Brain Res. 2004;1016(1):9095.[Crossref][PubMed][Web of Science ®][Google Scholar]]. NAC therapy had been suggested as a promising avenue for treating MA addiction [82McKetin RDean OMBaker AL, et al. A potential role for n-acetylcysteine in the management of methamphetamine dependence. Drug Alcohol Rev. 2016;36(2):153159.[Crossref][PubMed][Web of Science ®][Google Scholar]].

The opioid antagonist, naltrexone, has been demonstrated to inhibit cue-induced MA-seeking behavior in rats that are previously trained to self-administer MA [85Anggadiredja KSakimura KHiranita T, et al. Naltrexone attenuates cue- but not drug-induced methamphetamine seeking: A possible mechanism for the dissociation of primary and secondary reward. Brain Res. 2004;1021(2):272276.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Some studies have reported that μ-opioid receptor knockout mice fail to demonstrate MA-induced behavioral sensitization [86Shen XPurser CTien LT, et al. Mu-opioid receptor knockout mice are insensitive to methamphetamine-induced behavioral sensitization. J Neurosci Res. 2010;88(10):22942302.[Crossref][PubMed][Web of Science ®][Google Scholar]] and have a shorter recovery duration to basal levels of extracellular dopamine metabolites induced by MA compared to wild-type mice [87Lan KCMa TLin-Shiau SY, et al. Methamphetamine-elicited alterations of dopamine- and serotonin-metabolite levels within mu-opioid receptor knockout mice: A microdialysis study. J Biomed Sci. 2008;15(3):391403.[Crossref][PubMed][Web of Science ®][Google Scholar]].

There is also evidence regarding the potential role of endogenous hormones in MA treatment. Gou et al. [88Gou HWen DMa C, et al. Protective effects of cholecystokinin-8 on methamphetamine-induced behavioral changes and dopaminergic neurodegeneration in mice. Behav Brain Res. 2015;283:8796.[Crossref][PubMed][Web of Science ®][Google Scholar]] observed that cholecystokinin-8 (CCK-8) pretreatment significantly inhibited both the development and expression of MA-induced behavioral sensitization in a dose-dependent manner and attenuated the decrease of tyrosine hydroxylase and DAT in striatum. Peripheral administration of CCK-8 has been demonstrated to activate oxytocin-secreting neurons in the hypothalamus [89Motojima YKawasaki MMatsuura T, et al. Effects of peripherally administered cholecystokinin-8 and secretin on feeding/drinking and oxytocin-mrfp1 fluorescence in transgenic rats. Neurosci Res. 2016;109:6369.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Interestingly, there are promising results from a few research groups who have consistently demonstrated that administration of oxytocin attenuates MA-related reward and MA-seeking behavior [90Baracz SJEverett NAMcGregor IS, et al. Oxytocin in the nucleus accumbens core reduces reinstatement of methamphetamine-seeking behaviour in rats. Addict Biol. 2016;21(2):316325.[Crossref][PubMed][Web of Science ®][Google Scholar]92Cox BMBentzley BSRegen-Tuero H, et al. Oxytocin acts in nucleus accumbens to attenuate methamphetamine seeking and demand. Biol Psychiatry. 2016DOI:http://dx.doi.org/10.1016/j.biopsych.2016.11.011 [Google Scholar]], possibly through mechanisms other than oxytocin receptor activation [93Baracz SJCornish JLThe neurocircuitry involved in oxytocin modulation of methamphetamine addiction. Front Neuroendocrinol. 2016;43:118.[Crossref][PubMed][Web of Science ®][Google Scholar]].

Varenicline is a partial agonist at α4β2 nAChRs and a full agonist at α7 nAChRs that has shown promise for reducing nicotine dependence; yet, little preclinical evidence exists for its efficacy in MA models. Enhancement of acetylcholine neurotransmission will also be achieved through the use of anticholinesterase inhibitors, such as rivastigmine and perindopril that have been considered for use in the clinic for MA addiction. However, while activity at nicotine receptors (including varenicline) do not generally substitute for MA in discrimination tasks [94Desai RIBergman JDrug discrimination in methamphetamine-trained rats: effects of cholinergic nicotinic compounds. J Pharmacol Exp Ther. 2010;335(3):807816.[Crossref][PubMed][Web of Science ®][Google Scholar]], two very recent studies have suggested that for MA-experienced animals, varenicline may actually enhance MA relapse in both male and female subjects [95Pittenger STBarrett STChou S, et al. The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in female rats. Behav Brain Res. 2016;300:150159.[Crossref][PubMed][Web of Science ®][Google Scholar],96Pittenger STBarrett STChou S, et al. The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in male rats. Behav Brain Res. 2017;320:195199.[Crossref][PubMed][Web of Science ®][Google Scholar]].

An emerging pharmacological intervention strategy is to target neurotoxicity using anti-inflammatory agents. The agent, ibudilast, a nonselective phosphodiesterase inhibitor and promoter of glial cell-derived neurotrophic factor, significantly reduced MA prime- and stress-induced reinstatement of MA seeking in rats [97Beardsley PMShelton KLHendrick E, et al. The glial cell modulator and phosphodiesterase inhibitor, av411 (ibudilast), attenuates prime- and stress-induced methamphetamine relapse. Eur J Pharmacol. 2010;637(1–3):102108.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Furthermore, Charntikov et al. [98Charntikov SPittenger STThapa I, et al. Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (pebp1) produced by chronic methamphetamine intake in rats. Drug Alcohol Depend. 2015;152:1523.[Crossref][PubMed][Web of Science ®][Google Scholar]] reported that administration of ibudilast reversed the decrease in synaptic signaling protein produced by chronic MA intake by rats. Kim et al. [99Kim DHYang CHHwang MSauchinone blocks methamphetamine-induced hyperlocomotion and place preference in mice. Phytomedicine. 2013;20(12):10711075.[Crossref][PubMed][Web of Science ®][Google Scholar]] investigated sauchinone (a nitrous oxide inhibitor) and demonstrated that the agent blocked the acquisition of MA-induced CPP and pretreatment decreased MA-induced CPP. Sauchinone has been shown to significantly inhibit nitrite production and inflammatory mediators’ expression via heme oxygenase-1 upregulation [100Meng XKim IJeong YJ, et al. Anti-inflammatory effects of saururus chinensis aerial parts in murine macrophages via induction of heme oxygenase-1. Exp Biol Med (Maywood). 2016;241(4):396408.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Finally, Ren et al. [101Ren QZhang JCMa M, et al. 7,8-dihydroxyflavone, a trkb agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetamine. Psychopharmacology (Berl). 2014;231(1):159166.[Crossref][PubMed][Web of Science ®][Google Scholar]] observed that 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, treatment significantly protected against the reduction of DAT in the striatum after repeated MA dosing. Pretreatment with 7,8-DHF also significantly attenuated the development of behavioral sensitization. These data indicate that the agents listed above have several properties for effective management of MA use including improvement of dopaminergic and neuroinflammatory dysfunction and amelioration of behavioral changes.

New alternatives to the conventional pharmacotherapeutic strategies are anti-MA vaccines or immunotherapies. In contrast to the traditional pharmacodynamic approach, anti-MA vaccines are designed to generate antibodies that essentially act as pharmacokinetic antagonists that bind to MA and lessen brain concentration of MA. In line with this, a monoclonal antibody treatment for MA (mAB7F9) showed significant reduction in MA-induced locomotor activity over a 1-month period [102Hambuchen MDCarroll FIRuedi-Bettschen D, et al. Combining active immunization with monoclonal antibody therapy to facilitate early initiation of a long-acting anti-methamphetamine antibody response. J Med Chem. 2015;58(11):46654677.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Interestingly, an earlier study reported an initial compensatory effect to pharmacokinetic antagonism with an increase in acquisition of MA self-administration following the monovalent vaccine METH-EP54 [103Duryee MJBevins RAReichel CM, et al. Immune responses to methamphetamine by active immunization with peptide-based, molecular adjuvant-containing vaccines. Vaccine. 2009;27(22):29812988.[Crossref][PubMed][Web of Science ®][Google Scholar]]. However, at this point, the most promising immunopharmacotherapies are keyhole limpet hemocyanin (KLH)-conjugated MA vaccines that produce significant MA antibody levels with high affinities for MA [104Ohia-Nwoko OKosten TAHaile CNAnimal models and the development of vaccines to treat substance use disorders. Int Rev Neurobiol. 2016;126:263291.[Crossref][PubMed][Web of Science ®][Google Scholar]]. The KLH-conjugated MA-like hapten vaccine, MH6-KLH, has been shown to reduce MA-induced locomotor activity, thermoregulation [105Miller MLMoreno AYAarde SM, et al. A methamphetamine vaccine attenuates methamphetamine-induced disruptions in thermoregulation and activity in rats. Biol Psychiatry. 2013;73(8):721728.[Crossref][PubMed][Web of Science ®][Google Scholar]] and acquisition of MA self-administration in rats [106Miller MLAarde SMMoreno AY, et al. Effects of active anti-methamphetamine vaccination on intravenous self-administration in rats. Drug Alcohol Depend. 2015;153:2936.[Crossref][PubMed][Web of Science ®][Google Scholar]]. The MA conjugate vaccine ICKLH-SM09 was also affective in reversing the anorectic effect of MA administration in rats over a 4-month period [107Ruedi-Bettschen DWood SLGunnell MG, et al. Vaccination protects rats from methamphetamine-induced impairment of behavioral responding for food. Vaccine. 2013;31(41):45964602.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In mice, the vaccine succinyl MA (SMA–KLH) has been observed to decrease MA-induced locomotor activity and CPP in mice [108Shen XYKosten TALopez AY, et al. A vaccine against methamphetamine attenuates its behavioral effects in mice. Drug Alcohol Depend. 2013;129(1–2):4148.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Similarly, an agent with a different carrier protein, succinyl MA tetanus toxoid, has been reported to reduce acquisition and reinstatement of MA-induced CPP in mice [109Haile CNKosten TAShen XY, et al. Altered methamphetamine place conditioning in mice vaccinated with a succinyl-methamphetamine-tetanus-toxoid vaccine. Am J Addict. 2015;24(8):748755.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In order to produce continuing adequate levels of antidrug antibody, one research group has found that the administration of ICKLH-SM09 with the adjuvant glucopyranosyl lipid A in mice was more effective in elevating antibody levels over a 21-week period than using the adjuvant aluminium hydroxide [110Stevens MWGunnell MGTawney R, et al. Optimization of a methamphetamine conjugate vaccine for antibody production in mice. Int Immunopharmacol. 2016;35:137141.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Following on from this, the same research group has determined in rats that a combined monoclonal and polyclonal antibody approach produced effective reductions in brain MA for over 4 months [102Hambuchen MDCarroll FIRuedi-Bettschen D, et al. Combining active immunization with monoclonal antibody therapy to facilitate early initiation of a long-acting anti-methamphetamine antibody response. J Med Chem. 2015;58(11):46654677.[Crossref][PubMed][Web of Science ®][Google Scholar]]. While pharmacoimmunotherapy provides some promise for translation given that anti-MA antibodies do not cross the blood–brain barrier, therefore reducing the likelihood of psychiatric side effects from nonspecific actions, antibodies need to be maintained at an effective level with repeated administration, thus requiring greater cost and treatment engagement [111Chen YHWu KLTsai HM, et al. Treatment of methamphetamine abuse: an antibody-based immunotherapy approach. J Food Drug Anal. 2013;21(4):S82S86.[Crossref][PubMed][Web of Science ®][Google Scholar]].

3.2. Human laboratory and clinical studies

Human laboratory studies should provide an efficient mechanism to provide an early indication of the potential efficacy of new drugs emerging from preclinical studies in addition to those currently approved for other clinical indications before proceeding to more costly and potentially risky clinical trials. Human laboratory studies include investigations of compounds altering MA-induced cardiovascular, subjective (high, craving, etc.), and reinforcing effects (self-administration) in controlled conditions with a small number of individuals (see Table 1). Phase II clinical trials measure MA abstinence as the primary outcome and craving, reduction of use and treatment adherence as secondary outcomes over an extended period.

The literature from other drugs of abuse (e.g. heroin, cocaine) indicates that a large number of false positives are yielded from medications altering subjective effects whereas human self-administration more accurately predicts whether a compound will be clinically efficacious [112Haney MSpealman RControversies in translational research: drug self-administration. Psychopharmacology (Berl). 2008;199(3):403419.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Thus, altering the subjective effects of MA with a candidate compound in human laboratory studies may not necessarily have a correlation with clinical outcome in trials. For studies investigating treatments for MA use, there have been few studies that have both been tested in human laboratory paradigms and also been to clinical trial. It is thus currently difficult to determine which of these paradigms are robustly sensitive to new medications. With this in mind, the following therapeutic agents utilizing several different treatment strategies have been investigated.

The atypical antipsychotic, aripiprazole, has been investigated by several research groups with the potential to act as an antagonist to reduce the reinforcing effects of MA. Newton et al. [113Newton TFReid MSDe La Garza R, et al. Evaluation of subjective effects of aripiprazole and methamphetamine in methamphetamine-dependent volunteers. Int J Neuropsychopharmacol. 2008;11(8):10371045.[Crossref][PubMed][Web of Science ®][Google Scholar]] reported that aripiprazole treatment (15 mg, for 2 weeks) did not reduce MA-cue-induced craving and actually increased rewarding and stimulatory effects of MA. Sevak et al. [114Sevak RJVansickel ARStoops WW, et al. Discriminative-stimulus, subject-rated, and physiological effects of methamphetamine in humans pretreated with aripiprazole. J Clin Psychopharmacol. 2011;31(4):470480.[Crossref][PubMed][Web of Science ®][Google Scholar]] observed aripiprazole (20 mg) to reduce the cardiovascular, subjective, and reinforcing effects of MA. Similarly, Stoops et al. [115Stoops WWBennett JALile JA, et al. Influence of aripiprazole pretreatment on the reinforcing effects of methamphetamine in humans. Prog Neuropsychopharmacol Biol Psychiatry. 2013;47:111117.[Crossref][PubMed][Web of Science ®][Google Scholar]] demonstrated that acute aripiprazole (15 mg) pretreatment yielded a significant reduction in self-administration for low (4 mg) and intermediate (8 mg) doses of MA. However, in a double-blind randomized-controlled trial (DBRCT), Coffin et al. [116Coffin POSantos GMDas M, et al. Aripiprazole for the treatment of methamphetamine dependence: A randomized, double-blind, placebo-controlled trial. Addiction. 2013;108(4):751761.[Crossref][PubMed][Web of Science ®][Google Scholar]] failed to demonstrate that 12 weeks of aripiprazole (5–20 mg) treatment significantly reduced MA use. Similarly, Sulaiman et al. [117Sulaiman AHGill JSSaid MA, et al. A randomized, placebo-controlled trial of aripiprazole for the treatment of methamphetamine dependence and associated psychosis. Int J Psychiatry Clin Pract. 2013;17(2):131138.[Taylor & Francis Online][Web of Science ®][Google Scholar]] observed 8 weeks of aripiprazole (5–10 mg) to be safe but not effective in achieving abstinence from MA use.

Baclofen and gabapentin have also been investigated in a DBRCT to increase abstinence from MA in treatment-seeking outpatients. However, neither drug yielded significant beneficial effects on primary outcomes [118Heinzerling KGShoptaw SPeck JA, et al. Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence. Drug Alcohol Depend. 2006;85(3):177184.[Crossref][PubMed][Web of Science ®][Google Scholar]]. There has been some promise with the anticonvulsant, topiramate. In a phase II DBRCT, while not observing any significant difference on the primary outcome measures of MA abstinence, Elkashef et al. [119Elkashef AKahn RYu E, et al. Topiramate for the treatment of methamphetamine addiction: A multi-center placebo-controlled trial. Addiction. 2012;107(7):12971306.[Crossref][PubMed][Web of Science ®][Google Scholar]] demonstrated a reduction in median MA urine level and self-reported MA use in weeks 6–12 of the trial. Most recently, Rezaei et al. [120Rezaei FGhaderi EMardani R, et al. Topiramate for the management of methamphetamine dependence: A pilot randomized, double-blind, placebo-controlled trial. Fundam Clin Pharmacol. 2016;30(3):282289.[Crossref][PubMed][Web of Science ®][Google Scholar]] completed a 10-week DBRCT of topiramate (escalating doses of 50–200 mg) and observed a significant reduction in MA use by topiramate-treated patients relative to placebo by week 6 and significant reductions in severity and craving.

There have been two human laboratory studies investigating a role for the nicotinic receptor agonist varenicline in reducing MA use. Verrico et al. [121Verrico CDMahoney JJ 3rdThompson-Lake DG, et al. Safety and efficacy of varenicline to reduce positive subjective effects produced by methamphetamine in methamphetamine-dependent volunteers. Int J Neuropsychopharmacol. 2014;17(2):223233.[Crossref][PubMed][Web of Science ®][Google Scholar]] investigated the safety and efficacy of the varenicline, to reduce MA-induced positive subjective effects. They observed varenicline (1 and 2 mg) to significantly reduce some MA subjective effects such as ratings of ‘stimulated’ and attenuated ratings of ‘drug liking.’ No adverse events were reported. Given high rates of cognitive deficits in MA users and the potential impact of cognitive dysfunction on treatment, the role of investigational drugs in this domain is of therapeutic interest. In a study investigating the effect of varenicline on cognition in MA-dependent users, it was observed that varenicline (1 mg) improved information processing speed through a significant reduction on visual stimuli reaction time but had no impact on episodic or working memory [122Kalechstein ADMahoney JJ 3rdVerrico CD, et al. Short-term, low-dose varenicline administration enhances information processing speed in methamphetamine-dependent users. Neuropharmacology. 2014;85:493498.[Crossref][PubMed][Web of Science ®][Google Scholar]]. There have been no phase II DBRCTs of varenicline in reducing MA use.

The cholinergic enhancer, rivastigmine, has been investigated to modulate MA-related subjective and reinforcing effects in several human laboratory studies. De La Garza II and colleagues demonstrated 3 mg rivastigmine to reduce significantly attenuated MA-induced diastolic blood pressure elevations and subjective effects such as ‘desire’ [123De La Garza RShoptaw SNewton TFEvaluation of the cardiovascular and subjective effects of rivastigmine in combination with methamphetamine in methamphetamine-dependent human volunteers. Int J Neuropsychopharmacol. 2008;11(6):729741.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In a follow-up study investigating the effects of a higher dose, rivastigmine (6 mg) significantly reduced ratings of ‘likely to use’ but did not alter self-administration [124De La Garza R 2ndNewton TFHaile CN, et al. Rivastigmine reduces “likely to use methamphetamine” in methamphetamine-dependent volunteers. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37(1):141146.[Crossref][PubMed][Web of Science ®][Google Scholar]]. There have been no phase II DBRCTs investigating the efficacy of rivastigmine in treating MA use.

A novel class of medications, angiotensin converting enzyme (ACE) inhibitors, have been investigated as a pharmacotherapy for MA given evidence that they elevate striatal DA content [125Jenkins TAMendelsohn FAChai SYAngiotensin-converting enzyme modulates dopamine turnover in the striatum. J Neurochem. 1997;68(3):13041311.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Two human laboratory studies from the same group have investigated perindopril. Newton et al. [126Newton TFDe La Garza R 2ndGrasing KThe angiotensin-converting enzyme inhibitor perindopril treatment alters cardiovascular and subjective effects of methamphetamine in humans. Psychiatry Res. 2010;179(1):96100.[Crossref][PubMed][Web of Science ®][Google Scholar]] reported that perindopril was tolerated and did not significantly alter MA-induced changes in heart rate but did modify MA-induced changes in blood pressure. Perindopril did not alter MA-induced subjective effects except for ‘any drug effect.’ A follow-up study demonstrated that the moderate dose (8 mg) significantly reduced several subjective ratings including ‘anxious’ and ‘stimulated’ [127Verrico CDHaile CNDe La Garza R 2nd, et al. Subjective and cardiovascular effects of intravenous methamphetamine during perindopril maintenance: A randomized, double-blind, placebo-controlled human laboratory study. Int J Neuropsychopharmacol. 2016;19(7):pyw029.[Crossref][PubMed][Web of Science ®][Google Scholar]]. There have been no phase II DBRCTs evaluating perindopril in the treatment of MA use.

Agonist replacement therapy for MA use has thus far yielded mixed results. In a small, counterbalanced experimental study of dextroamphetamine (d-AMP), Pike et al. [128Pike EStoops WWHays LR, et al. Methamphetamine self-administration in humans during d-amphetamine maintenance. J Clin Psychopharmacol. 2014;34(6):675681.[Crossref][PubMed][Web of Science ®][Google Scholar]] showed that d-AMP produced no significant adverse events, reduced the MA-induced increases in systolic blood pressure and some subjective effects but no attenuation of MA self-administration. In a DBRCT over 8 weeks, Galloway et al. [129Galloway GPBuscemi RCoyle JR, et al. A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction. Clin Pharmacol Ther. 2011;89(2):276282.[Crossref][PubMed][Web of Science ®][Google Scholar]] demonstrated that sustained-release d-AMP (60 mg) did not have any beneficial treatment effect on abstinence from MA relative to placebo although significantly reduced craving and withdrawal scores. Rezaei et al. [130Rezaei FEmami MZahed S, et al. Sustained-release methylphenidate in methamphetamine dependence treatment: A double-blind and placebo-controlled trial. Daru. 2015;23(1):2.[Crossref][PubMed][Web of Science ®][Google Scholar]] conducted a DBRCT of sustained-release methylphenidate (MPH-SR) (escalating doses up to 54 mg/kg) in MA users finding that MPH-SR treatment led to a significant reduction in MA use, craving and depression scores relative to placebo with no significant differences in adverse events. Ling et al. [131Ling WChang LHillhouse M, et al. Sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder. Addiction. 2014;109(9):14891500.[Crossref][PubMed][Web of Science ®][Google Scholar]] conducted a 10-week DBRCT of MPH-SR (54 mg/kg) with behavioral intervention. They reported that MPH-SR was safe and while a beneficial treatment effect of MPH-SR on some outcomes such as self-reported MA use and craving, they observed no effect on the primary outcome of MA use in the last 30 days of the trial. Moreover, Ling et al. [131Ling WChang LHillhouse M, et al. Sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder. Addiction. 2014;109(9):14891500.[Crossref][PubMed][Web of Science ®][Google Scholar]] observed a significant effect of MPH-SR relative to placebo in patients with higher baseline MA use (>10 days of MA use at baseline) which is in line with the suggestion that stimulant replacement therapy should be targeted to moderate-to-high MA users [132Levin FRMariani JJBisaga A, et al. ’S ‘sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder’. Addiction. 2015;110(5):875876. .[Crossref][PubMed][Web of Science ®][Google Scholar]]. It has also been argued that the doses utilized for substitution therapy in these studies may not be high enough to yield an effect on MA use [129Galloway GPBuscemi RCoyle JR, et al. A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction. Clin Pharmacol Ther. 2011;89(2):276282.[Crossref][PubMed][Web of Science ®][Google Scholar],132Levin FRMariani JJBisaga A, et al. ’S ‘sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder’. Addiction. 2015;110(5):875876. .[Crossref][PubMed][Web of Science ®][Google Scholar]].

Modafinil is a wakefulness-promoting agent with several monoaminergic stimulating effects (e.g. dopamine, norepinephrine, orexin, histamine). De La Garza II et al. [133De La Garza R 2ndZorick TLondon ED, et al. Evaluation of modafinil effects on cardiovascular, subjective, and reinforcing effects of methamphetamine in methamphetamine-dependent volunteers. Drug Alcohol Depend. 2010;106(2–3):173180.[Crossref][PubMed][Web of Science ®][Google Scholar]] observed that modafinil (200 mg) attenuated MA-induced elevations in systolic blood pressure. One study investigated the effects of modafinil (200 mg) on cognition in MA users and found a facilitative effect of the agent on sustained attention but no improvement on other cognitive measures [134Dean ACSevak RJMonterosso JR, et al. Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans. J Stud Alcohol Drugs. 2011;72(6):943953.[Crossref][PubMed][Web of Science ®][Google Scholar]]. These authors reported as association of heavier frequency of baseline MA use and greater efficacy of modafinil on assessments relating to inhibition and processing speed. However, two DBRCTs have failed to demonstrate any beneficial treatment effect of modafinil on MA abstinence or cravings [135Shearer JDarke SRodgers C, et al. A double-blind, placebo-controlled trial of modafinil (200 mg/day) for methamphetamine dependence. Addiction. 2009;104(2):224233.[Crossref][PubMed][Web of Science ®][Google Scholar],136Heinzerling KGSwanson ANKim S, et al. Randomized, double-blind, placebo-controlled trial of modafinil for the treatment of methamphetamine dependence. Drug Alcohol Depend. 2010;109(1–3):2029.[Crossref][PubMed][Web of Science ®][Google Scholar]].

One of the most frequently investigated agents for the management of MA use is the antidepressant bupropion. Newton et al. [137Newton TFRoache JDDe La Garza R 2nd, et al. Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving. Neuropsychopharmacology. 2006;31(7):15371544.[Crossref][PubMed][Web of Science ®][Google Scholar]] demonstrated a beneficial effect of bupropion to reduce subjective (e.g. ‘high’) effects of MA and also craving measures following MA cue exposure. In two 12-week DBRCTs, Shoptaw et al. [138Shoptaw SHeinzerling KGRotheram-Fuller E, et al. Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence. Drug Alcohol Depend. 2008;96(3):222232.[Crossref][PubMed][Web of Science ®][Google Scholar]] and Elkashef et al. [139Elkashef AMRawson RAAnderson AL, et al. Bupropion for the treatment of methamphetamine dependence. Neuropsychopharmacology. 2008;33(5):11621170.[Crossref][PubMed][Web of Science ®][Google Scholar]] reported sustained-release bupropion (150 mg twice daily) to be effective in achieving a MA-free week relative to placebo in light but not heavy MA-dependent patients. However, in non-daily MA users, Anderson et al. [140Anderson ALLi SHMarkova D, et al. Bupropion for the treatment of methamphetamine dependence in non-daily users: A randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2015;150:170174.[Crossref][PubMed][Web of Science ®][Google Scholar]] reported no significant effects of sustained-release bupropion (150 mg twice daily) on MA use or treatment retention. Similarly, Heinzerling et al. [141Heinzerling KGSwanson ANHall TM, et al. Randomized, placebo-controlled trial of bupropion in methamphetamine-dependent participants with less than daily methamphetamine use. Addiction. 2014;109(11):18781886.[Crossref][PubMed][Web of Science ®][Google Scholar]] failed to observe any treatment effect on MA use in non-daily users in a 12-week DBRCT, although an effect on abstinence was found in participants compliant with medication and concurrent cognitive-behavioral therapy (CBT) versus non-adherent participants (54% vs. 18%). The antidepressant mirtazapine has also been investigated in a 12-week DBRCT in men who have sex with men [142Colfax GNSantos GMDas M, et al. Mirtazapine to reduce methamphetamine use: A randomized controlled trial. Arch Gen Psychiatry. 2011;68(11):11681175. .[Crossref][PubMed][Web of Science ®][Google Scholar]]. The agent was found to increase the rate of MA abstinence with a number needed to treat of 3.1, comparing favorably with the majority of MA trials.

The role of the opioid system in the reinforcing effects of MA and the potential naltrexone in treating MA use has gained some recent attention. Ray et al. [143Ray LABujarski SCourtney KE, et al. The effects of naltrexone on subjective response to methamphetamine in a clinical sample: A double-blind, placebo-controlled laboratory study. Neuropsychopharmacology. 2015;40(10):23472356.[Crossref][PubMed][Web of Science ®][Google Scholar]] found a significant effect of naltrexone in attenuating MA-induced craving and subjective responses to MA such as ‘drug high,’ ‘would like drug,’ and ‘stimulated.’ The endogenous opioid system may underlie some of the reinforcing characteristics of MA given that opioid receptors are highly expressed in regions of the mesolimbic reward pathway [144Boutrel BA neuropeptide-centric view of psychostimulant addiction. Br J Pharmacol. 2008;154(2):343357.[Crossref][PubMed][Web of Science ®][Google Scholar]]. However, in an 8-week DBRCT, no significant treatment effects of naltrexone (in combination with NAC) relative to placebo were observed, although this result may be due to a lack of power (N = 31) [145Grant JEOdlaug BLKim SWA double-blind, placebo-controlled study of n-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol. 2010;20(11):823828.[Crossref][PubMed][Web of Science ®][Google Scholar]].

NAC has been noted to be a potential candidate for MA dependence [82McKetin RDean OMBaker AL, et al. A potential role for n-acetylcysteine in the management of methamphetamine dependence. Drug Alcohol Rev. 2016;36(2):153159.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Studies thus far have been mixed. While Grant et al. [145Grant JEOdlaug BLKim SWA double-blind, placebo-controlled study of n-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol. 2010;20(11):823828.[Crossref][PubMed][Web of Science ®][Google Scholar]] failed to find a beneficial effect of up to 2400 mg/day on craving and MA use, more recently Mousavi et al. [146Mousavi SGSharbafchi MRSalehi M, et al. The efficacy of n-acetylcysteine in the treatment of methamphetamine dependence: A double-blind controlled, crossover study. Arch Iran Med. 2015;18(1):2833.[PubMed][Web of Science ®][Google Scholar]] demonstrated NAC 1200 mg to be safe and to significantly reduce craving for MA in a crossover DBRCT (N = 32). This inconsistency could be due to increased power by utilizing a cross over design and/or a potentiation effect from concurrent psychological intervention.

The anti-inflammatory agent, ibudilast, has been investigated in preliminary phase I trials. No significant interactions between ibudilast and MA on cardiovascular measures or pharmacokinetics have been reported, apart from a lower MA area under the curve to last time point [147DeYoung DZHeinzerling KGSwanson AN, et al. Safety of intravenous methamphetamine administration during ibudilast treatment. J Clin Psychopharmacol. 2016;36(4):347354.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In a within-subjects human laboratory study, Worley et al. [148Worley MJHeinzerling KGRoche DJ, et al. Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study. Drug Alcohol Depend. 2016;162:245250.[Crossref][PubMed][Web of Science ®][Google Scholar]] reported ibudilast to significantly attenuate MA-induced subjective effects such as ‘high,’ ‘like,’ and ‘stimulated.’ To date, there have been no phase II DBRCTs investigating the role of ibudlast in treating MA dependence.

4. Conclusion

There are several agents based on rational neurobiological targets that have been demonstrated to successfully reduce markers of MA dependence in animal models. In human laboratory studies and phase II trials over the last decade, many medications have been investigated including aripiprazole, bupropion, mirtazapine, baclofen, gabapentin, topiramate, rivastigmine, d-AMP and MPH-SR, modafinil, naltrexone, ibudilast, and NAC. There is mixed consistency across these studies and, while there have been some signals of efficacy at various points, no single medication has demonstrated a broad and strong effect in the MA-dependent population.

5. Expert opinion

Currently, there are no approved medications for the treatment of MA dependence and no medication is emerging with consistency from the scientific literature to yield a sound beneficial treatment effect. From the small number of DBRCTs, mirtazapine has shown some beneficial effect, while bupropion, MPH-SR, and topiramate have shown some efficacy depending on the level of MA use at baseline via post-hoc analyses.

Advancement in MA treatment, including clinical research and translation into practice, faces several challenges. Regarding the utilization of stimulant agonist substitution therapy such as MPH-SR, there is potential for exacerbation of cardiovascular and psychiatric problems from dopaminergic toxicity. However, Levin et al. [132Levin FRMariani JJBisaga A, et al. ’S ‘sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder’. Addiction. 2015;110(5):875876. .[Crossref][PubMed][Web of Science ®][Google Scholar]] outline that there have been few adverse events in studies thus far and the harm reduction benefits outweigh these risks. Some authors have indicated that the doses utilized for stimulant substitution therapy may not be high enough to yield an effect on MA use given that Ling et al. [131Ling WChang LHillhouse M, et al. Sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder. Addiction. 2014;109(9):14891500.[Crossref][PubMed][Web of Science ®][Google Scholar]] found an effect of MPH-SR in patients only with higher baseline MA use [129Galloway GPBuscemi RCoyle JR, et al. A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction. Clin Pharmacol Ther. 2011;89(2):276282.[Crossref][PubMed][Web of Science ®][Google Scholar],132Levin FRMariani JJBisaga A, et al. ’S ‘sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder’. Addiction. 2015;110(5):875876. .[Crossref][PubMed][Web of Science ®][Google Scholar]]. Several trials are currently underway, including a dose-escalating study in Australia, that will provide further information with regards to dose, safety, and efficacy of this approach [149Ezard NDunlop AClifford B, et al. Study protocol: A dose-escalating, phase-2 study of oral lisdexamfetamine in adults with methamphetamine dependence. BMC Psychiatry. 2016;16:(1):428.[Crossref][PubMed][Web of Science ®][Google Scholar]].

Promising avenues for treatment include drugs with novel therapeutic targets such as NAC, oxytocin, and ibudilast. Novel TAAR1-targeted compounds may also hold new opportunities for development. Agents with novel modes of delivery such as MA vaccines, which modulate the pharmacokinetics of MA and thus reduce the amount of drug entering the brain, may also have potential. However, antibodies need to be maintained at an effective level with repeated administration, which may prove difficult with MA blood levels and limit effective translation into practice. Regulatory approval is a rate-limiting factor for timely progression of novel agents from preclinical studies to human laboratory and phase II clinical studies [150Koob GFKenneth Lloyd GMason BJDevelopment of pharmacotherapies for drug addiction: A rosetta stone approach. Nat Rev Drug Discov. 2009;8(6):500515.[Crossref][PubMed][Web of Science ®][Google Scholar]].

A key component for drug discovery to treat MA dependence is to enable early stages of investigation to predict efficacy in larger scale phase II clinical trials. Medications with clinical efficacy should have robust effects in human laboratory paradigms yet those that are not should have negative or inconsistent outcomes. Compounds that perform well in the laboratory for MA have thus far not yielded positive signals in clinical trials (aripiprazole and to an extent, naltrexone), and there are several medications (some with signals of clinical efficacy such as mirtazapine and topiramate) that have not been tested in human laboratory designs. This can be contrasted with the extensive pharmacotherapy literature for the treatment of alcohol dependence, whereby there is concurrence across preclinical models, human laboratory, and clinical trials for naltrexone. There are only a small number of agents investigated in human laboratory MA studies that have progressed to larger RCTs such that it is difficult to outline which markers are predictive of efficacy at this point.

Validated preclinical and human laboratory models should be an efficient mechanism for translation by providing an early indication of the potential efficacy of medications in one or more stages of the addiction cycle. The cocaine and heroin translational research literature indicates that self-administration outcomes from human laboratory studies can have good predictive validity for effective pharmacotherapies [112Haney MSpealman RControversies in translational research: drug self-administration. Psychopharmacology (Berl). 2008;199(3):403419.[Crossref][PubMed][Web of Science ®][Google Scholar]], with effects associated with subjective outcomes leading to numerous false positives. In preclinical studies, the intravenous self-administration/relapse models are arguably the most valid as these allow the ‘choice’ of drug use by the animal, instead of contingent on administration by the experimenter. These models continue to grow in sophistication, allowing extended drug access paradigms, identification of genetic vulnerability for addictive phenotypes, and different experimental conditions during abstinence (extinction of operant responding or incubation) prior to relapse produced by known triggers (drug reexposure, cues associated with drug use, stress).

One particular challenge in clinical trials is low adherence to medication in MA users. Poor compliance is a common problem in the drug and alcohol field and limits the effectiveness of treatment in practice [151Morley KCLogge WPearson SA, et al. National trends in alcohol pharmacotherapy: findings from an australian claims database. Drug Alcohol Depend. 2016;166:254257.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Several of the phase II clinical trials have yielded low adherence and in some cases lower than 40% (see Table 2). Objective biomarkers of compliance are not often provided. Indeed, one study observed that the difference between compliance as recorded on medication event monitoring systems versus self-report was 26%. Further, one pooled event-level analysis of two RCTs (mirtazpine and buproprion) demonstrated that MA use is negatively associated with adherence to medication [152Hermanstyne KASantos GMVittinghoff E, et al. Event-level relationship between methamphetamine use significantly associated with non-adherence to pharmacologic trial medications in event-level analyses. Drug Alcohol Depend. 2014;143:277280.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Therapeutic agents should be integrated with interventions that include specific strategies to enhance medication adherence (e.g. compliance therapy [153Kemp RHayward PApplewhaite G, et al. Compliance therapy in psychotic patients: randomised controlled trial. Bmj. 1996;312(7027):345349.[Crossref][PubMed][Web of Science ®][Google Scholar]]) and/or interventions to improve neurocognitive impairments.

Table 1. Human laboratory studies of agents on the effects of MA.

Table 2. Phase II clinical trials of agents for the treatment of MA use.

Finally, the diverse range of clinical contexts arising from MA abuse may require different pharmacotherapeutic strategies. These may include dependent treatment seekers with varying severity of use, those with neurocognitive damage and/or poor treatment compliance, those with psychiatric comorbidity, and those presenting with medical or psychiatric symptoms associated with acute MA intoxication or also withdrawal. Research designs aimed at developing effective treatments may need to encompass these diverse clinical needs. Testing potential medications across a range of preclinical and human laboratory models is recommended. More clinical research will be required before we can ascertain whether MA human laboratory paradigms are robustly responsive to medications with proven signals of clinical efficacy. As the literature matures and greater efficacy in clinical research is reported, a clearer examination of preclinical and human laboratory data that is predictive of this efficacy will emerge such that these markers can then be used for ongoing drug discovery.

Article Highlights

  • Methamphetamine use is a serious public health concern in many countries.

  • No single medication has demonstrated a broad and strong treatment effect in clinical trials.

  • One trial demonstrated mirtazapine to be effective increasing rates of MA abstinence (primary outcome measure).

  • Post-hoc analyses have shown some efficacy according to baseline MA use such as MPH-SR (heavy users), bupropion (light users) and topiramate (abstinent use at baseline).

  • Compounds with novel therapeutic targets (eg anti-inflammatory) and modes of delivery (eg pharmacoimmunotherapy) are promising.

  • Progression in the field requires strategies to improve compliance as well as more clinical research into novel strategies for efficacy.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

 

 

While America wages war on opioids, meth makes its comeback – CNN

 

(CNN)For Capt. Mark Wollmershauser Jr. and the Tulsa Police Department, the late-2000s and early 2010s were an extremely dangerous time.

In Oklahoma, a state that is no stranger to the scourge of methamphetamine addiction, those years were the heyday of the “shake and bake” method — a rudimentary way of making meth using just cold medicine, some toxic chemicals and an empty two-liter bottle.
The technique is simple enough that many addicts can cook their own meth, but with one tiny misstep, the chemical reaction that occurs inside can cause deadly explosions.
By 2011, Wollmershauser and his narcotics unit were finding and dismantling hundreds of these vessels in meth labs around the city.
A display of items used in the &quot;shake-and-bake&quot; method of manufacturing methamphetamine is shown in Oklahoma City. The items shown were purchased for display purposes.

“People were not just burning themselves while cooking meth but were causing damage to other residents that had nothing to do with methamphetamine,” he said. “It was a really horrible time.”
When new laws were enacted to limit access to pseudoephedrine — an allergy drug used in making meth — the proliferation of these mobile labs waned. After responding to a high of 431 meth labs in 2011, his department encountered just 19 last year.
But Wollmershauser said that didn’t spell the end of Tulsa’s meth problem. In fact, officials across the state say they are seizing meth that is purer, cheaper and in greater quantities than ever before, with most of it coming from south of the border.
And while much of America is focused on combating the devastating impacts of opioid addiction, some states like Oklahoma are struggling to fight a new battle against an old foe.

The role of Mexican ‘superlabs’

Richard Salter has been with the Drug Enforcement Administration for 27 years, most recently as the special agent in charge for the state of Oklahoma.
He said the meth problem in Oklahoma is getting worse, and points to Mexican cartels — in particular, the powerful Sinaloa cartel — as the reason.
As it became more difficult and dangerous to produce meth in the United States, cartels recognized an opportunity to fill the void.
“They came in with much purer, much cheaper meth and just flooded this region of the country,” Salter said.
A Mexican Army expert stands near containers with crystal meth paste at a clandestine laboratory in Mexico&#39;s Baja California state. &quot;Superlabs&quot; like this one can produce hundreds of pounds of crystal meth daily.

Salter said in 2012, the DEA was buying meth undercover off the streets for $1,100 an ounce. Today, his agents are regularly getting ounces for just $250 to $450.
“That’s as cheap as I have ever seen methamphetamine my entire career,” he said.
The reason for the drop in prices is the scale of production that the Mexican cartels have achieved. Whereas “shake and bake” labs could turn out lots of small batches, so-called “superlabs” in Mexico produce hundreds of pounds daily.
Salter said most of the meth his agents seize first comes across the US-Mexico border in California or Arizona, before making its way through the interstate highway system and temporary stash houses on its way to Oklahoma.
Along the border, officials with US Customs and Border Protection also report a steep increase in the amount of meth they are seizing.
Anne Maricich, deputy director of field operations for the agency’s San Diego ports of entry, said her field office has seen a 50% increase in the amount of meth seized compared to this time last year.
“The other hard narcotics like cocaine, heroin and fentanyl, we see them — they’re prevalent at our border crossings, but nowhere near the quantities that we see of meth,” she said.
On the streets of Oklahoma, this influx of cheap and powerful meth has had deadly consequences.
The number of lethal meth overdoses in the state has more than doubled in recent years, rising from 140 in 2012 to 335 deaths in 2016. In 2017, there were 327 meth overdose deaths, but that tally is incomplete and the actual number is likely higher, according to Mark Woodward, spokesman with the Oklahoma Bureau of Narcotics.
“There’s so much attention — not just in Oklahoma, but nationwide — on the opioid crisis,” said Woodward. “But our single most deadly individual drug is methamphetamine.”
Perhaps no city has been hit harder by this latest meth epidemic than Tulsa.
In just the first six months of 2018, Wollmershauser said his Special Investigations Division has already surpassed the amount of meth they seized in all of 2017 by 30 pounds.
He can’t explain why the problem is more severe here than in other parts of the state, but he doesn’t think incarceration is the solution.
Wollmershauser said his department is trying to use more “front end diversion” tactics to help addicts get treatment without getting the criminal justice system involved, while also aggressively pursuing the cartels and other large-scale distributors.
While the amount of meth his officers has seized has risen, he said his department is on track to reduce the number of arrests by 40% this year.
“I think we’re definitely targeting the right folks that are taking advantage of our city and citizens, but the addiction is strong and it’s difficult,” Wollmershauser said.

How meth fueled a crisis behind bars

Lindsay McAteer’s struggles with anxiety and depression led her to self-medicate as a teenager.
At age 14, her boyfriend at the time introduced her to meth.
“I immediately liked it,” McAteer said. “It gave me a false sense of identity and a false sense of accomplishment.”
It was the beginning of a 20-year struggle with the drug that nearly ended with a life sentence.
After using meth for several years, she said she stopped for a brief period, but after she was laid off from work and had her house foreclosed on, her addiction spiraled out of control.
“I had nothing,” McAteer said. “I was losing everything, and meth was able to make me feel like everything was OK, despite the fact that nothing was OK.”
In addition to using meth, McAteer began selling the drug. She was eventually arrested for trafficking and found herself staring at a possible sentence of 12 years to life.
Mass incarceration is also an issue in Oklahoma — particularly among women — and lengthy sentences for drug offenses are a major contributing factor, according to analysis by Reveal from The Center for Investigative Reporting. The state has the nation’s highest female incarceration rate, with 149 out of every 100,000 women locked up, more than double the national average.
The total chaos of meth addiction

But even for those like McAteer who face time in prison, there are sometimes alternatives to a life behind bars. Women in Recovery, or WIR, is an intensive program for women who are looking at lengthy sentences for drug offenses in Tulsa County.
With the door of a prison cell the only other option that was open to her, McAteer entered WIR in August 2014.
Mimi Tarrasch, the executive senior director for WIR, said that many of the program’s participants are multi-substance users, but at least 60% have seen their addictions lead them to meth.
“Early on, because it’s a stimulant, they feel wonderful and it makes them productive and motivated,” said Roxanne Hinther, clinical director for WIR. “But ultimately, they can’t take care of their children and they lose everything they have.”
Tarrasch said that most of the women in her program have been battling addiction for 13 to 15 years, which takes a huge toll on their health and wellness, and that of their family. Many have also experienced traumatic events, from childhood abuse to sexual assaults and domestic violence.
Using a range of treatments, training and education, the program gives women who would be spending time behind bars a second chance at a productive and fulfilling life.
McAteer graduated from WIR in 2016 and has now been in active recovery for more than four years. Today, she works as a housing compliance specialist for the Mental Health Association Oklahoma.
Since Women in Recovery began in 2009, 390 women have graduated, with 6.7% of graduates relapsing or falling back into criminal activity.
“I can say that recovery is definitely possible, and I can say that treatment is the answer versus punishment,” McAteer said. “It’s not foolproof — I can’t say that everyone is able to use this [program] the way it’s designed to work, but the vast majority of us do.”
______________________________________________________________________________
Treatment of Methamphetamine use:
Abstract
Copyright © 2016, Zahedan University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Background
2. Objectives
3. Patients and Methods
4. Results
5. Discussion
Acknowledgements
Footnote
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Current Research on Methamphetamine: Epidemiology, Medical and Psychiatric Effects, Treatment, and Harm Reduction Efforts

Abstract

Background

Methamphetamine (MA) which is known as “shisheh” in Iran is a drug that widely is used in many parts of the world and it is near to a decade that is available for the most drug users and has a considerable prevalence of use. Due to high abuse prevalence and very new challenging phenomenon, it is very important that researchers and treatment providers become more familiar with different aspects of MA.

Discussion

It has multiple neurobiological impacts on the nervous system, some of which are transitory and some longer lasting. MA activates the reward system of the brain and produces effects that are highly reinforcing, which can lead to abuse and dependence. Routes of administration that produce rapid onset of the drug’s effects (i.e., smoking and injection) are likely to lead to more rapid addiction and more medical and psychiatric effects. No effective pharmacotherapies have been developed for the treatment of MA dependence; although, this is an area of very active research. Several behavioral treatments have been shown to reduce MA use, but better treatments are needed.

Conclusion

Harm reduction strategies for non-treatment seeking MA users are needed to reduce the risk of human immunodeficiency virus and other medical risks. The research agenda for MA is substantial, with development of effective pharmacotherapies as one of the most important priorities. Appropriate and effective response for prevention, treatment and harm reduction services due to increasing problems regarding MA in Iran and some other countries in the region.

Keywords: Methamphetamine, Epidemiology, Side-effects, Treatment, Harm reduction, Iran

Introduction

Worldwide, as many as 52 million individuals aged 15-64 are estimated to have used amphetamine-type stimulants for non-medical purposes at least once in the past year. Methamphetamine (MA) is the second most widely abused illicit drug in the world (following cannabis); its users nearly outnumber heroin and cocaine users combined. About two-thirds of the world’s MA/amphetamine users reside in East and Southeast Asia, followed by approximately one-fifth in the Americas (specifically the United States and Northern Mexico).

Iran has a special situation in Asia and Middle East, with regard to amphetamine type stimulants (ATS) availability and use. Prior to 2004, there were no reported seizures of ATS in Iran. The first reported of ATS seizure was in 2005, followed by an increasing number of seizures, year by year. The amount of MA seized qualified Iran for ranking 5th in ATS seizures in 2010 and 2011., There was a 400% increase in the amount of ATS seized in Iran between 2010 and 2011, this 1 year rate of increase compares to increases of 238% in Mexico 166% in Thailand, 153% in USA and 140% in China, put Iran in 1st ranking for an increase in seizure.

Discussion

Pharmacology of MA

MA increases activation of the dopamine, norepinephrine, and serotonin systems. MA use causes the release of dopamine into the synaptic cleft, increasing dopamine concentration. Furthermore, MA inhibits transport of dopamine into the storage vesicles, thus increasing the synaptic dopamine concentration. This abnormally high concentration of dopamine contributes to the severe neurotoxicity of MA. Heavy daily MA use and high dosages over a long duration result in neurobiological deficits that do not resolve until many months following cessation of use.

Besides the acute dopaminergic stimulation, MA produces norepinephrine effects such as mild elevation of pulse and blood pressure and cutaneous vasoconstriction, but it is important to know that some chronic users shows a unpredictable hypotension during general anesthesia in operation rooms, which one of the possible cause is down-regulation of endogenous catecholamine receptors.

Higher doses increase central nervous system stimulation, manifested as increased alertness and compulsive or repetitive behavior. MA users have increased sympathomimetic effects such as dizziness, tremor, hyperreflexia, pyrexia, mydriasis, diaphoresis, tachypnea, tachycardia, and hypertension. The drug has a prolonged half-life (10-12 h) and long duration of action. Elevated levels of dopamine in the central nervous system are associated with the reinforcing and highly addictive properties of MA.

Route of administration

MA can be used orally or intranasal, or it can be smoked or injected intravenously. Injection and smoked administration of MA carry higher risk for acute toxicity as well as greater potential for the development of addiction. In general, the rapid onset of euphoria provided by these routes of administration provides a powerful stimulus for re-administration of the drug to maintain the euphoria. When injected intravenously, MA reaches cerebral circulation in 10-15 s. When smoked, it reaches the brain in 6-8 s; smoking can achieve blood levels comparable to those reached through intravenous injection., These routes also have the most potential for toxicity due to rapid dose escalation. Intranasal insufflation (snorting) of MA produces euphoria in 3-5 min. Absorption of orally administered MA occurs more slowly from the intestines, with peak plasma levels being reached 180 min after dosing. Clinical reports recount dependence-level users taking 50 to 1000 mg of MA daily.

MA injection in Iran is reporting recently in different cities with high rate of injection and shared injection both in closed and open setting, which is an alarming sign for human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) prevention programs in Iran.

Symptoms of MA use, misuse, and dependence

MA use increases blood pressure, body temperature, heart rate, and breathing rate. Continued use is common because of rewarding effects such as euphoria, reduced fatigue, reduced hunger, increased energy, increased sex drive, and increased self-confidence. Negative acute effects include abdominal cramps, shaking, high body temperature, bruxism (teeth grinding), stroke, and cardiac arrhythmia, as well as increased anxiety, insomnia, aggressive tendencies, paranoia, and hallucinations.

The acute subjective effects of MA use depend on the amount used and route of administration. The effects of injection and smoking are rapid and intense, often described as a “rush,” followed by euphoria and a sense of increased energy, wakefulness, alertness, and increased libido. Heart rate, blood pressure, and breathing rate increase and many users will grind their teeth and pick at their skin. Effects of MA can last up to 12 h. Due to the development of tolerance, chronic MA users repeat dosing every few hours in “binging” episodes, which can result in paranoia, hallucinations, delusions, mood disturbance, and formication (tactile hallucination of bugs crawling on the skin).

After prolonged or heavy use of MA, a withdrawal syndrome may emerge characterized by dysphoric mood, anhedonia, fatigue, increased appetite, sleep disturbance, and slowing, or acceleration of psychomotor activity. The severity of withdrawal is related to the duration and intensity of recent MA use. MA-dependent individuals have reported remission of the most severe withdrawal symptoms within several days to 3 weeks; although, there have been numerous clinical observations of more subtle symptoms (i.e., anhedonia) lasting for several months., Apathy has been reported more frequently than depressed mood, suggesting that anhedonia may be more problematic than major depressive disorder following cessation of MA use.

Psychiatric considerations

MA-associated psychiatric impairment may occur in several domains: cognitive, intellectual, or affective. The drug’s contribution to impairment may be acute, delayed, or cumulative/residual. Psychiatric impairment appears to correlate with duration of use as well as total and peak amounts of MA absorbed. Neurocognitive deficits associated with chronic MA use include impairments in episodic memory, executive functions, and psychomotor tasks related to frontostriatal and limbic circuits. MA use may also be associated with deficits in attention, memory, and language. Neurocognitive impairment may persist for 9 months or longer following cessation of MA use, but recovery in DAT activity and improvement in cognitive functioning is possible with sustained abstinence.

Psychiatric symptoms have been well-documented in MA users. Anxiety, depression, insomnia, and psychosis are among the most commonly reported symptoms associated with MA dependence, and individuals presenting to the emergency department in the context of MA intoxication may be agitated, violent, or suicidal., Though minor agitation may be treated by placing the individual in a quiet, less stimulating environment, benzodiazepines, or neuroleptics may be required for more severe MA-related agitation or psychosis.

Psychiatric symptoms may vary as a result of individual differences in sensitivity to MA, amount and/or frequency of use, and route of administration. Individuals who use intravenously and who have a family history of psychotic symptoms are at heightened risk for the development of MA-related psychosis, which may mimic schizophrenia. Clinical symptoms of MA-induced psychosis include paranoia, delusions, and hallucinations., Psychosis occurs at least intermittently in a significant proportion of MA users, with wide variation in the severity and clinical course of symptoms.

Although the majority of MA-related psychiatric symptoms typically remit within a week of abstinence,a subset of MA users experience prolonged psychiatric symptomatology, even in the absence of a prior reported history of mental illness., Although MA is one of the most famous drugs in a drug-induced psychosis, but recent studies finding suggest that designer drugs may have severe side-effects in this domain than MA.

Medical considerations

Chronic use of MA results in a variety of medical consequences, including cardiovascular disease, pulmonary problems, neurological problems, and dental disease. Long-term MA use is associated with elevated rates of infectious diseases, including HIV, hepatitis B and C, and endocarditis. Factors mediating the relationship between MA use and infectious diseases include increased risky sexual behaviors occurring in the context of MA intoxication, as well as injection drug use and associated risk behaviors (e.g., needle sharing).

Clinical considerations

The groups disproportionately impacted by MA have been women and men who have sex with men (MSM). Unlike with cocaine and heroin, where a very high proportion of users are male, women use MA at rates almost equal to men. Surveys among women suggest that they are more likely than men to be attracted to MA for weight loss and to control symptoms of depression. Over 70% of MA-dependent women report histories of physical and sexual abuse and are more likely than men to present for treatment with greater psychological distress. MA has been a popular drug among MSM since the 1980s. MSM report using MA to combat feelings of loneliness and isolation and to promote sexual desire and sexual behavior., In addition to the appeal of its sexual effects, MA serves as a coping tool for many MSM with HIV or AIDS. MSM with HIV report using MA to manage symptoms of HIV disease, such as fatigue, or to remedy HIV-related “burn out” and depression.

MA’s dramatic effect on sexual desire and sexual behavior has been a major public health concern, as it has been associated with increasing risk for transmission of HIV., Sexual practices associated with MA use include increased numbers of casual and anonymous sexual partners, increased anal intercourse, decreased condom use, sex trading, group sex, and more frequent and longer episodes of sexual activity. The multicenter AIDS cohort study and several other studies found a high correlation between MA use and HIV seroconversion and other sexually transmitted infections, such as syphilis, gonorrhea, and hepatitis. Treatment of MA dependence may be one of the most effective strategies in reducing the spread of HIV and other associated sexually transmitted infections.

Pharmacotherapy treatments

Until date, there is limited literature on evidence-based pharmacological treatment approaches for MA withdrawal. Antidepressants and anxiolytics may be used to ameliorate depressive and anxiety symptoms, though research suggests only limited benefits of antidepressants in reducing withdrawal symptoms.Neuroleptics may be used to treat MA-induced psychotic symptoms in the context of intoxication or recent use, and a recent study demonstrated the equivalent efficacy of Olanzapine (Zyprexa), an atypical neuroleptic, and haloperidol (Haldol), atypical neuroleptic, in improving psychotic symptoms related to amphetamine use.

The research literature lacks substantiation of efficacy of any medication as a treatment for MA dependence. Past work has failed to determine the efficacy of compounds such as selegiline (Eldepryl), sertraline (Zoloft), gabapentin (Neurontin), rivastigmine (Exelon), risperidone (Risperdal), ondansetron (Zofran), and Abilify (Aripiprazole) as potential treatments for MA dependence.

Medication development for MA addiction generally strives to address deficits caused by MA use or associated with withdrawal. The target of therapeutic development has focused on initiation of abstinence and prevention of relapse. Bupropion (Wellbutrin), modafinil (Provigil), naltrexone, mirtazapine (Remeron), and baclofen (Lioresal) have exhibited limited utility in treating MA addiction, especially in conjunction with behavioral therapy. Other medications (e.g., lobeline, vigabatrin) are under consideration, but evidence for efficacy is lacking and the scant data that do exist contain no information regarding the suitability for various populations. Also of interest is a “replacement” or “substitution” approach with other stimulants such as methylphenidate,, akin to methadone for opioid addiction. As with methadone, however, such a pharmacotherapy enables the patient to rehabilitate in other life areas, but does not lead to near-term abstinence from stimulants. There is at least one clinical trial in Iran, which recently compared aripiprazole with risperidone for treatment of MA induced psychosis, based on findings of this study risperidone is better choice for patients with positive psychosis symptoms and vice versa aripiprazole is better for patients with negative psychosis symptoms.

Matrix model of cognitive behavioral therapy (CBT): The matrix model incorporates principles of CBT in individual and group settings, family education, motivational interviewing, and behavioral therapy that employ CBT principles. This manualized therapy has been proven effective in reducing MA use during the 16-week application of the intervention, in comparison to a “treatment as usual” condition. The matrix model has been evaluated as a stand-alone treatment for subgroups of MA abusers (e.g., gay and bisexual men and heterosexuals) and as the behavioral treatment platform in pharmacotherapy trials for MA dependence.

Contingency management (CM) therapy for treatment of stimulant use disorders employs principles of reinforcement for demonstration of desired behaviors. Drug use can be brought under control if desired behaviors that replace or compete with drug use are followed by rewards to increase the frequency of these behaviors. Thus, CM combined with a pharmacotherapy, such as modafinil that potentially enhances cognition or restores memory/learning processes impacted by MA dependence could be a potent approach. CM and CBT have been assessed for comparative effectiveness in treating stimulant dependence with a group of cocaine- and MA-dependent individuals-participants who received CM were retained in treatment significantly longer than those who received only CBT and they provided more stimulant-negative urine samples.

Another approach is empowering patients and their families by empower based interventions which could be effective for Iranian patients.

Harm reduction

Some MA users who do not want treatment and cannot stop using MA should be considered as a target group of harm reduction services. Harms of MA use includes:

  • Direct medical harms such as cardiovascular disease, pulmonary problems, liver disease, strokes, pregnancy complications, neurological/mental complications, and dental complications.
  • Indirect medical harms such as HIV and hepatitis B and/or C because increase in high risk sex behaviors and sharing behaviors. Even in non-injecting MA users we can see an increase in the rate of hepatitis C because of pipe sharing.
  • Indirect social harms such as increase in minor and major crimes, and violence.,

Current harm reduction strategies have been established in the context of heroin injecting drug users (IDUs) and have been shown to be effective for controlling HIV epidemic among these opiate using IDUs. Many of the harm reduction strategies developed for IDUs are likely to be useful for injecting MA users. Needle exchange has been shown to be an effective harm reduction strategy with opiate injectors, but there is evidence that MA injectors prefer to take, but avoid engagement with service providers resulting in less opportunity for patient education. Establishment of harm reduction facilities that are accepting, non-stigmatizing and provide food, and support services could be useful for engaging MA users into a safe environment. Furthermore, there is some evidence that the availability of smoking equipment such as pipes may provide some benefit in reducing injection use.

MA use increases sexual risk behaviors61 Condom promotion programs as well as safer sex education and safer sex negotiation for both male and female MA users can be part of harm reduction activities for MA users. In countries such as Iran that already have established harm reduction strategies for IDUs, MA harm reduction activities should be integrated with current activities to expand the impact of the programs. Consideration should be given to employing communication tools including mobile phones, virtual social networks, and text messaging to expand outreach activities.

Conclusion

MA, a drug that is widely used in many parts of the world, produces significant acute and chronic medical and psychiatric conditions. Currently, there are no medications that have shown evidence of efficacy in the treatment of MA dependence. Several behavioral treatments have been shown to reduce MA use, but additional treatments are needed to provide a sufficient set of clinical tools to adequately treat the majority of MA-dependent individuals. The development of effective treatments that can reduce the use of MA as well as its consequent medical and psychiatric comorbidities is an important priority for future research. Integration of MA harm reduction strategies in current harm reduction programs as well as tailoring new innovative methods for better access to harm reduction assistance for both injecting and non-injecting MA users should be considered as a priority. Iran and many other developing countries in the region are newly facing problems with MA, rapidly and widely, it is highly recommended that responsible authorities and scientific communities try to establish appropriate and effective response for prevention, treatment and harm reduction services, which specially should be tailored considering local resources and characteristics.

Acknowledgments

Dr. Radfar was supported by the IAS-NIDA fellowship grant in 2012. Dr. Rawson was supported by the NIH Fogarty Grant D43-TW009102. The authors would like to thank Kris Langabeer for her editorial assistance with the manuscript.

Footnotes

Conflicts of Interest

The Authors have no conflict of interest.

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Bupropion for the Treatment of Methamphetamine
Dependence

Bupropion_for_the_Treatment_of_Methamphe

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This
was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse
treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV
diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and
79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments,
urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a
methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant (p ¼ 0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline (po0.0001). Comorbid depression and attention-deficit/ hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition.
Neuropsychopharmacology (2008) 33, 1162–1170; doi:10.1038/

_________________________________________________________________________

Chronic Methamphetamine Effects on Brain Structure and Function in Rats

Methamphetamine (MA) is a widely abused drug with devastating health effects [1]. MA increases extracellular concentrations of dopamine (DA), norepinephrine (NE) and serotonin (5HT) by acting on the transporter of each neurotransmitter [24] and by reversing neurotransmitter transport direction [5]. Chronic abuse of MA has been associated with damage to DA and 5HT terminals [57].

Additionally MA is rapidly taken by various organs in the body, including the lungs, brain, liver, pancreas, stomach, and kidneys, where it clears slowly [8], which could explain the association between MA and pulmonary hypertension [9] and kidney damage [10] among others. However, most MA studies have focused on the central nervous system. Studies in humans and non-human primates using magnetic resonance imaging (MRI) have shown structural abnormalities in the brain of MA users, including lower gray matter volumes [11], increased white matter volumes [11], enlarged striatal volumes [1217] and larger volumes of the parietal cortex [14]. This increased brain volume in MA users has been hypothesized to reflect inflammatory changes in these brain regions, including microglial activation, and has been positively correlated with deterioration of performance in reversal learning [17]. Still, volumetric increases in the striatum of MA users have also been positively correlated with novelty seeking [15] and with improved cognitive performance [1316], which suggests that increased striatal volume after MA use may also reflect compensatory changes in response to MA-induced neurotoxicity.

Using positron emission tomography (PET) and the glucose analog fluorodeoxyglucose (FDG), regional brain glucose metabolism (BGluM) has been assessed in MA users. In detoxified MA users, metabolic activity was increased in the parietal cortex and decreased in the thalamus and striatum [1819], although some recovery of function was seen in the thalamus after protracted abstinence [19]. Other studies have reported increased metabolism in the parietal cortex [20], increased metabolism in the cingulate, amygdala, ventral striatum, and cerebellum, but decreased metabolism in the insular and orbitofrontal area in abstinent MA users [21]. In addition PET studies have reported a downregulation of DA transporters (DAT) [22] and of DA D2 receptors in the striatum of MA abusers [23] with evidence of some recovery in DAT levels after protracted detoxification [2425]. Finally PET studies using [11C]PK 11195, which serves as a marker of microglia activation have also provided evidence of neuroinflammatory changes in the brain of MA users [26].

Together, these studies show that chronic MA use can lead to structural and functional brain deficits, although the possibility of pre-existing vulnerabilities in the brain of human MA users cannot be excluded. To further characterize the effects of long term MA use, the present study examined in rodents, the structural changes using magnetic resonance imaging (MRI), functional changes using PET to measure regional BGluM, and microglial activation with in vitro [3H]PK 11195 autoradiography. We hypothesized that chronic MA treatment would result in structural and functional deficits throughout the brain and that these effects would be potentiated in regions linked to the dopaminergic system, including the striatum and the nucleus accumbens. Furthermore, [3H]PK 11195 autoradiography would allow us to assess if MA-induced structural and functional changes in the brain were associated with neuroinflammation.

_______________________________________________________________________________________

Pharmacological treatments for methamphetamine addiction current status and future directions

ABSTRACT
Introduction: Methamphetamine (MA) abuse remains a global health challenge despite intense research interest in the development of pharmacological treatments. This review provides a summary of clinical trials and human studies on the pharmacotherapy of methamphetamine use disorder (MUD).

Areas covered: We summarize published clinical trials that tested candidate medications for MUD and
also conducted PubMed and Google Scholar searches to identify recently completed clinical trials using the keywords ‘methamphetamine’ ‘addiction’ ‘pharmacotherapy’ and ‘clinical trial.’ To determine the status of ongoing clinical trials targeting MUD, we also searched the ClinicalTrials.gov online database.
We conclude this review with a discussion of current research gaps and future directions.

Expert commentary: Clinical trials examining the potential for pharmacotherapies of MUD have largely
been negative. Future studies need to address several limitations to reduce the possibility of Type II errors: small sample sizes, high dropout rates or multiple comorbidities. Additionally, new treatment targets, such as MA-induced disruptions in cognition and in the neuroimmune system, merit trials with agents that selectively modulate these processes.

Pharmacotherapeutic agents in the treatment of methamphetamine dependence

Pharmacotherapeutic agents in the treatment of methamphetamine dependence

 

5.1. Dopamine agonist treatment

The primary therapeutic premise of agonist treatment for drug abuse is to replace a more addictive, unsafe drug with a less addictive and safer medication. Examples of established agonist treatment approaches include methadone and buprenorphine for opioid use disorder and nicotine replacement for tobacco use disorder (see [56Hutson PHPennick MSecker RPreclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: a novel d-amphetamine pro-drug. Neuropharmacology. 2014;87:4150.[Crossref][PubMed][Web of Science ®][Google Scholar]] for a critical review of the agonist treatment). Agonist treatment approaches have also been examined for the treatment of MUD. Because preclinical and clinical studies have shown that chronic exposure to MA leads to a hypo-dopaminergic state in the ventral striatum, characterized by decreases in D2 DA receptor density and hypo-responsiveness to dopamine receptor agonist challenges [57Barr AMMarkou APhillips AGA “crash” course on psychostimulant withdrawal as a model of depression. Trends Pharmacol Sci. 2002;23:475482.[Crossref][PubMed][Web of Science ®][Google Scholar]], treatment with a D2 agonist may counteract this hypo-dopaminergic state by increasing synaptic DA activity.

To date, the agonist medications dextroamphetamine and methylphenidate have been systematically examined in three studies (Table 1). In an 8-week, double blind, randomized, placebo controlled clinical trial of individuals with MUD (n = 60), sustained release dextroamphetamine (60 mg/day) was no more effective than placebo in reducing MA use, as assessed by urine toxicology. However, the dextroamphetamine group did display less craving and withdrawal symptoms than the placebo group [15Galloway GBuscemi RCoyle J, et al. A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction. Clin Pharmacol Ther. 2011;89:276282.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Similarly, in a placebo-controlled, double blind, randomized 10-week study of sustained release methylphenidate (54 mg) in 110 individuals with MUD, group differences were not observed for self-reported days of MA use during the last 30 days of the active phase. However, the active group, compared with the placebo group, did report fewer MA use days and lower cravings from baseline through the active phase [16Ling WChang LHillhouse M, et al. Sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder. Addiction. 2014;109:14891500.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Finally, in a recent placebo controlled, 10-week clinical trial, escalating doses of methylphenidate-SR produced less craving and MA positive urines in individuals with MUD than did placebo treatment [17Rezaei FEmami MZahed S, et al. Sustained-release methylphenidate in methamphetamine dependence treatment: a double-blind and placebo-controlled trial. DARU J Pharm Sci [Internet]. 2015 [cited 2016 Apr 3]:23. Available from:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298048/ [Google Scholar]].

An additional DA agonist medication currently under study is lisdexamphetamine, a prodrug that consists of dextroamphetamine chemically linked to the amino acid l-lysine. Once ingested, lisdexamphetamine is cleaved by enzymes within red blood cells resulting in the release of the active dextroamphetamine. A theoretical safety advantage of lisdexamphetamine is its long duration of effect and reduced abuse potential [58Newton TFKalechstein ADDuran S, et al. Methamphetamine abstinence syndrome: preliminary findings. Am J Addict. 2004;13:248255.[Taylor & Francis Online][Web of Science ®][Google Scholar]]. Lisdexamphetamine is currently the focus of an ongoing clinical trial for MUD (NCT02034201) (Table 2).

5.2. Antipsychotics

Antipsychotics may attenuate the reinforcing effects of MA by blocking D2-type DA receptors. An added partial agonist activity at D2 receptors in the ventral striatum and other brain regions could theoretically alleviate the hypo-dopaminergic state that is associated with long-term MA use. In a randomized, 12-week, placebo controlled study in 90 individuals with MUD, the group treated with aripiprazole, an antipsychotic with D2 partial agonist activity, did not differ from the placebo group in the number of confirmed MA positive urine samples [21Coffin POSantos G-MDas M, et al. Aripiprazole for the treatment of methamphetamine dependence: a randomized, double-blind, placebo-controlled trial. Addiction. 2013;108:751761.[Crossref][PubMed][Web of Science ®][Google Scholar]] (Table 1).

5.3. Antidepressants

The similarity of MA withdrawal symptoms and depression [59Baker DAMcFarland KLake RW, et al. N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci. 2003;1003:349351.[Crossref][PubMed][Web of Science ®][Google Scholar]], as well as the high comorbidity between major depressive disorder and MUD, has led researchers to hypothesize that antidepressants may be an effective treatment for MUD (Table 1). However, clinical trials with imipramine [13Galloway GPNewmeyer JKnapp T, et al. A controlled trial of imipramine for the treatment of methamphetamine dependence. J Subst Abuse Treat. 1996;13:493497.[Crossref][PubMed][Web of Science ®][Google Scholar]] and sertraline [14Shoptaw SHuber APeck J, et al. Randomized, placebo-controlled trial of sertraline and contingency management for the treatment of methamphetamine dependence. Drug Alcohol Depend. 2006;85:1218.[Crossref][PubMed][Web of Science ®][Google Scholar]] have been negative and a recent 12 week randomized, double blind, placebo controlled study comparing 300 mg/day of bupropion (n = 100), an inhibitor of NE and DA reuptake, to placebo (n = 104) did not find group differences in abstinence from MA (defined as at least two negative urine samples on weeks 11 and 12) [11Anderson ALLi S-HMarkova D, et al. Bupropion for the treatment of methamphetamine dependence in non-daily users: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2015;150:170174.[Crossref][PubMed][Web of Science ®][Google Scholar], p.201]. More recently, mirtazapine, an antidepressant that enhances NE and serotonergic transmission by blocking both alpha2-adrenergic receptors and 5-HT2 and 5-HT3 receptors, was examined in a 12-week, double blind, randomized clinical trial in gay men with MUD. Treatment with 30 mg mirtazapine (n = 30) as compared to placebo (n = 30), reduced MA use measured as the proportion of positive urine test (RR of 0.57; CI 0.35–0.93; p = .02), and also reduced sexual risk behaviors [12Colfax GNSantos GDas M, et al. Mirtazapine to reduce methamphetamine use: a randomized controlled trial. Arch Gen Psychiatry. 2011;68:11681175.[Crossref][PubMed][Web of Science ®][Google Scholar]]. It is important to note that participants in these studies were excluded if they had a diagnosis of major depressive disorder, and, as compared to placebo, none of the antidepressants improved depressive symptoms as measured with established scales. This raises the possibility, as already stated by Newton [60Deepmala DSlattery JKumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 2015;55:294321.[Crossref][PubMed][Web of Science ®][Google Scholar]], that the depressive symptoms commonly reported in early MA withdrawal represent a distinct clinical syndrome.

5.4. GABA/glutamate modulators

Topiramate is an anticonvulsant with a complex mechanism of action that includes blockade of voltage-dependent sodium channels, increased GABA activity, antagonism of several glutamate receptors and inhibition of the enzyme carbonic anhydrase. Because topiramate has demonstrated promise for the treatment of alcohol and tobacco use disorders, it was examined in a recent 13-week multicenter, randomized, double blind, placebo controlled study in MUD comparing 200 mg/day (n = 69) and placebo (n = 71). Although there were no group differences in MA weekly abstinence during weeks 6–12, 30 subjects were identified as ‘responders’ by either having reduced MA use over time or by achieving abstinence. This demonstrates that topiramate may a favorable effect in a subset of individuals with MUD [19Ma JZJohnson BAYu E, et al. Fine-grain analysis of the treatment effect of topiramate on methamphetamine addiction with latent variable analysis. Drug Alcohol Depend. 2013;130:4551.[Crossref][PubMed][Web of Science ®][Google Scholar]].

The pro-glutamatergic compound N-acetylcysteine (NAC) is thought to normalize extracellular glutamate levels in the nucleus accumbens by stimulating the cystine–glutamate antiporter [61Weinshenker DSchroeder JPThere and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacol. 2007;32:14331451.[Crossref][PubMed][Web of Science ®][Google Scholar]] and is clinically used for the treatment of acetaminophen (Tylenol) overdose. NAC has been examined as a treatment for a wide range of psychiatric conditions, including addictions to nicotine, cocaine, cannabis and gambling [62Lingham TPerlanski EGrupp LAAngiotensin converting enzyme inhibitors reduce alcohol consumption: some possible mechanisms and important conditions for its therapeutic use. Alcohol Clin Exp Res. 1990;14:9299.[Crossref][PubMed][Web of Science ®][Google Scholar]]. NAC has also been examined in the treatment of MUD in a small randomized, placebo controlled, double blind trial of 14 subjects that used a combination of NAC and naltrexone (an opioid antagonist) with negative results [22Grant JEOdlaug BLKim SWA double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur Neuropsychopharmacol. 2010;20:823828.[Crossref][PubMed][Web of Science ®][Google Scholar]]. However, a recent study demonstrated that NAC can reduce craving in MA dependent subjects [23Mousavi SGSharbafchi MRSalehi M, et al. The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study. Arch Iran Med. 2015;18:2833.[PubMed][Web of Science ®][Google Scholar]] and NAC may therefore be useful as a pharmacological adjunct to behavioral interventions in patients with MUD.

The GABA-B receptor agonist baclofen and the anticonvulsant gabapentin, a drug with a complex mechanism of action including activity at a subunit of the voltage-gated calcium channel, have been examined in a 16-week randomized, placebo controlled study of baclofen (n = 25), gabapentin (n = 26) and placebo (n = 37). Although no group differences in primary or secondary outcomes were found, a post hoc analysis revealed a significant effect of increased medication compliance and reduction in MA use, especially in the baclofen group [20Heinzerling KGShoptaw SPeck JA, et al. Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence. Drug Alcohol Depend. 2006;85:177184.[Crossref][PubMed][Web of Science ®][Google Scholar]].

Finally, vigabatrin (gamma-vinyl-GABA), an antiepileptic medication with potent GABA-enhancing properties through its inhibition of GABA transaminase, is being studied in a randomized, double blind, placebo controlled clinical trial of 180 individuals with MUD. The results are currently pending (NCT00730522; www.clinicaltrials.govTable 2).

5.5. Medications targeting NE and DA

In many brain regions, NE and DA transmission are closely linked. There are neuroanatomical connections between the neurons projecting from the locus coeruleus (principal center of NE projections in the brainstem) and DA neurons of the ventral tegmental area. In addition, stimulation of NE neurons activates the dopaminergic system through the alpha-1 adrenergic receptors [63Noble FLenoir MMarie NThe opioid receptors as targets for drug abuse medication. Br J Pharmacol. 2015;172:39643979.[Crossref][PubMed][Web of Science ®][Google Scholar]]. These preclinical data suggest that the modulation of NE systems is a viable therapeutic target with the alpha-1 adrenergic receptor antagonists prazosin and doxazosin currently being evaluated in clinical trials for MUD (NCT01371851 and NCT01178138; www.clinicaltrials.govTable 2).

Other pharmacological candidates that target NE systems include perindopril, an angiotensin-converting enzyme (ACE) inhibitor and candosartan, an angiotensin receptor blocker. Preclinical studies have shown an inhibitory effect of these medications on brain NE and DA neurotransmission although the exact effects have not been fully elucidated [64Pal RMendelson JEFlower K, et al. Impact of prospectively determined A118G polymorphism on treatment response to injectable naltrexone among methamphetamine-dependent patients: an open-label, pilot study. J Addict Med. 2015;9:130135.[Crossref][PubMed][Web of Science ®][Google Scholar]]. If effective, these medications could additionally reduce the elevated cardiovascular morbidity/mortality associated with MA use (NCT01062451; www.clinicaltrials.govTable 2).

Finally, entacapone, a drug that increases synaptic levels of DA and NE by inhibiting catechol-O-methyltransferase (COMT), an enzyme that degrades DA, NE and other catecholamines, is currently the focus of a Phase I study of MUD (Table 2).

5.6. Medications targeting the opioid system

The opioid system is thought to mediate the euphoric and rewarding effects of different substances of abuse [65Ray LABujarski SCourtney KE, et al. The effects of naltrexone on subjective response to methamphetamine in a clinical sample: a double-blind, placebo-controlled laboratory study. Neuropsychopharmacology. 2015;40:23472356.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In fact, naltrexone, a mu opioid antagonist, is an FDA approved treatment for alcohol use disorder. However, several different clinical trials on MUD have not shown a clear benefit of naltrexone, including the already referenced study using a combination of NAC and naltrexone [21Coffin POSantos G-MDas M, et al. Aripiprazole for the treatment of methamphetamine dependence: a randomized, double-blind, placebo-controlled trial. Addiction. 2013;108:751761.[Crossref][PubMed][Web of Science ®][Google Scholar]], and a pilot study examining sustained release intramuscular naltrexone in MA dependent subjects carrying the A118G polymorphism of the mu receptor [66Salehi MEmadossadat AKheirabadi GR, et al. The effect of buprenorphine on methamphetamine cravings. J Clin Psychopharmacol. 2015;35:724727.[Crossref][PubMed][Web of Science ®][Google Scholar]]. However, in a recent laboratory study, cue-induced and subjective responses to MA were reduced in those subjects who received naltrexone over placebo [67Lacagnina MJRivera PDBilbo SDGlial and neuroimmune mechanisms as critical modulators of drug use and abuse. Neuropsychopharmacology. 2017Jan;42(1):156177. doi:10.1038/npp.2016.121.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In addition, there are ongoing clinical trials studying the effects of a combination of bupropion or oxazepam and naltrexone (Table 2).

An additional opioid drug with potential utility is buprenorphine, a partial mu opioid agonist and a kappa receptor antagonist that is primarily used for maintenance therapy in individuals with opioid use disorder. In a recent placebo controlled human study of 40 participants with MUD, buprenorphine reduced cravings for MA as compared to the placebo group [68Thomas DMWalker PDBenjamins JA, et al. Methamphetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharmacol Exp Ther. 2004;311:17.[Crossref][PubMed][Web of Science ®][Google Scholar]]. However, a significant limitation of using opioids in the treatment of MUD is the unknown risks associated with exposing patients who do not have a history of abusing opiates to a class of drugs with clear abuse liability.

6. Novel treatment approaches

6.1. Neuroimmune modulators

Cumulating evidence suggests that the pharmacological reduction of neuroinflammation is a potential treatment for MUD [69Sofuoglu MMooney MKosten T, et al. Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans. Psychopharmacol (Berl). 2011;213:6168.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In preclinical studies, amphetamine-type stimulants activate microglia, an important mediator of inflammation in the CNS, and the blockage of microglia activation prevents the reinforcing effects of MA and MA-induced neurotoxicity [70Worley MJHeinzerling KGRoche DJO, et al. Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study. Drug Alcohol Depend. 2016;162:245250.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Although limited, human studies indicate that chronic MA use is associated with microglia activation and increased biomarkers of neuroinflammation suggesting that medications which modulate neuroimmune signaling, such as minocycline and ibudilast, may have potential utility in the treatment of MUD.

Minocycline, an antibiotic commonly used to treat acne, has anti-inflammatory and neuroprotective effects in the CNS that are thought to be mediated by the inhibition of microglia activation. Consequently, minocycline is under investigation for the treatment of a variety of neurodegenerative and neuropsychiatric disorders. In a clinical study of healthy controls, 5 days of minocycline (200 mg/day), compared to placebo, attenuated the subjective rewarding effects of oral dextroamphetamine (20 mg/70 kg) and improved response inhibition function as measured by the Go/No-Go task [71Sofuoglu MDeVito EEWaters AJ, et al. Cognitive enhancement as a treatment for drug addictions. Neuropharmacology. 2013;64:452463.[Crossref][PubMed][Web of Science ®][Google Scholar]]. The effects of minocycline in individuals with MUD remain to be determined.

An additional candidate neuroimmune modulator is ibudilast, a phosphodiesterase-4 inhibitor that increases brain levels of glial derived neurotrophic factor and reduces microglial activation and pro-inflammatory cytokine production. In a clinical study of 7 days of 100 mg/day, ibudilast reduced the acute subjective effects of 30 mg of MA administered intravenously [72Bates MEPawlak APTonigan JS, et al. Cognitive impairment influences drinking outcome by altering therapeutic mechanisms of change. Psychol Addict Behav J Soc Psychol Addict Behav. 2006;20:241253.[Crossref][PubMed][Web of Science ®][Google Scholar]].

An additional feature of targeting activated glial cells is the reduction of secreted pro-inflammatory mediators that exacerbate the neurological dysfunction caused by MA. Consequently, the pharmacological targeting of activated microglia may also improve HIV-associated cognitive dysfunction that is often comorbid with MUD (NCT01860807; www.clinicaltrials.gov).

6.2. Cognitive enhancement

As stated above, the chronic use of stimulants, especially cocaine and MA, is associated with deficits in cognitive functioning, most notably decision-making, response inhibition, planning, working memory, and attention [73Sofuoglu MCognitive enhancement as a pharmacotherapy target for stimulant addiction. Addict Abingdon Engl. 2010;105:3848.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In clinical studies of individuals undergoing treatment, these cognitive deficits are associated with higher rates of attrition and poor treatment outcomes, possibly because these deficits interfere with the ability to engage in the treatment activities [74Verrico CDMahoney JJThompson-Lake DGY, et al. Safety and efficacy of varenicline to reduce positive subjective effects produced by methamphetamine in methamphetamine-dependent volunteers. Int J Neuropsychopharmacol. 2014;17:223233.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In addition, given that cognitive deficits may negatively affect treatment outcomes and general functioning, regardless of their cause, cognitive enhancement may serve as an important treatment target. Consequently, pharmacotherapies that ameliorate cognitive deficits represent a novel treatment strategy for MUD [75Kim C-HHahn MKJoung Y, et al. A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder. Proc Natl Acad Sci U S A. 2006;103:1916419169.[Crossref][PubMed][Web of Science ®][Google Scholar]] and include the use of cholinesterase inhibitors (e.g. rivastigmine or galantamine), partial nicotinic acetylcholine receptor (nAChR) agonists (e.g. varenicline), norepinephrine transporter (NET) inhibitors (atomoxetine), DA and NE transporter inhibitors (modafinil) and a prodrug for choline (citicoline) [73Sofuoglu MCognitive enhancement as a pharmacotherapy target for stimulant addiction. Addict Abingdon Engl. 2010;105:3848.[Crossref][PubMed][Web of Science ®][Google Scholar]].

Cholinesterase inhibitors have been used for the treatment of dementia and other disorders characterized by cognitive impairment [38Sofuoglu MMooney MCholinergic functioning in stimulant addiction: implications for medications development. CNS Drugs. 2009;23:939952.[Crossref][PubMed][Web of Science ®][Google Scholar]]. Rivastigmine is an inhibitor of the enzyme acetylcholinesterase that degrades acetylcholine and has been used in a completed clinical trial that has not yet been published (NCT01073319; www.clinicaltrials.gov). Varenicline is a partial nicotinic agonist that acts on neuronal α4β2 receptors and in a human laboratory study of 22 volunteers with MUD, pretreatment with varenicline at 2 mg was associated with a reduction in the positive subjective effects of 30 mg of smoked MA [76Bymaster FPKatner JSNelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002;27:699711.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In addition, a clinical trial has examined the efficacy of varenicline for MUD but the results have not yet been published (NCT01365819; www.clinicaltrials.gov).

Atomoxetine, a selective NET inhibitor used for the treatment of attention deficit hyperactivity disorder (ADHD), is another promising medication targeting cognitive enhancement. In the prefrontal cortex, the NET is responsible for the reuptake of NE, as well as DA, into presynaptic nerve terminals [77Swanson CJPerry KWKoch-Krueger S, et al. Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat. Neuropharmacology. 2006;50:755760.[Crossref][PubMed][Web of Science ®][Google Scholar]] and the blockage of both of these actions may contribute to the cognitive-enhancing effects of atomoxetine [78Mereu MBonci ANewman AH, et al. The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders. Psychopharmacol (Berl). 2013;229:415434.[Crossref][PubMed][Web of Science ®][Google Scholar],79Wignall NDBrown ESCiticoline in addictive disorders: a review of the literature. Am J Drug Alcohol Abuse. 2014;40:262268.[Taylor & Francis Online][Web of Science ®][Google Scholar]]. A recently completed clinical trial that examined the efficacy of atomoxetine in individuals with MUD awaits publication (NCT01557569; www.clinicaltrials.gov).

Modafinil is a cognitive enhancer with weak stimulant-like properties (and hence less potential for abuse and diversion) and is approved by the FDA for the treatment of sleep apnea, narcolepsy and shift work-induced sleep disorder. It is a weak inhibitor of DA and NE transporters and has additional actions on brain GABA, glutamate and orexin [80Ohia-Nwoko OKosten TAHaile CNAnimal models and the development of vaccines to treat substance use disorders. Int Rev Neurobiol. 2016;126:263291.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In a 12-week multicenter, randomized, double blind study comparing 200 mg of modafinil (n = 72), 400 mg of modafinil (n = 70) and placebo (n = 68) no group differences were found in the primary outcome of 1 week of MA negative urine. However, the study was confounded by a medication adherence rate of only 50% as determined by urine modafinil concentrations [18Anderson ALLi S-HBiswas K, et al. Modafinil for the treatment of methamphetamine dependence. Drug Alcohol Depend. 2012;120:135141.[Crossref][PubMed][Web of Science ®][Google Scholar]]. In addition, the study did not assess cognitive performance of the study participants and it remains to be examined if modafinil would be more effective in MA users with cognitive deficits, but as noted above, the interpretation of neurocognitive performance in the context of MA use is a complex issue requiring further study.

Finally, citicoline an intermediate in the generation of phophatidylcholine, a major phospholipid in biological membranes, also facilitates synthesis of DA and acetylcholine. In preclinical and clinical studies, citicoline has cognitive enhancing and neuroprotective properties [81Sarnyai ZKovács GLOxytocin in learning and addiction: From early discoveries to the present. Pharmacol Biochem Behav. 2014;119:39.[Crossref][PubMed][Web of Science ®][Google Scholar]] and a recently completed, but yet unpublished, clinical trial has tested the efficacy of citicoline for MUD (NCT00950352).

6.3. Vaccine immunotherapies

Despite previous inconsistent results, there is a renewed interest in the use of immunotherapies, especially vaccines, for the treatment of different drugs of abuse including nicotine, cocaine and MA [82Baracz SJCornish JLThe neurocircuitry involved in oxytocin modulation of methamphetamine addiction. Front Neuroendocrinol [Internet]. [cited 2016 Oct 1]. Available from:http://www.sciencedirect.com/science/article/pii/S0091302216300346[Web of Science ®][Google Scholar]]. Immunotherapies reduce the amount of drug that reaches the brain by stimulating the production of antibodies that bind to the drug molecule after it has been systemically absorbed during drug use. The limitations of a vaccine include the prolonged time it takes to develop sufficient circulating antibodies, the large variation in the antibody titer and incomplete blockage of drug effects. Furthermore, the antibodies developed are specific for a given drug molecule and this limits effectiveness in individuals using multiple drugs [82Baracz SJCornish JLThe neurocircuitry involved in oxytocin modulation of methamphetamine addiction. Front Neuroendocrinol [Internet]. [cited 2016 Oct 1]. Available from:http://www.sciencedirect.com/science/article/pii/S0091302216300346[Web of Science ®][Google Scholar]]. For MUD, vaccines could be most effective in preventing relapse in individuals who use MA sporadically. While there are several ongoing MA vaccine studies, there is also a completed clinical trial using Ch-mAb7F9, a human–mouse monoclonal antibody that binds to methylphenidate (NCT01603147; www.clinicaltrials.gov).

6.4. Oxytocin

There is cumulating evidence of a potential benefit in the use of the ‘pro-social’ hormone oxytocin for treating substance use disorders [83Scott JCWoods SPMatt GE, et al. Neurocognitive effects of methamphetamine: a critical review and meta-analysis. Neuropsychol Rev. 2007;17:275297.[Crossref][PubMed][Web of Science ®][Google Scholar]]. So far, results are inconclusive with both positive and negative effects in humans that may depend on the type of substance used. Although the exact mechanisms remain elusive, some authors have proposed an inhibitory effect of oxytocin in the reward circuit, particularly in the nucleus accumbens and subthalamic nucleus projections [84Simon SLDean ACCordova X, et al. Methamphetamine dependence and neuropsychological functioning: evaluating change during early abstinence. J Stud Alcohol Drugs. 2010;71:335344.[Crossref][PubMed][Web of Science ®][Google Scholar]]. A recent clinical trial will examine the potential utility of oxytocin combined with motivational enhancement group therapy in HIV positive gay men with MUD (NCT02881177; www.clinicaltrials.gov).

7. Conclusions

Despite the significant advances made over the past several decades in the understanding of the basic neurobiology of stimulant addiction, these advances have not been translated into effective pharmacological treatments for MUD. Clinical trials testing potential medications for MUD have largely been negative, and currently there are no consistently effective pharmacological treatments for MUD. Novel treatment targets include cognitive-enhancement strategies, the modulation of the neuroimmune system and immunotherapy through vaccine development. These and other promising treatment approaches need to be tested in well designed and adequately powered clinical trials while the results of recent studies with novel therapeutic targets await publication.

8. Expert commentary

Similar to MUD, there are no effective pharmacological treatments for addiction to cocaine, a similarly acting stimulant for which a much larger number of clinical trials using various medications has been conducted. This failure in progress for development of pharmacological treatment for MUD could be influenced by multiple factors including small sample sizes in the majority of studies compounded by high dropout rates, in the range of 40–50 %. Therefore, the majority of clinical pharmacological trials for MUD are simply underpowered. In addition, there is also an ongoing debate about which clinically significant outcome measures should be used in clinical trials of stimulant use disorders. Future work should address these methodological limitations.

As noted earlier, individuals with addiction, including those with MUD, have many comorbid disorders including other addictions, anxiety, psychosis and mood disorders. These disorders have overlapping symptom clusters across different diagnostic categories and therefore, new treatment approaches that use trans-diagnostic treatment targets, rather than trying to develop specific treatments for individual addictions and other psychiatric disorders, may be constructive. Consistent with the Research Domain Criteria (RDoC) initiative of the National Institute of Mental Health (NIMH), using such an approach is responsive to what some have called a ‘therapeutic stagnation’ for mental health disorders. The proposed RDoC approach, by identifying trans-diagnostic treatment targets, may be especially fruitful in developing pharmacotherapies for highly comorbid conditions like stimulant addiction where neuroimmune mechanisms, especially microglia activation and cognitive deficits, are relevant targets across a range of psychiatric disorders. Although not novel for other addictions, immunotherapies for MUD have already demonstrated some promising findings.

Finally, pharmacogenetics is another area of research that may enhance the benefits from pharmacotherapies for SUDs. The ability to predict treatment response and adverse effects based upon genetic markers can lead to an optimal treatment matching. While promising, the effect of pharmacogenetic testing on treatment outcomes in clinical settings requires further study.

9. Five-year view

An important issue that has not yet been addressed is the development of a consensus on the main outcome measures to be used across clinical trials for MUD. Currently, clinical trials use a wide range of outcome measures focusing on MA use during the clinical trial. However, the clinical significance of these measurements is not always clear. The standard outcomes that are widely used for clinical trials in tobacco and alcohol use disorder are noteworthy predicates to consider in this regard. In addition, given the historically low retention rates in MA studies, sample sizes need to be increased to ensure that future clinical trials have adequate power to test the efficacy of promising treatments. Conducting multisite studies can help with addressing this sample size issue, while interventions like contingency management are effective in improving retention. With the implementation of improved clinical trial methodology, the field will be better positioned to effectively test the potential for novel treatments of MUD.

Key issues

  • On a global basis, methamphetamine (MA) and related stimulants continue to be the second most widely abused drug class after cannabis. Currently available treatments for methamphetamine use disorder (MUD) are primarily behavioral and have limited efficacy.

  • Despite considerable effort, no medications have been approved for the treatment of MUD. Numerous clinical trials have been conducted utilizing medications that act on a variety of different targets including DA agonist treatments (dextroamphetamine, methylphenidate), antipsychotics (aripiprazole), antidepressants (imipramine, sertraline, mirtazapine, bupropion), GABA/glutamate modulators (topiramate, N-acetylcysteine, baclofen and gabapentin). Other pharmacological systems are currently under study and include medications targeting NE and DA (prazosin, doxazosin, candosartan, entacapone), and the opioid system (naltrexone, buprenorphine).

  • Novel and exciting approaches for the treatment of MUD include neuroimmune modulators (minocycline, ibudilast), cognitive enhancers (rivastigmine, galantamine, varenicline, atomoxetine, modafinil, citicoline), vaccines, and oxytocin.

  • The future of the field will likely depend on overcoming methodological limitations (high drop-out rates, small samples, agreement on outcome measures), and might benefit from the development of trans-diagnostic criteria.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

References

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