Alcohol Addiction Relapse Might Be Thwarted By Turning Off Brain Trigger
Researchers at the Ernest Gallo Clinic and Research Center at UC San Francisco have been able to identify and deactivate a brain pathway linked to memories that cause alcohol cravings in rats, a finding that may one day lead to a treatment option for people who suffer from alcohol abuse disorders and other addictions.
In the study, researchers were able to prevent the addicted animals from seeking alcohol and drinking it, the equivalent of relapse.
“One of the main causes of relapse is craving, triggered by the memory by certain cues – going into a bar, or the smell or taste of alcohol,” said lead author Segev Barak, PhD, at the time a postdoctoral fellow in the lab of co-senior author Dorit Ron, PhD, a Gallo Center investigator and UCSF professor of neurology.
“We learned that when rats were exposed to the smell or taste of alcohol, there was a small window of opportunity to target the area of the brain that reconsolidates the memory of the craving for alcohol and to weaken or even erase the memory, and thus the craving” he said.
The study, also supervised by co-senior author Patricia H. Janak, PhD, a Gallo Center investigator and UCSF professor of neurology, was published online on June 23 in Nature Neuroscience.
Neural Mechanism That Triggers Alcohol Memory
In the first phase of the study, rats had the choice to freely drink water or alcohol over the course of seven weeks, and during this time developed a high preference for alcohol.
Segev Barak, PhD
In the next phase, they had the opportunity to access alcohol for one hour a day, which they learned to do by pressing a lever. They were then put through a 10-day period of abstinence from alcohol.
Following this period, the animals were exposed for five minutes to just the smell and taste of alcohol, which cued them to remember how much they d drinking it.
The researchers then scanned the animals’ brains, and identified the neural mechanism responsible for the reactivation of the memory of the alcohol – a molecular pathway mediated by an enzyme known as mammalian target of rapamycin complex 1 (mTORC1).
They found that just a small drop of alcohol presented to the rats turned on the mTORC1 pathway specifically in a select region of the amygdala, a structure linked to emotional reactions and withdrawal from alcohol, and cortical regions involved in memory processing.
They further showed that once mTORC1 was activated, the alcohol-memory stabilized (reconsolidated) and the rats relapsed on the following days, meaning in this case, that they started again to push the lever to dispense more alcohol.
“The smell and taste of alcohol were such strong cues that we could target the memory specifically without impacting other memories, such as a craving for sugar,” said Barak, who added that the Ron research group has been doing brain studies for many years and has never seen such a robust and specific activation in the brain.
Drug that Erases the Memory of Alcohol
In the next part of the study, the researchers set out to see if they could prevent the reconsolidation of the memory of alcohol by inhibiting mTORC1, thus preventing relapse. When mTORC1 was inactivated using a drug called rapamycin, administered immediately after the exposure to the cue (smell, taste), there was no relapse to alcohol-seeking the next day.
Strikingly, drinking remained suppressed for up to 14 days, the end point of the study. These results suggest that rapamycin erased the memory of alcohol for a long period, said Ron.
The authors said the study is an important first step, but that more research is needed to determine how mTORC1 contributes to alcohol memory reconsolidation and whether turning off mTORC1 with rapamycin would prevent relapse for more than two weeks.
The authors also said it would be interesting to test if rapamycin, an FDA-approved drug currently used to prevent organ rejection after transplantation, or other mTORC1 inhibitors that are currently being developed in pharmaceutical companies, would prevent relapse in human alcoholics.
“One of the main problems in alcohol abuse disorders is relapse, and current treatment options are very limited.” Barak said. “Even after detoxification and a period of rehabilitation, 70 to 80 percent of patients will relapse in the first several years.
It is really thrilling that we were able to completely erase the memory of alcohol and prevent relapse in these animals.
This could be a revolution in treatment approaches for addiction, in terms of erasing unwanted memories and thereby manipulating the brain triggers that are so problematic for people with addictions.”
The other co-authors of the paper are Feng Liu, PhD, Sami Ben Hamida, PhD, Quinn V. Yowell, BS, Jeremie Neasta, PhD, and Viktor Kharazia, PhD, all of the Gallo Center and UCSF Department of Neurology.
The study was supported by funds from the National Institute on Alcohol Abuse and Alcoholism and funds from the State of California for Medical Research on Alcohol and Substance Abuse administered through UCSF.
The UCSF-affiliated Ernest Gallo Clinic and Research Center is one of the world’s preeminent academic centers for the study of the biological basis of alcohol and substance use disorders. Gallo Center discoveries of potential molecular targets for the development of therapeutic medications are extended through preclinical and proof-of-concept clinical studies.
Alcohol Craving Predicts Relapse After Residential Addiction Treatment
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Replicate the previously reported association of elevated alcohol craving, measured by Penn Alcohol Craving Scale (PACS) during residential treatment, with post-treatment relapse and explore whether elevated craving scores 3 months post-treatment are also associated with subsequent relapse.
Alcohol craving was assessed with the PACS on admission and at several time points post-treatment in 190 subjects with DSM-IV diagnosis of alcohol dependence admitted to residential treatment.
Data about relapse to any drinking (primary outcome measure) was collected at 3, 6, 9 and 12 months after treatment. Cox regression models were used to determine whether PACS scores were associated with relapse.
Statistical models were adjusted for meaningful demographic and clinical covariates.
Follow-up data was available for 149/190 (78%) of subjects. Elevated PACS scores at discharge were associated with increased relapse risk within the first 3 and 12 months after discharge (P = 0.032 and P = 0.
045, respectively). Elevated PACS scores at 3 months were associated with increased risk of subsequent relapse within 12 months after treatment in contacted subjects (P = 0.034) and in the intent-to-treat analysis (P = 0.
Our findings indicate strong association of post-treatment relapse with elevated alcohol craving measured at treatment completion and at 3 months after treatment and justify the use of this measure to guide relapse-prevention efforts.
Craving is a subjective motivational state experienced by alcohol and drug dependent individuals that precedes and may precipitate relapse in those pursuing abstinence (Sinha and O’Malley, 1999).
Craving is considered a clinically important concept, which allows prediction of relapse and constitutes a target for pharmacotherapy (Vukovic et al., 2008) (Mann, 2004) and psychotherapy interventions (Witkiewitz et al., 2011).
As such, it is an important part of the ICD-10 criteria for alcohol dependence (Vukovic et al., 2008) and the DSM-5 criteria for an alcohol use disorder (Murphy et al., 2014).
Craving is often conceptualized within the context of the three-pathway psychobiological model of reward, relief, and obsessive motives (Verheul et al., 1999).
These motives correspond to the core stages of addiction, including binge/intoxication (reward craving), withdrawal/negative affect (relief craving) and preoccupation/anticipation (obsessive craving) (Koob and Volkow, 2016). The Inventory of Drug Taking Situations (IDTS) (Turner et al.
, 1997) as well as 10-item Reward-Relief Drinking Scale (RRDS) (Mann and Nakovics, 2016) and the 20 item Craving Typology Questionnaire (CTQ) (Martinotti et al., 2013) were developed to distinguish between these craving types.
There are also several validated methods allowing measurement of craving intensity. These include the Yale Craving Scale (YCS), which examines craving for both cigarettes and alcohol (Rojewski et al.
, 2015), along with the more commonly used and seemingly better performing Obsessive-Compulsive Drinking Scale (OCDS), Alcohol Urge Questionnaire (AUQ) and Penn Alcohol Craving Scale (PACS) (Kavanagh et al., 2013). (Flannery et al., 2003).
In addition, efforts to streamline the administration of craving scales led to the development and validation of the 5-item MACE scale (Coates 2017), and a single item measure ‘Temptation to Drink’ was found predictive of multiple negative drinking outcomes for up to 3 years post-treatment in alcohol dependent subjects (Witkiewitz, 2013). Although there is no ‘gold standard’ to measure craving, the PACS and OCDS have been found to be among the better-performing measures compared to others (Flannery et al., 2003, Kavanagh et al., 2013).
Previous research associated increased alcohol craving with return to drinking after outpatient addiction treatment (Bottlender and Soyka, 2005) and worse clinical outcomes in several pharmacotherapy trials (Flannery et al., 1999, Ray et al., 2006).
Data from a large pharmacotherapy trial indicated that participation in cognitive behavioral modules targeting craving led to decreased negative mood and less heavy drinking days while in treatment (Witkiewitz et al., 2011).
In an analysis of the COMBINE data set, roughly half of the treatment-related increase in percent days abstinent (PDA) was attributed to reduction in cravings (Subbaraman et al., 2013). Increased craving was a significant predictor of return to any drinking during treatment in a CBT-based 3-month outpatient alcohol dependency treatment program (Law et al., 2016).
One other study suggested that alcohol craving is a predictor for same-day drinking rate in subjects with comorbid post-traumatic stress disorder (PTSD) (Browne et al., 2016), while another indicated that craving is a clinically relevant predictor of any drinking in the following week (McHugh et al., 2016).
We previously reported that elevated PACS scores at the time of residential treatment admission and discharge were associated with increased risk of post-treatment relapse in alcohol dependent subjects (Schneekloth et al., 2012).
In this study we attempted replication of our previous findings in a new sample and investigated whether craving intensity at 3 months after discharge (measured by the PACS) is also associated with risk of subsequent relapse to alcohol use.
Approval for this study was granted by the Institutional Review Board of the Mayo Clinic, Rochester. All subjects included in the study signed a HIPPA release form for retrospective research inclusion.
American Board of Psychiatry and Neurology (ABPN) certified addiction psychiatrists determined the diagnosis of alcohol dependence by DSM-IV criteria, or alcohol use disorder, moderate or severe, by DSM-V criteria for all included subjects.
All study participants completed a 30-day residential intensive addictions treatment program (IAP), which is a community-based program affiliated with Mayo Clinic in Rochester, Minnesota.
Daily programming consists of a variety of modalities including didactic groups with facilitated discussions, addiction process group therapy, family programming, co-occurring (addiction and other psychiatric disorder) groups, mindfulness training, CBT, 12-step facilitation and recreational therapy interventions.
Care is coordinated through psychiatrist-lead multi-disciplinary teams, which include licensed alcohol and drug counselors, social workers, chaplains, recreational therapists and nicotine counselors. Abstinence during treatment is verified through regular urine drug screens and breathalyzer tests.
Subjects are offered various pharmacotherapy options for alcohol cravings. After discharge, some patients attend formal aftercare outpatient programs, while some of them attend mutual help groups.
At the time of treatment admission, a chronological history of alcohol use was collected by a Licensed Alcohol and Drug Dependency Counselors (LADC) as a part of a standard clinical evaluation.
In addition, clinical data collection included standardized assessment of depressive symptoms with a Patient Health Questionnaire (PHQ-9) and anxiety symptoms with a Generalized Anxiety Disorder 7-item scale (GAD-7). Propensity to use alcohol in emotionally positive or negative situations (i.e.
context of craving triggers) was assessed using the Inventory of Drug (and alcohol) Taking Situations (IDTS); however, results of this assessment were not analyzed in the context of this study.
Participants also completed the PACS, which is a self-administered 5-item questionnaire that assesses frequency of cravings, the intensity of cravings at their most severe, time spent preoccupied with drinking, power of craving given easy access, and overall craving over the previous week. Scores range from 0 up to a maximum of 30 points (Flannery et al., 1999). PACS scores were assessed weekly during treatment and at program discharge.
Subjects entering our Intensive Addictions Program were also asked to voluntarily participate in outcome monitoring after dismissal.
Treatment outcome surveys were mailed to subjects at 3, 6, 9 and 12 months after dismissal. If there was not a timely response, subjects were contacted via telephone for collection of survey data.
Surveys included PACS and other clinically relevant measures, such as return to alcohol use and its severity.
Data analysis and statistics
The primary outcome measure was relapse by subject self-report at 3, 6, 9 and 12 months after treatment. We defined relapse as drinking of any quantity of alcohol during follow-up.
The primary predictor variable was alcohol craving intensity measured by PACS. Other predictor variables included the PHQ-9 scores upon admission and discharge, age at the start of regular drinking (as defined by drinking at least once per month for at least 6 months).
We examined subject relapse risk in three separate time frames. First, we attempted to replicate previous findings by Schneekloth et al. (2012) that examined relapse risk in the 12 months after treatment discharge.
Next, we examined factors contributing to relapse risk between treatment discharge and 3 months post-treatment. Finally, we looked from 3 months prospectively at risk for relapse in the subsequent 9 months post-treatment.
Primary analysis included subjects with available follow-up data or known post-discharge relapse prior to loss-to-follow-up.
Because a substantial proportion of subjects were lost to follow-up with unknown relapse status, we also conducted an intent-to-treat (ITT) analysis to avoid selection bias.
In the ITT analysis, subjects with unknown relapse status were considered relapsed to drinking the day following their last contact. Dichotomous PACS variables were examined to establish a threshold value that could be used clinically to guide relapse prevention efforts.
Time to alcohol relapse was assessed with univariate Cox proportional hazard models, where PACS scores and other demographic and clinical variables were considered as predictors. Multivariable Cox models were then examined using backwards stepwise selection for all predictors with univariate association P-values