Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice.
PLoS One. 2012;7(3):e33693. Epub 2012 Mar 21.
Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ.

Abstract
BACKGROUND:
Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia.

METHODOLOGY/PRINCIPAL FINDINGS:
Through the use of stereological counting methods, we observed a significant reduction (∼20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing.

CONCLUSION:
Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.

PMID: 22470460

Stimulants always increase inflammation. Stimulants increase norepinephrine signaling, the primary signal for stress. This then signals the immune system cells of the body – including the brain’s microglia – to enter a pro-inflammatory state to help protect the body. The primary problem is that the increase in pro-inflammatory signaling, particularly if there already is an increase or if it is in excess of what the body can tolerate, can cause dysfunction. This includes impairing nervous system cell function, metabolism, etc.

Criticism of the study: the authors focused only on methyphenidate’s ability to increase dopamine and pronounced that the increase is toxic. They ignore the effects of the increase in norepinephrine.

Criticism of the study: The methylphenidate dose used of 10 mg/kg is extremely high and way over the therapeutic and unrealistic. This is equivalent to a dose of 700 mg a day in an average sized man of 70 kg, when the usual dose maximum is 72 mg a day, and the dose I use is around 10-20 mg a day. The main problem of using excessive doses is that I would a priori expect such a high dose to be toxic. The primary question is: does such a dose occur in real life? No. Studies like this which use excessive doses of substances to show they are toxic at lower doses use a logical fallacy called argumentum ad absurdum.

The study focuses on substantia nigra neurons. These are the neurons involved in Parkinson’s Disease. They are already overworked in daily use to control our motor movements. Such overwork is thought to lead to their death. When excessive cell death occurs, a person develops Parkinson’s Disease. The study points out that driving these neurons more strongly with stimulant treatment can make them more susceptible to cell death. Certainly, the neurons with stimulant use are more sensitive to the toxic effects of MPTP, a substance used to cause Parkinson’s diease.

Criticism: The problem is that these findings do not extend to the other dopamine systems – where the dopamine neurons are not overdriven as in the substantia nigra. These other neurons are the target of stimulant treatment.

In any case, when considering treatment with a stimulant, it is important to assess whether or not a person can tolerate the treatment. A sign a person may not tolerate such treatment is excessive hypothalamic-adrenal dysregulation since this leads to an excess in norepinephrine and pro-inflammatory signaling. The presence of a mood problems such as anger or panic indicates one should be careful about stimulant treatment since it may not be tolerated and can instead contribute to the mood problem. Ongoing immune system problems should make one careful about adding stimulant treatment, weighing the risks versus benefits. etc.

And once on stimulant treatment, it is important to protect the patient from adverse effects from excessive stress and inflammatory signaling. For example, it may be important to restore HPA Axis function and maintain it during treatment. An anti-inflammatory diet may be needed. Treatments to minimize stress signaling may be needed. etc.

As with any treatment, there are benefits and risks. Even 81 mg Aspirin in daily use can cause substantial problems in the wrong patients. Many times, it is unavoidable to use medication treatment. It is up to the practitioner to lead the patient to the best route for treatment.