Oxytocin, the hormone that promotes emotional bonding, also regulates a variety of behaviors. Two recent studies suggest that in rats, an injection of oxytocin can prevent drug-seeking behavior.
In the first study, researcher Gary Aston-Jones found that oxytocin reduced the rats’ interest in methamphetamine. The effect was strongest in the rats that started out with the strongest interest in the methamphetamine.
In the second study, researcher Luyi Zhou and colleagues determined that oxytocin also reduced cocaine-seeking behavior in rats. In addition, the oxytocin reversed changes in the brain’s glutamate signaling pathway that were caused by cocaine use.
Both studies, which were presented at the 2016 meeting of the Society of Biological Psychiatry, suggest that oxytocin is a promising potential treatment for drug addictions.
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.
The antioxidant N-acetylcysteine (NAC) has been found to be an effective treatment for a variety of habit-based behaviors—substance abuse, including cocaine, alcohol, marijuana, and nicotine; gambling; obsessive-compulsive behaviors; trichotillomania (compulsive hair-pulling), and repetitive behaviors among people with autism. Recent research by researcher Jon Grant and colleagues revealed that NAC can also treat skin-picking disorder.
At a 2015 scientific meeting, Grant reported that 1200–3000mg of NAC per day led to improvement in 47.1% of patients with a skin-picking disorder, compared to 19.2% improvement in patients who received placebo.
In addition to its positive effects in people with addictions and habit-based behaviors, NAC has also improved mood and anxiety in bipolar disorder and treated negative symptoms of schizophrenia, such as withdrawal and lack of motivation.
Editor’s Note: Given NAC’s effectiveness in such a wide range of disorders and behaviors, it could be a particularly useful treatment for people with major psychiatric disorders, such as bipolar disorder or schizophrenia, with co-occurring substance abuse.
Deaths from opiate abuse are occurring in the US at about the same rate as automobile fatalities. At a recent talk, researcher Richard Ries discussed treatment of opiate addictions and the current epidemic of unintended opiate overdoses. Most opiates being abused come from other people’s leftover prescriptions. The best way to prevent opiate abuse is to throw out unused painkillers when they are no longer needed.
Many overdoses from opiates also involve alcohol and benzodiazepines, which can contribute to breathing difficulties.
There are several treatments available that can help patients abstain from using opiates. Treatment with opioid receptor antagonists (such as naltrexone (Rivia or long-acting Vivitrol, which is taken as an injection and lasts for 1 month), partial agonists (like buprenorphine), or full agonists (like methadone) results in, on average, an 80% decrease in the rate of hospitalization and an 80% reduction in crime, as well as a marked decrease in AIDS transmission. Without treatment, it is very difficult for people with opiate addictions to maintain abstinence, and relapse rates are extraordinarily high.
Treatment of Alcohol Abuse and Benzodiazepines
Ries also discussed data on treatment of alcohol abuse. He emphasizes that some aspects of withdrawal, such as sleep disturbance, can last a month or more after a parient’s last drink, putting the patient at high risk for relapse. Gabapentin, which is most often prescribed to prevent seizures, helps patients with this phase. Ries endorsed the combination of gabapentin and naltrexone as especially helpful. Carbamazepine is widely used in Europe for the treatment of alcohol abuse, and Ries also strongly endorsed the drug as another way of avoiding benzodiazepines. Several large placebo-controlled trials suggest that the anticonvulsant topiramate is also effective for long-term alcohol avoidance.
Editor’s Note: Another researcher, Mark Frye, found that women with bipolar disorder are more than seven times more likely than women in the general population to abuse alcohol, often in an attempt to self medicate their residual anxiety and depression. Excellent treatment of mood in bipolar disorder may have the double benefit of helping patients avoid alcohol abuse. The nutritional supplement n-acetylcysteine (NAC) also helps improve mood in bipolar disorder and has positive placebo-controlled data in heroin, cocaine, and alcohol avoidance.
It appears that the nutritional supplement n-acetylcysteine (NAC) may be useful for people who want to quit smoking. Researcher Eduardo S. T. Prado et al. reported that compared to placebo, NAC decreased the number of cigarettes a patient smoked per day and the amount of carbon monoxide they exhaled. Participants in the study took 1,500mg of NAC twice a day.
Editor’s Note: It looks as though NAC is effective in most addictions, including gambling, cocaine, heroin, marijuana, alcohol, and now smoking. Since it also helps depressed mood and anxiety in patients with bipolar illness (a finding first reported by researcher Michael Berk et al. in 2008), and can improve trichotillomania and obsessive compulsive disorder (OCD), it could be an important adjunctive treatment for many patients with bipolar illness who also suffer from many of these comorbidities. The usual dose in most of these studies was 500mg twice a day for one week, then 1,000mg twice a day thereafter, as opposed to the doses of 1,500mg twice a day that were used in the smoking study.
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.
In last week’s article we discussed how fearful memories can be changed during the window in which they are reconsolidated (5 minutes to 1 hour after active recall of the long-term memory). Now the memory reconsolidation window has been used in animals and people to extinguish an addiction to cocaine or heroin. The results in humans were reported by Xue et al. in the journal Science in April 2012.
In a typical recovery scenario, a cocaine addict is repeatedly presented cocaine cues (such as paraphernalia) without the delivery of cocaine, and craving for cocaine becomes extinguished. While the patient stops craving the drug, some biological signs of the addiction remain, such as autonomic hyper-reactivity (e.g. changes in skin conductance, pulse, or blood pressure) in response to the cocaine cues. When the sober cocaine addict leaves the recovery program, he may believe he is no longer subject to cocaine craving even upon the sight of cocaine-related cues, but this craving can return spontaneously or be reactivated by cocaine-related environments or friends who were also users, and he typically relapses.
In order to make the extinction learning more powerful, it must be experienced during the reconsolidation window. In the animal experiments by Xue et al., rodents were trained to press a lever to receive an injection of cocaine or heroin. In the extinction process, the animals were returned for 15 minutes to the same environment where they had learned to press the lever and receive the drug. This was meant to activate memories associated with the drug. Then, after a 10-minute waiting period, a 180-minute extinction training was given. The process was repeated daily for 14 days and resulted in almost complete absence of relapse to drug use with passage of time (spontaneous recovery), exposure to the drug (reinstatement), or exposure to the drug-associated environment (renewal). Moreover, the expected changes in heart rate and blood pressure upon re-exposure to the drug cues were also fully extinguished. Extinction training that began one hour after activation of the memory was also successful.
When the same extinction training was given 6 hours after placing the animal in the drug administration environment, the animal remained prone to drug re-instatement and relapse in the same or different environments or spontaneously. It can be presumed that this occurred because the extinction training took place after the reconsolidation window had closed.
These well-controlled data with both cocaine and heroin self-administration in animals were then taken to the clinic to test their validity in humans.
The same procedure worked in humans addicted to heroin. Two consecutive days of sixty-minute extinction learning within the reconsolidation window, i.e. starting 10 minutes after a 5-minute retrieval of drug-associated memories by watching a video resulted in amelioration of drug craving for at least 184 days, and amazingly, as in the animals, also resulted in the loss of the unconscious biological reactivity in heart rate and to a lesser extent, blood pressure. Patients did not relapse during 6 months of followup. The same extinction process was unsuccessful when it occurred outside of the reconsolidation window, i.e. 6 hours after retrieving the drug-related memories.
Editor’s Note: These results could be of considerable potential therapeutic value in a variety of psychiatric illnesses. This process is conceptual breakthrough that has great promise for clinical use. Psychiatrists, psychologists, and patients should become familiar with these data and the principles of exploiting the reconsolidation window for potentially transformational results.
How quickly these principles can be incorporated into mainstream psychotherapeutic encounters remains to be seen. However, clinicians should begin to familiarize themselves with these data and concepts so that they can soon be put to use for more effective clinical treatment of psychiatric conditions involving pathological learning, conditioning, and habits.
N-acetylcysteine (NAC), a readily available substance from health food stores, is able to reestablish glutamate homeostasis (regulation and balance) in the reward area of brain (the nucleus accumbens), reported Peter Kalivas of the University of South Carolina at the “Staging neuropsychiatric disorders: Implications for idiopathogenesis and treatment” meeting in Mojacar, Spain this past November. Kalivas reported that NAC appears to be effective across a spectrum of addictions, including cocaine, heroin, alcohol, cigarette smoking, and gambling.
Even more remarkably, NAC also appears to have positive effects in placebo-controlled studies in the treatment of patients with bipolar illness, report Mike Berk and colleagues, who are studying the same substance in Australia. Compared with placebo, patients taking adjunctive NAC showed improvement in all outcome measures, especially depression, after 3 and 6 months. In another article, also published in Biological Psychiatry in 2008, Berk’s research group demonstrated that NAC improved some negative symptoms of schizophrenia. NAC has also shown positive effects in trichotillomania and on nail-biting, suggesting that it has a variety of potential clinical uses in conditions associated with pathological compulsive behavioral patterns.