Amphetamines long-term effects

Melega, W.P., Quintana, J., Raleigh, M.J. et al. 6-[18F]Fluoro-L-DOPA-PET studies show partial reversibility of long-term effects of chronic amphetamine in monkeys. Synapse. 22 63, 1996. 

Amphetamines also pass into a nursing mother s milk. For this reason, women taking amphetamines should avoid breastfeeding. Dextroamphetamines are not recommended for the treatment of ADHD in children under the age of 3, as the drugs have not been sufficiently tested in this age group. In addition, there are few long-term follow-up studies on the long-term effects of extended dextroamphetamine use by pediatric ADHD patients. 

As noted in Chapter 3, stimulant drugs such as cocaine and the amphetamines are thought to affect the brain primarily through complex actions on monoamine neurotransmitters dopamine, norepinephrine, and serotonin. For example, both cocaine and the amphetamines block rcuptake of norepinephrine, serotonin, and particularly dopamine (Meyer 8c Quenzer, 2005). In addition, the amphetamines and methylphenidatc also increase the release of dopamine (Sulzer, Sonders, Poulsen, 8c Galli, 2005). Thus, the initial effect of stimulants is to produce a storm of activity in neural pathways that are sensitive to the monoamine transmitters. Because of this increased activity, however, and particularly because reuptake is blocked so that enzymes break down the neurotransmitters, the long-term effects of stimulant use involve depletion of monoamines. If you remember that low levels of monoamines are linked to clinical depression (see Chapter 3), tlien you have the basis for one theory of why the aftereffects of heavy cocaine use involve depression (Dackis 8c Gold, 1985). To explain this hypothesis, we must turn briefly to data from the animal laboratory. 

Until recently, d-fenfiuramine was used to control appetite, in preference to d-amphetamine, because it has a lower affinity for the catecholamine transporter and so its uptake into noradrenergic and dopaminergic neurons is much less than that of amphetamine. This is thought to explain why, at anorectic doses, this compound lacks the psychotropic effects and dependence-liability that are real problems with if-amphetamine. Unfortunately, despite this therapeutic advantage, this compound has had to be withdrawn from the clinic because of worries that it might cause primary pulmonary hypertension, valvular heart disease and even long-term neuropathy. 

If you look at the court records, you see that story repeatedly, i.e., this reactive component. And you can see the same thing in chronic animals. You do have to take them out to a 3- or 6-month period to see those effects. During long-term chronic use, the dopamine at that point is markedly depleted. We are talking about animals that have 20 or 30 percent of the original dopamine levels a month or so after they have been given the last dose of amphetamine. 

The side effects of amphetamine are related to its stimulant effects, especially at high doses and with long-term use. Side effects include irritability, insomnia, confusion, anxiety, paranoia, hallucinations, seizures, and aggressiveness. Amphetamines cause irreversible destruction of blood vessels in the brain, which can cause stroke—even in young people. These drugs also cause the potentially lethal side effects of increased heart rate, irregular heartbeat, and increased blood pressure. 

Long-term amphetamine abuse results in many damaging effects, not least of which is addiction. Chronic abusers exhibit symptoms that can include violent behavior, anxiety, confusion, and insomnia. They also can display a number of psychotic features, including paranoia, auditory hallucinations, mood disturbances, and delusions (for example, the sensation of insects creeping on the skin). The paranoia can result in homicidal as well as suicidal thoughts. 

Despite the documented efficacy and safety of the psychostimulants, their mechanism of action is not fully understood. Stimulants affect central nervous system (CNS) dopamine (DA) and norepinephrine (NE) pathways crucial in frontal lobe function. The stimulants act by causing release of catecholamines from the DA axons and blocking their reuptake. Methylphenidate releases catecholamines from long-term stores, so its effects can be blocked by pretreatment with reserpine. Amphetamines, on the other hand, release catecholamines from recently formed storage granules near the surface of the presynaptic neuron, so their action is not blocked by reserpine. In addition, the stimulants bind to the DA transporter in striatum (see Figures 2.6 and 2.7) and block the reuptake of both DA and NE. This action reduces the rate that catecholamines are removed from the synapse back into the axon and leads... 

McGough JJ, Biederman J, Wigal SB, et al Long-term tolerahility and effectiveness of once-daily mixed amphetamine salts (Adderall XR) in children with ADHD. J Am Acad Child Adolesc Psychiatry 44 530-538, 2005a... 

Even when effective in controlling behavior, Ritalin and other stimulants have side effects common with use of amphetamines. These include nervousness, insomnia, and perhaps some more long-term problems such as dependency, slowed growth, or depression. Critics sometimes note the similarity between cocaine and the active chemical ingredient in Ritalin, methylphenidate. Both stimulate the dopamine system of the brain, but cocaine does so quickly and methylphenidate does so slowly. The similarities show in the abuse of Ritalin for its pleasure-inducing qualities. 

Long-term cocaine or amphetamine abuse leads to a deterioration of the nervous system. The body recognizes the excessive stimulatory actions produced by these drugs. To deal with the overstimulation, the body creates more depressant receptor sites for neurotransmitters that inhibit nerve transmission. A tolerance for the drugs therefore develops. Then, to receive the same stimulatory effect, the abuser is forced to increase the dose, which induces the body to create even more depressant receptor sites. The end result over the long term is that the abusers natural levels of dopamine and norepinephrine are insufficient to compensate for the excessive number of depressant sites. Lasting personality changes are thus often observed. 

Recall from our discussion of cocaine and amphetamines that the body responds to the long-term abuse of these stimulants by creating more depressant receptor sites. Likewise, the body recognizes the excessive inhibitory actions produced by alcohol and tries to recover by increasing the number of synaptic receptor sites that lead to nerve excitation. A tolerance for alcohol therefore develops. To receive the same inhibitory effect, the drinker is forced to drink more, which induces the body to create even more excitable synaptic receptor sites. Eventually, an excess of these excitatory receptor sites leads to perpetual body tremors, which can be subdued either by more drinking or, with greater difficulty, by a long-term cessation of alcohol consumption. 

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