Table 2. Symptoms of methamphetamine withdrawal (NIAAA, 2007).

• Anxiety
• Insomnia
• Depression
• Restlessness
• Craving
• Dysphoria (feeling unwell or unhappy)

Some scientists believe that anxiety-like symptoms associated with withdrawal from meth abuse may be very important in causing people to continue abuse (Weiss, 2001); and these symptoms of anxiety and unease appear to be more closely related to alterations in GABAergic neurotransmission (Breese, 2005; Reddy, 1997).

What Happens to GABA during Development of Methamphetamine Dependence and Withdrawal?
There is little doubt that changes in the GABAergic system play an important role in withdrawal symptoms. Animal studies have shown that the activity of this system is decreased during meth withdrawal and that this leads to symptoms of hyperexcitation in the brain (Esel, 2006). GABA levels in the fluid surrounding the brain have also been found to be low during meth withdrawal (Tsai, 1998).  

Changes in a specific type of GABA receptor called the GABAa receptor may be particularly important in the symptoms that occur with meth withdrawal. For example, chronic meth administration reduces the ability of GABA and drugs commonly used to treat anxiety called benzodiazepines to activate the inhibitory calming effect of GABAa receptors (Morrow 1995; Buck 1996). After meth withdrawal, benzodiazepines become less effective for treatment of anxiety. Studies in mice, rats, and nerve cells grown in laboratories show that chronic meth exposure alters the activity of genes that direct the manufacture of the parts that make up GABAa receptors, increasing the levels of some while decreasing others. These changes may decrease the effectiveness of this receptor (Figure 9) and lead to some of the symptoms of meth withdrawal (Finn, 1997).

Figure 9. Changes in GABAa receptor function with methamphetamine
abuse and withdrawal.

GABAergic inhibitory neurotransmission is reduced following chronic meth administration. In the absence of meth (left), the neurotransmitter GABA opens GABAa receptor-chloride (Cl-) channels, inhibiting neurotransmission and exerting a “calming” effect on the brain. Meth increases GABA’s effect (middle), allowing more chloride to enter the neuron and increasing inhibition.  In meth dependence and withdrawal (right), both GABA and meth have smaller effects on GABAa receptors. Less chloride enters the neuron, and this permits neurons previously inhibited by GABAergic neurotransmission to become more active (Finn, 1997).

Results from several studies have shown further that levels of GABAa receptors normally expressed in the brain are substantially decreased in patients with methamphetamine dependence and those undergoing withdrawal (Figure 10) (Agi-Darbham, 1998).