There is currently no Food and Drug Administration–approved treatment for cocaine addiction. One reason may be that in studies of treatments for cocaine use, participants may have a wide variety of exposure to cocaine. Some may be regularly using cocaine, while others may have gone some time without using the drug. A recent study by Margaret Haney and colleagues addressed some of these challenges by comparing the addiction treatment modafinil to placebo in different scenarios—such as when cocaine users have access to cheap cocaine versus expensive cocaine—and determining under which circumstances modafinil reduces the use of smoked cocaine.
In the study, presented at a scientific meeting in 2015, Haney and colleagues reported that among people who were not currently smoking cocaine, modafinil reduced cocaine use compared to placebo, but modafinil did not reduce cocaine use among people who had recently smoked cocaine. Modafinil also reduced cocaine use when the drug was expensive, but not when participants had access to cheap $5 cocaine. According to the researchers, these findings suggest that modafinil may be more useful at preventing relapse than at helping current users of cocaine achieve abstinence.
Editor’s Note: While they are not FDA-approved, two other treatments can reduce cocaine use, according to placebo-controlled studies: the antioxidant N-acetylcysteine (NAC) and the anticonvulsant topiramate.
Glia are brain cells that surround neurons and synapses, protecting and insulating them. Chronic cocaine use and withdrawal changes the way certain glial cells, called astrocytes, interact with neurons. In particular, chronic cocaine use and withdrawal can shrink astrocytes and cause them to pull away from neurons. Cocaine use and withdrawal also interfere with the way the neurotransmitter glutamate is cleared from synapses and transported into astrocytes.
New research shows that certain medications that regulate and increase the movement of glutamate from the synapse into glial cells can reduce cravings for cocaine.
In studies of rats chronically exposed to cocaine and then denied access to it, treatment with these glutamate-targeting medications reduces the rats’ cocaine-seeking behaviors. The medications include N-acetylcysteine (NAC), an antioxidant that can reduce habitual behaviors, including addictive behaviors; riluzole, a treatment for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease; the antibiotic ceftriaxone; and propentofylline, which has been explored as a possible treatment for dementia and stroke.
Repeated transcranial magnetic stimulation, or rTMS, is a non-invasive treatment in which a magnetic coil placed near the skull transmits electrical signals to the brain. It is an effective treatment for depression, and now it appears it may also be useful in the treatment of addictions.
A pilot study by Alberto Terraneo and colleagues published in European Neuropsychopharmacology in 2016 compared rTMS treatment delivered to the dorsolateral prefrontal cortex to pharmacological treatment in 32 patients who wanted to stop using cocaine. Those in the rTMS group received one session of the treatment per day for five days, followed by one session per week for three weeks. Those who received rTMS had a higher number of cocaine-free urine tests than those who had been treated with pharmacological treatments. Among those who received rTMS, 69% had a positive outcome, compared to 19% of the control group. RTMS also reduced cravings for cocaine. Both treatments improved depression.
Antonello Bonci, another author of the study who is also scientific director at the US National Institute on Drug Abuse, suggested that rTMS may work by “scrambling” the pattern of neural activity that leads to cocaine craving.
Now that there is some evidence suggesting that rTMS may be useful in the treatment of addictions, the researchers are planning a placebo-controlled study of rTMS treatment for cocaine use, in which they will give some patients a sham treatment instead of real rTMS.
Other studies are examining whether rTMS can be used to treat smoking and alcohol use disorders in addition to depression.
In 2015 Claudia Chauvet and colleagues reported in the journal Neuropsychopharmacology that the brain-penetrating statins simvastatin and Atorvastatin reduced cocaine seeking behaviors in mice that were taught to self-administer cocaine and then were denied access to it for 21 days compared to pravastatin, a statin that does not penetrate the brain as thoroughly. The researchers found that the brain-penetrating statins also reduced nicotine seeking, but not food reward seeking. The statins also worked in mice that had stopped seeking cocaine but relapsed due to stress, allowing them to abstain from cocaine seeking again.
Statins are considered a very safe treatment in humans. The ability of statins to prevent relapse to addictions in mice may mean that one day they could be used to treat addictions in people as well. A review article by Cassie Redlich and colleagues in the journal BMC Psychiatry in 2014 indicated that statins may reduce recurrence of depression in people. The researchers found that simvastatin had a protective effect while Atorvastatin was associated with increased risk of depression, so the choice of statins may be important for both depression and addiction.
In studies of rodents, running on a wheel reduces cocaine self-administration. A recent study by Richard de la Garza and colleagues investigated whether running or walking on a treadmill can reduce cocaine cravings and use in humans. In the study of 24 participants who had been using cocaine an average of 19.7 years, participants were randomized to run, walk, or sit for 30 minutes three times per week for four consecutive weeks. After exercising, the participants reported having less craving for cocaine. Fitness measures such as body weight and resting heart rate improved in both walkers and runners. While not statistically significant, by the end of the study there was a trend indicating that exercise improved abstinence from cocaine and decreased daily craving for cocaine.
Editor’s Note: Exercise Increases brain-derived neurotrophic factor (BDNF) and neurogenesis. In rodents, cocaine is associated with decreases in BDNF in the frontal cortex, and injecting BDNF there decreases cocaine seeking. Whether this BDNF effect or the general effects of exercise on mood and conditioning account for these positive cocaine effects remains to be ascertained.
Researchers hope to map out the neurocircuitry by which stress leads to compulsive drug taking. A recent study by Klaus Miczek and colleagues examined different rodents’ responses to the stress of being repeatedly placed in the cage of a larger, more aggressive rodent, developing what is known as defeat stress, a set of behaviors that mimic human depression. Mice and rats showed increases in the stress hormone corticosterone that did not diminish over repeated run-ins with a larger animal. Rodents who were exposed to this stress became sensitized to cocaine or amphetamine, showing hyperactivity that increased each time they accessed the drug (the opposite of a tolerance response). Some also “binged” on cocaine, which they were able to self-administrate by pushing a lever to receive infusions. The mice and rats that went through the social defeat showed elevated levels of dopamine in the nucleus accumbens, the brain’s reward center. Levels were related to the severity of their stressful experience.
Later the rodents had a choice between water and a 20% alcohol solution. The researchers determined what type of stress led the rodents to consume the alcohol solution instead of the water. The maximal effect was seen in two types of mice that suffered an attack of less than five minutes that resulted in a moderate number of attack bites (30); this resulted in the mice consuming large amounts (15–30 g/kg/day) of the alcohol solution. Earlier sensitization to cocaine or amphetamine did not predict later alcohol or cocaine self-administration.
When the researchers injected the rodents with antagonists of the receptors for corticotropin-releasing factor, a hormone and neurotransmitter important in stress response, prior to each episode of social defeat, the rodents did not escalate their cocaine or alcohol self-administration, indicating that CRF plays an essential role in the process by which stress makes animals prone to using substances.
In related research by Camilla Karlsson and colleagues, IL-1R1 and TNF-1R, the receptors for two inflammatory cytokines, mediated the effects of social stress on escalated alcohol use in mice.
Stress can trigger former drug users to begin taking drugs again. In clinical trials, the bonding hormone oxytocin has been found to reduce stress-induced cravings for certain drugs, including alcohol and marijuana. A new study in animals suggests that oxytocin may be able to reduce stress-induced cocaine cravings as well.
Brandon Bentzley and colleagues combined an unpredictable shock to the foot with an alkaloid called yohimbe that comes from a particular tree bark to apply stress to animals who had previously developed a cocaine self-administration habit that had since been extinguished. The combination of the foot shocks and yohimbe brought back robust reinstatement of the animals’ cocaine seeking behaviors, but pretreatment with oxytocin (at doses of 1 mg/kg) prevented this reinstatement.
This research suggests that oxytocin has potential to prevent stress-induced cocaine cravings in people.
Colleen Hanlon, a researcher at the Medical University of South Carolina, has found that biofeedback can be used to decrease cocaine craving in people with substance abuse problems. In her research, patients were given real time feedback from functional magnetic resonance imaging (fMRI) and learned to decrease the activation of a part of the brain called the anterior cingulate when exposed to cocaine cues (reminders of their desire for cocaine). They were able to decrease drug craving as well as heart rate and skin conduction, which often accompany it.
Researchers have identified neurons responsible for remembering conditioned fear in the amygdala of rodents, and can turn them on and off. At the 2013 meeting of the Society of Biological Psychiatry, Sheena A. Josselyn gave a breath-taking presentation on this process.
When animals hear a tone they have learned to associate with the imminent delivery of a shock in a given environment, they learn to avoid that environment, and they reveal their learning of the tone-shock association by freezing in place. Josselyn was able to observe that 20% of the neurons in the lateral nucleus of the amygdala were involved in this memory trace. They were revealed by their ability to increase the transcription factor CREB, which is a marker of cell activation. Using cutting-edge molecular genetic techniques, the researchers could selectively eliminate only these CREB-expressing neurons (using a new technology in which a diphtheria toxin is attached to designer receptors exclusively activated by designer drugs, or DREADDs) and consequently erase the fear memory.
The researchers could also temporarily inhibit the memory, by de-activating the memory trace cells, or induce the memory, so that the animal would freeze in a new context. Josselyn and colleagues were able to identify the memory trace for two different tones in two different populations of amygdala neurons.
The same molecular tricks with memory also worked with cocaine cues, using what is known as a conditioned place preference test. A rodent will show a preference for an environment where it received cocaine. Knocking out the selected neurons would remove the memory of the cocaine experience, erasing the place preference.
The memory for cocaine involved a subset of amygdala neurons that were also involved in the conditioned fear memory trace. Incidentally, Josselyn and her group were eventually able to show that amygdala neurons were in competition with each other as to whether they would be involved in the memory trace for conditioned fear or for the conditioned cocaine place preference.
New discoveries in neuroanatomy are helping clarify what addiction looks like in the brain. Peter Kalivas of the Medical University of South Carolina reported at the 2013 meeting of the Society of Biological Psychiatry that most drugs of abuse alter glutamate levels and the plasticity of synapses in the nucleus accumbens, the reward area of the brain. Glutamate is the main excitatory neurotransmitter in the brain, and compulsive habits may be associated with increased release of glutamate in this brain area.
During chronic cocaine administration, for example, the neurons in the nucleus accumbens lose their adaptive flexibility and their ability to respond to signals from the prefrontal cortex. Normally, low levels of stimulation would induce long-term depression (LTD) while high levels of stimulation would induce long-term potentiation (LTP). These are long-term changes in the strength of a synapse, which allow the brain to change with learning and memory. When long-term potentiation and long-term depression are no longer possible, memory and new learning in response to messages from the prefrontal cortex are diminished.
Given this absence of flexible responding, animals extinguished from cocaine self-administration (when a lever they had pressed to receive cocaine ceases to provide cocaine) are highly susceptible to cocaine reinstatement if a stressor is presented or if a signal appears that suggests the availability of cocaine. This cocaine reinstatement is associated with high levels of glutamate in the nucleus accumbens, so Kalivas reasoned accurately that lowering these levels would be associated with a lesser likelihood of cocaine reinstatement.
The drug N-acetylcysteine (NAC), which is available from health food stores, decreases the amount of glutamate in the nucleus accumbens by inducing a glutamate transporter in glial cells that helps clear excess synaptic glutamate. In Kalivas’ research, NAC prevented cocaine reinstatement, cocaine-induced anatomical changes in spine shape (bigger, stubby spines), and the loss of long-term potentiation and long-term depression in the nucleus accumbens.
The findings on NAC in animal studies led to a series of important small placebo-controlled clinical trials in people with a variety of addictions, and positive results have been found using NAC in people addicted to opiates, cocaine, alcohol, marijuana, and gambling. It also decreases hair-pulling in trichotillomania and reduces stereotypy and irritability in children with autism.
NAC also appears to be effective in the treatment of unipolar and bipolar depressed patients in placebo-controlled trials by Australian researcher Michael Berk. Thus, NAC could be useful for patients with affective disorders who are also having difficulties with comorbid substance use.
Some antibiotics (that are not commonly available) also induce the glutamate transporter and glial cells of the nucleus accumbens, offering a potential new approach to treating some addictions.