ADHD, and PSYCHOSTIMULANTS and ADDICTION

By Werner Van den Bergh, neuro-psychiatrist in Leuven

click here to read this article in the original Flemish

A major reason why many people, including some scientists, hesitate to prescribe psycho-stimulants is the fear of possible addiction, especially following prolonged use. On the other hand, quite a few doctors often prescribe these medications but with inadequate up to date knowledge of new research, so that they cannot make the best possible defence against there critics. This article reviews some surprising and counterintuitive research, and is intended not just for lay people but also many professionals.

Addictions to alcohol, nicotine, amphetamines (speed) and cocaine occur in people with ADHD twice as often in the general population. This may be partly genetically explained. A gene produces the protein that forms the dopamine-2 receptor on the "postsynaptic" neuron in the striatum of the midbrain (postsynaptic refers to the neuron terminal after the synaptic cleft or gap between the two neurons). This receptor receives dopamine from the presynaptic neuron. The gene exists in two forms: A1 and an A2 type. The A1 type occurs in 20% of the general population, but in 50% of people with ADHD and in 87% of cocaine addicts. It is known that not everyone who smokes cigarettes or drinks alcohol becomes addicted; moreover that only 25% of cocaine users become addicted. Genetic factors could therefore play a role. Moreover, the impulsiveness of young people with ADHD and their feelings of awkwardness about themselves often lead to experimentation with drugs, which they experience as a form of self medication. People with ADHD often think more clearly and become calmer after taking amphetamines rather then feeling the’ high’ experienced by people without ADHD.

Schematic diagram of a synapse, showing, at the top of the diagram, the terminal of the presynaptic neuron where dopamine (DA) is released into the neighbourhood of the postsynaptic receptor D2 at the bottom of the diagram. Dopamine is competitively taken up by the DAT transporter in the presynaptic neuron. Ritalin, amphetamine and cocaine block the presynaptic DAT-transporter so that more dopamine remains available in the synaptic gap to stimulate the post synaptic neuron.

It is a paradox that ADHD is often treated successfully with Ritalin or amphetamine, without addiction developing, despite people with ADHD being at a greater general risk of addiction. There are even studies that demonstrate that children with ADHD who have been treated for some years with Ritalin have a lower risk of ever developing any addiction then children with ADHD who were not treated with Ritalin. The information flow in neuronal circuits is achieved by electrical potentials that spread along the axons to the presynapse at the terminal where it is carried by neurotransmitters such as dopamine.
Dopamine then binds to a receptor on the postsynaptic terminal of the next neuron in the circuit .This triggers the ‘ion channels ‘in the post synaptic membrane to open, temporarily allowing electrically positively charged calcium ions to flow within the neuron. The change in charge leads to the generation of a new electrical action potential responsible for further postsynaptic information flow.

It is remarkable that Ritalin has much the same effect on neurons as cocaine: it blocks the dopamine receptor on the presynaptic nerve cells that normally re-uptakes the dopamine. Indeed, it been shown that a large group of people with ADHD had too many presynaptic dopamine receptors, thus too little dopamine was available in the cleft to excite the postsynaptic neurons.

Ritalin normalizes this so that the ADHD symptoms diminish. Not only improving focus, but boring tasks are better prioritized (e.g. revision) and impulsiveness is reduced.

Cross sectional image using Single Photon Emission Tomography (SPECT) of the brain of a person with ADHD. A radio nucleotide is introduced into the bloodstream, which binds to presynaptic dopamine receptors in the striatum. The image on the left shows a greatly increased signal in someone with ADHD (yellow in colour) in the striatum of both hemispheres. On the right, imaged sometime after the administration of Ritalin. The colour is faded: this demonstrates that Ritalin blocks the presynaptic dopamine receptors and thereby normalises dopamine transmission to levels comparable to people without ADHD.

Why is it that someone with ADHD, who normally runs an elevated risk
of addiction, is helped by Ritalin or amphetamine without becoming addicted to the medication? And why, then, are there problems with cocaine addiction? The answers are many:

1) In ADHD the amount of dopamine available in the synaptic cleft is
NORMALIZED (whereas as in people without ADHD Ritalin increases dopamine abnormally).
2) Cocaine is usually inhaled or injected giving a very quick dopamine increase (peak effect after 5 minutes) and a "high" feeling. If Ritalin is inhaled or injected the same "high" feeling is obtained .In both, the "high" feeling lasts about 20 minutes. If
Ritalin is taken by mouth the peak concentration in the brain lasts about 60
minutes, without any "high”.
3) The peak concentration of dopamine after taking a Ritalin pill occurs after15-20 minutes, whereas for cocaine it is 2-4 minutes. With Ritalin the increased amount of available dopamine in the brains falls to half after 90 minutes, with cocaine it takes just 20 minutes. The rapid reduction after cocaine ingestion motivates the user to take another dose, this is not the case with Ritalin the amount of dopamine remains optimal for a long time. Moreover Ritalin releases the dopamine in a "tonic" way, that is, evenly over time, place, simulating the natural release of dopamine , leading to normalisation If an artificially regulated dosage of cocaine is given so that the dopamine stays saturated then there is no is no new "high".

4) In a therapeutic context, Ritalin is administered using a strict schedule, and is not tied to pleasure seeking. Rather, it is mainly used for boring tasks, allowing a more meaningful experience, closer to that of people without ADHD. Cocaine is used in circumstances of pleasure which in itself is more naturally associated with dopamine release.
5) Cocaine also acts on the serotonin system, which is not the case with Ritalin or amphetamine.
6) "Speed" in illicit use is taken in unmeasured dose but the estimated dose is 10 times higher than for therapeutic use in ADHD. Moreover, the drug user often injects speed rather then administers by mouth.
7) There are indications that Ritalin maybe neuroprotective (at the postsynaptic neuron) against excitoneurotoxicity a. Also, there are indications that it will protect against deterioration of dopaminergic neurons in Parkinson’s disease. Nicotine is also neuroprotective against Parkinson’s disease and Alzheimer's disease, but, of course the disadvantages of chronic nicotine use outweigh these potential benefits.

Furthermore, there remains the delicate problem of how someone with ADHD who is addicted to cocaine can best be treated. In this area there is still much research to be done, but there are already some publications showing that in some cases it may be possible to replace cocaine with Ritalin.

LONG-TERM EFFECTS OF RILATINE AND AMPHETAMINES

It is often rightly pointed out that there are no scientific studies on the long-term effects of the therapeutic use of these medications to treat ADHD. Yet we know that almost half of children with ADHD outgrow ADHD and the need for medication.

Traditionally, there was a presumption that the lessening of ADHD symptoms was due to natural maturation so that there was no further need for amphetamine or Ritalin. But recently scientists have begun to entertain the possibility that these drugs produce long-term positive permanent change in the brain, brought about by neuroplasticity, which in recent years has become a hot topic in neuroscience.

1) NEUROPLASTICITY THAT LEADS TO NORMALISATION
continuing use of medication will not only provide better signal transfer in neuronal circuits, but also activate genes in postsynaptic neurons, stimulating the creation of proteins that are the building blocks of new postsynaptic dopamine receptors. Possibly, these proteins also create a decrease in presynaptic dopamine receptors. This would effectively mean NORMALISATION; we could even speak of HEALING. Therefore, it is now recommended to cease medication every 2-3 years temporarily to see if further treatment is needed. LONG-TERM EFFECTS OF RILATINE and amphetamines

2) NEURO plasticity THAT LEADS TO DEPRESSION
Researchers using young rats treated with intravenous Ritalin found that as adults the rats exhibited symptoms of depression, ambient incentives usually experienced as pleasant (such as sugar water) seemed to give them no satisfaction and stressful or conflicted situations produced despairing behaviour. This has led to the view that the neuronal plasticity exhibited here can lead to unfavourable outcomes such as DEPRESSION. If this is extrapolated to humans, it means that after years of

Ritalin use depression could develop. This has not yet been demonstrated by researchers Moreover, there are two important points to make. First, the rats were administered with Ritalin intravenously which is quite different to oral ingestion. Secondly, the researchers used healthy rats. In theory, one can imagine that for people without ADHD this hypothesis of resulting long term depression may have some validity., but that in ADHD a normalization through neuronal plasticity occurs:. Conceivably by this hypothesis in healthy people long term use of Ritalin may lead to the occurrence of a neuroplasticity though over shooting. If that is true great importance must be attached to correct diagnosis of ADHD prior to beginning a long-term treatment with Ritalin or amphetamine.

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It is inadmissible to let the decision to begin long term medication depend on the symptomatic effects of trial doses. Medication will, in the short term have positive effects in people without ADHD. It must be emphasized that an ADHD diagnosis cannot be concluded from a positive reaction to a few administrations of Ritalin.

3) NEUROPLASTICITY THAT LEADS TO ADDICTION

Only with non-therapeutic use of these medications, where high doses are taken, often intravenously, and in the context of pleasure seeking does addiction arise. Often only when a genetic disposition also contributes to the addiction. In the latter case, the chronic overabundance of dopamine would trigger even more postsynaptic protein synthesis and the production of more postsynaptic receptors. Research shows that this occurs not only in the striatum (nucleus accumbens among others) but also occurs in the prefrontal cerebral cortex (orbito frontal cerebral cortex, located above the orbital, i.e. the eye socket) to which it is connected. It has demonstrated that the cocaine addict shows over activity in this area during cocaine intake or during acute rehabilitation.

Imaging using Positron Emission Spectroscopy (PET) of the brain (cross section) of a cocaine addict. Left Image, after administration of a placebo: low activity in the orbito frontal cerebral cortex. Right after intravenous administration of Ritalin (methylphenidate) there is over activation in these areas

After months of rehabilitation, the activity in this area is too low as well as in the nucleus accumbens. This leads to less activity in the prefrontal cortex in response to natural rewards, and the possibility that the drug of addiction may no longer be experienced as a reward. This also leads o the prefrontal cerebral cortex overreacting to the signalling of drug availability which induces over activity in the nucleus accumbens.

4) Rare problem of HABITUATION to long term therapeutic use of Ritalin or amphetamine in cases of ADHD
About 2-5% of patients report that after a few months (or sometimes more than one year) Ritalin no longer has a positive effect. This can probably also be explained by a form of neuronal plasticity achieving a different balance than the ones described previously. In these cases it is recommended to switch to another medication e.g. amphetamine or a noradrenergic antidepressant (desipramine, imipramine), Efexor or Strattera (also has a noradrenergic effect). It may also be necessary to switch medication a few times a year employing a rotation scheme.

translated from the Flemish by Stephanie Clark

What is ADHD?

click to view Article in the original Flemish

Attention deficit / hyperactivity disorder (ADHD) is common in school children (2 to 5%). It is marked by concentration difficulties and can be accompanied by hyperactivity and impulsiveness. The cause lies in changes in brain functioning.

In the past, it was believed that the disorder disappeared in adulthood, but since the 1970’s science publications have described the persistence of adhd into adulthood in 30 to 50% of children. That means that 1 to 3% of adults suffer ADHD.

Adult ADHD

In adulthood the most common symptoms are impaired concentration, day dreaming, forgetfulness and frequent changes in activity. In adults, hyperactivity and restlessness are rarer; however ADHD is often associated with other problems such as boredom, chronic conflicts and social adjustment difficulties, leading to problems at work and home. Furthermore, alcohol or drug abuse, anxiety and depression are frequent complaints.

More and more often practitioners are confronted with patients’ questions about the diagnosis and treatment of ADHD. Professionals in the adult psychiatric sector may struggle to respond, professional training and traditional thinking often ill prepares them for this problem. A brief overview of the subject is of topical interest.

A little known pathology

The diagnosis of ADHD (attention deficit / hyperactivity disorder) has been generally recognized for many years in child psychiatry, and, according to the DSM-IV affects 2-5% of all children. The diagnostic term ADHD is of American origin and includes the non-hyperactive subtype, in contrast to Europe’s much more restrictive concept of hyper-kinetic syndrome in the ICD-10. In 30-50% of children with ADHD the origin is genetic. If ADHD persists into adulthood, the genetic contribution is greater; an adult with ADHD has an 84% chance that at least one of his children will have ADHD. It is known that 30 to 50 % of the children continue to have adhd related problems in adulthood.
However, in the adult psychiatric health sector a lack of familiarity with this disorder persists. Several factors may explain this:

1 In adults motor hyperactivity decreases and attention and organisational difficulties come to the fore, so one thinks less of it

2 In adults ADHD is often associated with mood instability and emotional reactivity, often interpreted as manifestations of a personality disorder.

3 Under the restrictive criteria of the ICD-10 diagnosis of hyper-kinetic syndrome cannot be made if there is a comorbidity such as depression

4 In the DSM-IV, ADHD is listed in the chapter about childhood disturbances; consequently adult psychiatry is less familiar with ADHD.

5 Child psychiatrists and adult psychiatrists have little or no contact, either in training or in practice, so that children reaching adulthood with ADHD are not automatically referred to adult services.

6 It is easier for people to accept and understand a disorder of self control in children then in adults.

Diagnosis

As with children, a patient history is the cornerstone of diagnosis. It is necessary to establish if the difficulties existed since childhood. The clinician should be aware of the possibility of ADHD and take a focused history; care should be taken to avoid colouring the childhood history with a priori psychodynamic or system theoretical perspectives. In adults it may be difficult to obtain an accurate retrospective view of childhood functioning. Additionally, adult life may be complicated by many factors, differential diagnoses, co morbidities, so that getting a clear perspective on adult problems is not always easy.

The diagnostic criteria listed in the DSM_IV are also applicable in adulthood. Several authors have suggested that the minimum criteria for adults should be four or five of the nine symptoms of hyperactivity/impulsivity (instead of six as stipulated in the DSM-IV for children) and four of five of the nine symptoms of inattention, because the severity of symptoms in adults is less marked.

The Utah criteria for ADHD in adults are the best validated (although drawn up solely for the hyperactive subtype):

· The symptoms must be present from childhood onwards.

· There should be clear mild difficulties with attention and motor unrest.

· At least two of the following five criteria should be met: mood swings, organizational problems, irascibility, emotional reactivity, impulsiveness.

Further, an EEG study of the cognitive evoked brain potential can be useful for an objective neuropsychological examination of the attentional and frontal lobe functions. The specificity and sensitivity of these tests have their limitations. However, against the background of these test results ,the patient can better understand and accept that there exist objective reasons for his difficulties, especially as the personal history data obtained is often questionable and subjective.

Differential diagnosis and comorbidity

1) Depression and Dysthimia (depressive neurosis): depression is present in 20-30% of patients with ADHD (in the general population it is 15%). The differential diagnosis can be difficult: Dysthymia can also express with chronic attention difficulties, however negative self-perception with an inability to experience pleasure are clearly central.

2) Addictions occur in 10-40% of patients with ADHD.

3) Borderline, antisocial and histrionic personality disorder: the differential diagnosis can be difficult. In borderline personality disorder a more markedly contorted personality exists , coupled with feelings of emptiness, more manipulative behaviour, suicidal behaviour , self mutilation, abandonment fears with attachment problems, and identity disorders. The impulsiveness in borderline personality disorder is more driven and often self-destructive (whilst the impulsiveness of ADHD is short-lived and more thoughtless). One needs to take in account the possibility of the combination of the 2 disorders with a more targeted patient history.

Treatment

1. Psycho-education: the provision and explanation of the diagnosis is in itself therapeutic. Often the patient has had many years of personal troubles and (troubles adapting to their environment) without understanding the reasons. Often the patient has had years of psychotherapy without success, often only resulting in further disappointments and misunderstandings However, the diagnosis should not be used as an excuse for every continuing problem: correct diagnosis should lead to measures for finding solutions. Any comorbidities must be explained, where a diagnosis of adhd does not cover all the problems. It is important that the practitioner not only knows the symptom lists, but is familiar with the current explanatory neuropsychological models- such as Barkley’s, in order to consider the broader picture. Also, the practitioner must be familiar with the impact of ADHD problems in the entire daily life, working life and partner relationships.

2. Medication: Although traditionally doctors in Europe are reluctant to prescribe psycho-stimulants (especially Ritalin, but also some stimulant antidepressants), in the United States it might be seen as a serious medical error not to offer medication. The recommended course is to offer a months trial (Ritalin 3 times a day, every 4 hours, at constructive dosages). In 25-78% of cases there is a positive result, although still often residual problems persist. This result is reflected in all areas: not just attention, hyperactivity and impulsiveness, but also self control over mood swings, motivation and emotional over reactivity and organizing functions. If this medication is clearly indicated and properly prescribed, under supervision, there is no reason to fear for addiction.

3. Psychotherapy, coaching: Coaching and organization skill learning is important , one should, however, be aware that a finished plan, practical tips and good intentions often still lead to failures because often patients with ADHD know, by definition,’ what they should do, but do not do what they know’. Psychotherapy is only useful if there are difficulties; handling past failures, or adapting to new patterns of functioning under medication, or difficulties with comorbidities or relationships. But one should be careful of explaining ADHD symptoms in a psychodynamic or system theoretical manner.

4. Contact with Fellow-Sufferers: Regional Support Groups for adults with ADHD in Flanders started an organization ("Aandacht"), with its own website (www.adhd-volwassenen.be). The mutual recognition and validation is frequently a revelation and support for many participants. The exchange of experiences, tips and information, and the experience of seeking solutions jointly often has a major significance for group members and their surroundings.

Dr. W. Van den Bergh (Leuven)
De Agenda Psychiatrie Nr. 19, Mei 2001, p. 8-9

Thank you to Dr Van Den Bergh for permission to translate this article.

Stephanie Clark. With help from Anne.