Professional Addiction

Neural Basis for Methamphetamine Addiction – Rethinking the Definition of Dependence

Mary F Holley MD

1. Background
Addiction to methamphetamine is a serious disabling condition that affects individuals, families, and communities as end stage addicts destroy their lives, abuse their children, and lose their jobs. The availability of effective treatment is limited by the economic resources available to treat what many consider an incurable moral failure. Taxpayers and donors are often unwilling to devote large amounts of money to rehabilitate people who voluntarily ingest drugs of abuse. The need for prolonged periods of rehabilitation and extended supervision is even greater for methamphetamine addiction than for other drugs of abuse. A better understanding of addiction is needed on all fronts, by addicts, their families, health care policy makers and payers, the legal and judicial fields, and the community at large.

Because of the shortage of available treatment, an overwhelming burden is being placed on our corrections system by the sheer volume of inmates sentenced primarily for drug offences. Corrections facilities are designed to punish and deter antisocial behavior in rational persons. They are now being asked to intervene in the disease of addiction although they are neither funded nor staffed to treat addiction. Addicts do not usually make rational choices but rather are driven by a brain disease that must be treated in order to prevent the recidivism that plagues our current system.

Even in the field of psychiatry there is tremendous reluctance to admit that methamphetamine is a neurotoxin. This in spite of the persuasive animal and human data confirming the serious neurotoxicity, particularly to the frontal lobes, related to methamphetamine use. And this reluctance is seen in card carrying Darwinists. Can methamphetamine be a neurotoxin in all known animal models and yet fall harmless to the ground when confronted with the mystical, magical human brain? There is nothing special about human neurons that renders them impervious to the oxygen free radicals compounds released by methamphetamine.

If we wish to convince the general public and health care policy makers that addiction a brain disease and not merely a moral failure, we must define it in objective terms, not just in behavioral terms. Our current definition of dependence has as much to do with the tolerance of the patient’s employer for poor performance as it does with the patient’s neurochemistry. We should instead define addiction in terms of neurochemical, behavioral, and personality changes, which appear early in the clinical course, long before ‘dependence’ is diagnosed under the current paradigm.

2. Neurotransmission
Changes in the neurotransmitter levels of the brain underlie many of the personality changes and mental illnesses associated with methamphetamine. The principle chemicals affected by the use of meth are the monoamines dopamine, serotonin, nor-epinephrine, and cortisol a stress hormone.

Methamphetamine stimulates a massive release of mono-amines, especially nor-epinephrine -2000% increase, ( Rothman 2001), dopamine -500-1000% increase (Izawa 2006, Gough 2002), and serotonin -300- 500% increase (Ago 2008) by both presynaptic and post-synaptic mechanisms. Meth causes the accelerated release of vesicles containing these neurotransmitters, and reverses the presynaptic transporter molecule that normally reabsorbs neurotransmitter once released (Zaczek 1991). Methamphetamine changes the conformation of the transporter molecule causing the ‘vacuum cleaner’ to go into reverse and spew neurotransmitter out instead of reabsorbing it (Yudko 2003). This is in contrast to cocaine, which only blocks the reabsorption of neurotransmitter.

Post-synaptically, meth inhibits the enzyme mono-amine oxidase (MAO), which is responsible for metabolizing these neurotransmitters once they are released. This increases the length of time the transmitter is active at the receptor site and thus its effects in the brain (Ramsay 2003). When MAO is inhibited, alternate routes of metabolism are used resulting in hydroxy free radical formation. Methamphetamine stimulation also triggers an increase in gluatamine receptor density in nucleus accumbens, acutely increasing its responsiveness to repetitive stimulation (Chao 2002).

Methamphetamine also disrupts the hypothalamic pituitary axis, causing a release of cortisol, a stress hormone. Higher cortisol levels are associated with greater dopamine release in the striatum and more positive subjective drug effects (Oswald 2005). Glucocorticoid receptors in the midbrain are affected in the striatum and hippocampus, which is thought to underlie stress related relapse (Wang 2005).

3. Sensitization stage of addiction
Methamphetamine addiction progresses through two distinct biochemical stages. Only the later stage is characteristically recognized as ‘addiction’ or ‘dependence’ in the terminology of DSM IV. Those patients still in the initial sensitization stage are considered users, but have not yet had negative sequellae from their drug use and so have not tried to quit or cut down. In sensitization, each dose feels even better than before, lasts longer, and more intense. Having heard about tolerance, the addict understands that only when his drug use accelerates would he be considered an addict, so during this early stage, he assures himself he must be okay. He does not believe his methamphetamine use is having any effect on his brain.

During the sensitization period, neural tracts that are hyper stimulated on an occasional basis by low intensity use become more responsive to methamphetamine. These neural tracts have been shown to increase their sensitivity to repeated doses of methamphetamine, both by increasing numbers of receptors for monoamine neurotransmitters, and also by increasing numbers of glutamate receptors in the brain (Xui – Ti Hu 2002).. We add more lanes to accommodate increased traffic.

And in the sensitization period, the neurons still have a reserve of intracellular neurotransmitter that can be mobilized by axonal transport, to replenish the terminals with fresh supplies of neurotransmitter, thus enabling the cells to function in the face of massive losses in their neurotransmitter supplies (Yudko 2003). This is why, in the early stage of addiction, function is maintained between ‘highs’ and the ‘crash’ after using is just a mild depression, not even as bad as the hangover after an evening of heavy alcohol intake.

This phase may last for years in the case of oral use of small doses of methamphetamine, and there are medical uses for methamphetamine for treatment of ADHD, narcolepsy and weight loss in small closely monitored doses. The military has used methamphetamine in small closely regulated doses for many years with a long record of safety. Unmonitored use however readily lends itself to compulsive and repetitive use with resultant personality changes, what any unbiased observer would call ‘addiction.’

At this early stage the addict is almost never willing to admit he has a problem. He uses frequently, but perhaps not daily. He feels focused and energetic while on methamphetamine. His family members notice his personality changes, his short temper and impatience, but he thinks everything is fine. He cannot quit using for any prolonged length of time – what the average person would consider addiction – but he has never really tried to quit, nor does he consider himself impaired in any way, and so a psychiatrist would not diagnose him ‘dependent’. Psychiatry has rejected the word ‘addiction’ as a diagnostic term. It is used here purely as a functional term referring to the habitual and compulsive use of a substance.
Dependence is diagnosed only when strict criteria are met including three of the following conditions:

Withdrawal symptoms
Escalation of use
Effort to control use
Occupies time, effort
Replaces other activities
Use despite impairment

Only in the later stage of addiction, when drug use impairs functioning and replaces normal healthy activities, resulting in the loss of relationships or employment does a psychiatrist consider him an addict (dependent). This functional definition has more to do with the reaction of his wife and the demands of his employer than it does with the biochemical effects the drug is having in his brain. The addict won’t make an effort to control his use until threatened with an employee drug test. The level of denial in such a person guarantees that the subjective measures used here to define addiction will not apply to him until a set of handcuffs has been applied at least once. The changes in his brain are at an advanced stage by now. By the time dependence is diagnosed, serious mental health problems are often evident, and recovery of normal cognition and personality features will require months, if not years, of intense therapy.

Early diagnosis and intervention are impossible with the current definition of dependence (or addiction) used by psychiatrists. In fact people requesting treatment for their addiction are sometimes turned away by mental health providers because they are ‘not addicted enough,’ particularly in the public sector.

4. Late Stage Addiction
In later stage addiction, neurotransmitter reserves have been depleted as continued massive releases of mono-amines have exhausted the cell’s capacity to manufacture these complex chemicals de-novo (Vacca 2006). Presynaptic function is impaired by chronic methamphetamine exposure, with corresponding behavioral changes, an effect that persists at least four months into recovery in an animal model (Megala 2008). Striatal dopamine concentration (reserve) is reduced by 20% and presynaptic dopamine transporter density is reduced by 35%. Chronicpresynaptic depression of function is ‘re-normalized’ in cortico-striatal pathways by re-administration of methamphetamine, restoring the system to apparent normalcy (Bamford, 2008).

At the same time, the post synaptic side has responded to the massive hyper stimulation by phospohorylating, sequestering, and degrading its receptors (Volcow 2001). While D1 receptors in the striatum are preserved, they are delinked from the adenylyl cyclase that serves as its second messenger in the post synaptic cell (Tong 2003). The dopamine response is suppressed in response to both psycho stimulants and natural rewards in withdrawal from methamphetamine (Vacca 2006). More and more stimulation is required to trigger a post synaptic response. The crash becomes more symptomatic and longer lasting as neurotransmitters and receptors are depleted. The addict accelerates his drug dose and interval in an effort to reclaim the high and/or avoid the crash. As dopamine transmission is impaired in the reward circuit, higher doses of methamphetamine are required to maintain function. The recreational user can’t wait till Friday to use again, and the functional user needs higher doses to maintain his current level of productivity. As higher doses are used, side effects including jitteriness and disorganization are seen which impair his occupational adjustment. He is generally oblivious to this change and to the personality changes that are also occurring. His boss and his wife however usually are not oblivious to these changes.

His irritability has by now progressed to domestic violence – either verbal or physical. His children are afraid of him. His work performance has become erratic and customers and co-workers are complaining. Personality changes are the hallmark sign of the methamphetamine user. They are much more prominent than those seen in heroin or even cocaine users, and they affect every aspect of life. Some of these personality changes are quite reversible since they are mediated by biochemical changes in brain function, not by structural changes. But they improve very slowly, over the course of many months of abstinence as neurotransmission is reestablished (Wang 2004).

Other changes seen in later stage methamphetamine addiction are not as readily reversible. The loss of memory, cognitive ability, motivation, and reality testing are related to structural damage to brain tissue caused by cellular damage to the brain (Thompson 2004). These changes also result in the deepening of his addiction as key structures related to self control are compromised.

5. Cytotoxicity
The massive release of neurotransmitter caused by methamphetamine use results in high levels of nitrogen and oxygen free radical formation (Acikgov 2000). These free radicals are formed by the metabolism of methamphetamine, and also by the breakdown of the huge amounts of mono-amine neurotransmitters that have been released both intra and extra cellularly. These mono-amine neurotransmitters must also be broken down, and MAO, the usual enzyme to do that, is inhibited by methamphetamine. Alternative metabolic routes are used resulting in the generation of large amounts of hydroxyl free radicals nitric oxide and peroxynitrite, which are extremely toxic to brain cells (Jeng 2006).

Free radical compounds denature proteins, damage DNA and generally wreak havoc in the areas of the brain in which they are concentrated (Cubbels 1994). Because most of the neurotransmitters are released in the midbrain, nucleus accumbens, striatum, and in the prefrontal cortex, those areas are disproportionately affected by methamphetamine abuse with progressively worsening cognitive and executive function (Li 2008). The power of these chemicals to damage the human brain was demonstrated most vividly by Thompson in 2004 when he demonstrated up to 15% loss of brain tissue in large areas of the brain including both cortical and subcortical tissue. These findings were correlated with cognitive and memory deficits in the subjects studied. Thompson described it as a forest fire of brain damage with real world consequences in occupational failure, disintegration of relationships, and challenges in treatment.

Methamphetamine use causes persistent hypometabolism in the frontal white matter and impairment in frontal executive function on PET scanning (Kim 2005). Abstinent meth users showed impaired performance on the Wisconsin card sorting test associated with reduced metabolism in the right superior frontal lobe. Hypofrontality in methamphetamine addicts has been thought to contribute to the significant cognitive deficits, memory loss, and poor impulse control that cause significant social failure and complicate treatment participation and success (Homer 2008). A realistic assessment of the nature and extent of these deficits is essential to developing effective treatment programs.

6. The Pleasure Circuit
The pleasure circuit has been well described, and consists of the nucleus accumbens, anterior bed nuclei, anterior lateral hypothalamus, stria terminalis, lateral preoptic area, median forebrain bundle, ventral tegmental area, ventral pallidum, and prefrontal cortex. These areas are profoundly affected by methamphetamine administration, with altered sensitivity and receptor changes in animal models (Yong 2003, Broom 2005, Brady 2005). Direct stimulation of the nucleus accumbens by dopamine results in euphoria. The ventral tegmental area sends numerous dopamine neurons to the nucleus accumbens contributing to reward and motivation. Methamphetamine increases dopamine in the nucleus accumbens by up to 1000-1200% constituting a powerful pleasurable sensation and triggering a powerful motivator. As these dopamine receptors are damaged by over-stimulation, natural rewards are not appreciated, and motivation is impaired.

The prefrontal cortex is an integral part of the reward circuit. Pleasures are experienced in all their richness in the prefrontal cortex, and cravings originate in these areas as marked by intense neural activity on exposure to triggers (Klavinas 2005). Prefrontal cortex is hyper-responsive to drug cues driving the nucleus accumbens, while at the same time executive function is reduced diminishing cognitive control. Wilson’s analysis of these studies showed the orbitofrontal and dorsolateral orbitofrontal cortex were more active in addicts anticipating drug usage, while anterior cingulate cortex was more activated in those trying to resist the urge to drug usage – treatment seeking individuals (Wilson 2004).

Appeals to the pleasure circuit to explain all aspects of addictive behavior are found wanting in that as addiction proceeds, pleasurable sensations decline, and addicts are often motivated to use substances which no longer give them very much pleasure. Motivation shifts from obtaining pleasure and avoiding the pain and anxiety of withdrawal, to compulsive use in the face of serious adverse consequences. The ability of the conscious mind to control behavior is seriously compromised in addiction, particularly methamphetamine addiction, even when competent cognitive behavioral therapy is received and mastered. This suggests a parallel and separate anatomic basis for behavior control apart from hedonic perception.

7. The Control Circuit
The control circuit is less understood, and is not included in most text books on the neurophysiology of addiction. The original literature however supports the existence of a dedicated set of structures that serve to facilitate control of behavior in the face of desire or craving. This control circuit consists of the prefrontal cortex, anterior cingulate gyrus, the lateral habenula, and fasciculus retroflexus, which exerts inhibitory GABA-A control over the craving centers in the ventral tegmental area (Ji, 2007). There are also direct inhibitory connections between prefrontal cortex and VTA which are also GABA mediated (Carr 2000).

The influence of this circuit in the modulation of addiction has been delineated in several human studies. Volkow in 2001 demonstrated a loss of dopamine transporters in the entire orbitofrontal cortex in abstinent methamphetamine users. More specifically, methamphetamine users showed significantly reduced cerebral blood flow in the anterior cingulate gyrus, with a significant persistent reduction even after six months abstinence. This suggests a structural change, not just a functional neurotransmitter mediated effect, in the anterior cingulate gyrus, an important area for control of impulses and behavior (Huang 2006).

Multiple studies have demonstrated reduced task related activation of the anterior cingulate gyrus in methamphetamine users. Paulus in 2005 showed that those addicts who eventually relapsed had markedly reduced activation of the dorsolateral prefrontal cortex and anterior cingulate gyrus compared to addicts who did not subsequentlyrelapse. Subjects were followed for up to three years to observe for relapse, and the predictive power of this functional measure of brain activity in these areas was impressive.

The cingulum bundle conducts impulses from anterior cingulate gyrus and other prefrontal areas posteriorly, primarily to the hippocampus, but also to multiple other midbrain structures including the lateral habenula. The cells in this transmission line are exquisitely sensitive to methamphetamine, with destruction of over 90% of the cingulum bundle demonstrated after just a single intoxicating dose of methamphetamine in animal models (Zhou 1998). This is not just a change in the sensitivity of the neurons, but the destruction of a key pathway between the cingulate gyrus and midbrain structures including hippocampus and lateral habenula.

The lateral habenula itself is sensitive to the effects of methamphetamine with specific degeneration of large areas of lateral habenula with continuous exposure to meth as would be seen in a binge pattern of self administration (Ellison 1992). In 2000 Carlson reported that many drugs of abuse impair function in the habenula and fasciculus retroflexus, dubbing it ‘the weak link in addiction.’ This line of research was then almost completely neglected for many years until recent studies have further delineated the significance of Ellison’s and Carlson’s findings.

The lateral habenula is a significant processing center conveying information from cognitive cortical areas to subcortical areas. Habenular lesions result in learning deficits, and reductions in memory and attention consistent with its central role in cognition (Lecourtier 2007). In humans, the lateral habenula is especially responsive to feedback about errors, exerting inhibitory impulses when errors are detected and response patterns need to be changed (Ullsperger 2003).

Lateral habenula neurons in the primate are activated in a no-reward condition, exerting inhibitory control over dopamine release from the ventral tegmental area (Matsumoto 2007). In this study even weak stimulation of lateral habenula elicited strong inhibition of dopamine release. Dopamine levels are thus decreased when predicted rewards do not occur, a biological basis for disappointment (Pagnoni 2002).

Specifically, lateral habenula in turn exerts a powerful inhibitory effect on dopamine transmission by the ventral tegmental area via the fasciculus retroflexus, a GABAergic pathway. Ji 2007 did the definitive study of this tract demonstrating that single-pulse stimulation of the lateral habenula effectively shut down the activity of 97% of the dopaminergic neurons in the substantia nigra and ventral tegmental area. Stimulation of the lateral habenula resulted in a complete cessation of spontaneous firing in nearly all dopamine neurons in the substantia nigra and ventral tegmental areas. Lesions of the fasciculus retroflexus completely blocked this strongly inhibitory effect on dopamine neurons.

These ventral tegmental dopaminergic signals are responsible for recurrent drug taking behaviors even in the absence of an external trigger for the hedonic reward pathway (Nakijima 2004). Uncontrolled ventral tegmental stimulation of the nucleus accumbens produces dopamine signals that are experienced in the frontal cortex as cravingsand the desire to get high. If sufficient inhibitory control in the frontal cortex is not present to suppress these signals, behavior is likewise uncontrolled.

8. Proposed Treatments
Since a number of interrelated adaptations to drug use occur in multiple areas of the brain, it would be expected that intervention would also have to occur at multiple levels for successful rehabilitation. There are adaptations in the reward areas, motivation and drive, memory and conditioning, and inhibitory control areas that result in long lasting changes in a person’s responsiveness to natural rewards, cognitive ability and inhibitory control. While acute drug intake increases dopamine release, chronic use impairs it not only in the reward centers but also in the frontal lobes (cognitive ability) and cingulate gyrus (inhibitory control) (Volkow 2004). GABA mediated inhibitory control is a target for many of the newly proposed treatments for addiction, including baclofen, gabapentin, and vigabatrin. These drugs are GABA A agonists (baclofen), or GABA transaminase inhibitors (gabapentin and vigabatrin) essentially amplifying the inhibitory signals and thus improving impulse control and reducing craving. Animal studies were very promising (Di Ciano 2004, Barrett 2005, Filip 2007) as were open label studies using Baclofen and Gabapentin (Urschell 2007) and vigabatrin (Brodie 2005, Fetchner 2006) However double blind studies of Baclofen and Gabapentin showed no effect (Shoptaw 2003 Heinzerling and Shoptaw 2006). A randomized controlled trial of vigabatrin is needed. Though vigabatrin has been linked to visual field defects with long term use, its safety in short term use is suggested by the open label studies completed (Brodie 2005).

Reducing the reward value of methamphetamine is another biochemical target area that is open to intervention. As in the case of heroin addiction, there is a partial agonist for stimulants in the form of modafinil. In animal studies, modafinil substituted partially for both cocaine and amphetamine in rats trained to discriminate these stimulants from saline, but was much less potent (Dolpheide 2007). While it is not a dopamine receptor agonist, it has a similar clinical profile to stimulants with alertness and cognitive improvement and does increase dopamine release in the nucleus accumbens (Murillo-Rodríguez 2007). A double blind controlled trial of modafinil showed it is effective in reducing cocaine dependence with few adverse effects (Dackis 2005). It is especially beneficial in improving cognitive performance and thus participation with cognitive behavioral therapy (Minzenberg 2007). Buproprion treatment itself has been shown effective in a subset of men using low doses of methamphetamine, but was not effective for the population at large (Elkashef 2008, Shoptaw 2008).

9. Non-pharmacologic approaches
But there are non-pharmacologic ways of influencing the self control tract of the brain and enhancing its function, some of which the rehabilitation industry has used for years without really understanding the neurobiology behind them. One of them is the ‘boot camp’ approach. All rehabilitation programs include at least a component of this approach, and some are almost exclusively a boot camp experience. Chores and schedules and responsibilities are expected and are recognized as important to recovery from addiction.

The value of these interventions consists of the conditioning, and in some cases regeneration, of damaged tissue restoring function in the areas of the brain mediating self control. Classical rehabilitation techniques are used from the physical therapy paradigms and applied to behavioral rehabilitation with good success. When a neural tract is impaired, for instance after a stroke, rehabilitation consists for forcing the relevant area of the brain to work, thus facilitating the recruitment of surrounding surviving cells to take over the function of the diseased tissue, a process called activity dependent plastic change, or neuroplasticity (Ward 2005).

In the same way, when the self control pathway is compromised, rehabilitation consists of imposing conditions which force the patient to exert inhibitory control over his behavior, facilitating recruitment of surviving cells to take over the function of the diseased tissue. This is particularly effective at the cortical level in retraining the anterior cingulate cortex to control behavior. Addicts are ‘forced’ to get up at a given time, do chores and keep a schedule, so that impulse inhibiting areas are stimulated to function on a regular basis. The principles of neuroplasticityensure that such ‘exercise’ will stimulate recovery of function by dendritic arborization, increases in brain-derived neurotrophic factor (BDNF) and synaptic plasticity.

Contingency management capitalizes on these same principals as an external motivator is used to improve compliance and modify behavior. Coupled with cognitive behavioral therapy and the social support found in the group therapy setting, success in treatment of methamphetamine addiction is comparable to treatment of other addictions.

Cognitive and attentional problems limit the application of cognitive behavioral techniques in early abstinence, but as the brain heals and remodels, retention and insight improve, and treatment outcomes are comparable to those obtained with treatment of cocaine and other drug addictions (Rawson 2000).

10. Future Directions
Until now, most neuropharmacology research has been devoted to understanding the reward system of brain physiology with an eye towards blocking the rewards associated with drug abuse. Clinical usefulness is limited to those patients who are willing to forgo all rewards for an indefinite period of time. Compliance with such therapy is usually confined to the court ordered population.

More attention should be directed towards the self control system to develop new treatments based on enhancing the addict’s control over his own behavior. This could lead to improvements in the effectiveness of our current contingency management and motivational enhancement techniques, both of which are components of effective cognitive behavioral treatment. A greater understanding of the neurologic components and functional biochemistry of the self control would extend pharmacologic and non-pharmacologic support to empower addicts to control their own lives instead of being controlled by drugs of abuse.

Our enhanced biological understanding of addiction would also permit a more objective definition of drug dependence itself, thus avoiding the denial and deception that complicate the accurate diagnosis of addiction. We are in dire need of an accessible biochemical or radiological marker for drug dependence that does not rely on subjective discomfort, third party report, or personal desire for change, all of which can be missing in a person who is shooting up daily and sustaining serious neurologic damage. The level of denial and deception among drug users is legendary. A scan documenting the loss of dopamine activity in the midbrain might be fairly motivating to a patient considering rehabilitation for his drug problem. Earlier intervention would be possible if addiction could be diagnosed at an earlier stage before significant frontal lobe damage has occurred.

Much work needs to be done to identify dopamine serotonin or nor-epinephrine metabolites in peripheral blood, develop scanning techniques to identify brain cell dysfunction that could inform users of the effect drug use is having on their brains. We are close to having the capability of doing just that. Morris (2008) has validated a PET based technique that accurately measures microdialysis confirmed dopamine levels non-invasively. Such documentation of neural impairment associated with meth may motivate patients to take action, even if they are not ‘dependent’ by current clinical criteria. Our reliance on the recognition of late behavioral changes is keeping us behind the curve when assessing the impact methamphetamine is having on individual lives and on society as a whole.

Addiction must be defined and diagnosed in neurologic terms if it is to be recognized as a ‘brain disease’ deserving of comprehensive and compassionate treatment and not a ‘moral failure’ subject to incarceration. A better public understanding of addiction as a brain disease would move it out of the court system and into the therapist’s office, with corresponding improvements in public perception, patient self image, relegation of public resources, and insurance coverage.


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