Chronic Cocaine Users Research Articles

Neural mechanisms of extinguishing drug and pleasant cue associations in human addiction: role of the VMPFC.

The neurobiological mechanisms that underlie the resistance of drug cue associations to extinction in addiction remain unknown. Fear extinction critically depends on the ventromedial prefrontal cortex (VMPFC). Here, we tested if this same region plays a role in extinction of non-fear, drug and pleasant cue associations. Eighteen chronic cocaine users and 15 matched controls completed three functional MRI scans. Participants first learned to associate an abstract cue (the conditioned stimulus, CS) with a drug-related (CSD+ ) or pleasant (CSP+ ) image. Extinction immediately followed where each CS was repeatedly presented without the corresponding image. Participants underwent a second identical session 24hours later to assess retention of extinction learning. Results showed that like fear extinction, non-fear-based extinction relies on the VMPFC. However, extinction-related changes in the VMPFC differed by cue valence and diagnosis. In controls, VMPFC activation to the CSD+ (which was unpleasant for participants) gradually increased as in fear extinction, while it decreased to the CSP+ , consistent with a more general role of the VMPFC in flexible value updating. Supporting a specific role in extinction retention, we further observed a cross-day association between VMPFC activation and skin conductance, a classic index of conditioned responses. Finally, cocaine users showed VMPFC abnormalities for both CSs, which, in the case of the CSD+ , correlated with craving. These data suggest a global deficit in extinction learning in this group that may hinder extinction-based treatment efforts. More broadly, these data show that the VMPFC, when functionally intact, supports extinction learning in diverse contexts in humans.

Cocaine and coronary artery diseases: a systematic review of the literature.

Cocaine is associated with important cardiac complications such as sudden death, acute myocarditis, dilated cardiomyopathy, life-threatening arrhythmias, and myocardial ischemia as well as infarction. It is well known that cocaine may induce vasospasm through adrenergic stimulation of the coronary arteries. Moreover, cocaine may promote intracoronary thrombosis, triggered by alterations in the plasma constituents, and platelet aggregation, leading to subsequent myocardial infarction. The long-term use of cocaine may stimulate atherosclerosis, probably through endothelial cell dysfunction. Significant and severe coronary atherosclerosis is common in young chronic cocaine users and there is probably a relationship between the duration and frequency of cocaine use and the extent of coronary disease.

Erratum: Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny

This corrects the article DOI: 10.1038/mp.2017.8.

Coronary Plaque Progression and Regression in Asymptomatic African American Chronic Cocaine Users With Obstructive Coronary Stenoses: A Preliminary Study.

Although rapid progression of coronary atherosclerosis was observed in chronic cocaine users, it is unknown whether reduced cocaine use retards the progression of atherosclerosis. We investigated whether reduced cocaine use over a 12-month period was associated with coronary plaque regression in cocaine users. Fifteen African American chronic cocaine users with previously coronary computed tomography angiography (CCTA)-confirmed >50% coronary stenosis in Baltimore, Maryland, were enrolled in a study to investigate whether reduced cocaine use is associated with changes in coronary plaque burden over a 12-month period of cash-based incentive intervention, which was implemented to systematically reinforce cocaine abstinence. In addition to previous CCTA (preintervention), CCTA was performed at the intervention baseline and at postintervention. Plaque analyses were performed to determine the trajectory of plaque changes in the absence of intervention by comparing the preintervention with the intervention baseline studies; the trajectory of plaque changes associated with the intervention by comparing the intervention baseline with the postintervention studies; and (3) whether reduced cocaine use was independently associated with changes in coronary plaque burden. During the 12-month cash-based incentive intervention period, cocaine use in participants was lower. The medians of noncalcified plaque indices were 37.8 (interquartile range [IQR] 29.3-44.0), 43.1 (IQR 38.3-49.0), and 38.7 (IQR 31.2-46.8) mm at preintervention, intervention baseline, and postintervention, respectively. Multivariable generalized estimating equation analysis showed that both total plaque and noncalcified plaque indices at preintervention were significantly lowered as compared with intervention baseline levels; both total plaque and noncalcified plaque indices after intervention were significantly lowered as compared with intervention baseline levels; and reduced cocaine use was independently associated with lower total plaque volume index (P < 0.0001) and noncalcified plaque volume index (P = 0.010). Our findings suggest that continued cocaine use may be associated with noncalcified plaque progression, whereas reduced cocaine use may be associated with noncalcified plaque regression. Larger studies are needed to confirm these findings.

Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny.

Paternal environmental perturbations including exposure to drugs of abuse can produce profound effects on the physiology and behavior of offspring via epigenetic modifications. Here we show that adult drug-naive male offspring of cocaine-exposed sires have memory formation deficits and associated reductions in NMDA receptor-mediated hippocampal synaptic plasticity. Reduced levels of the endogenous NMDA receptor co-agonist d-serine were accompanied by increased expression of the d-serine degrading enzyme d-amino acid oxidase (Dao1) in the hippocampus of cocaine-sired male progeny. Increased Dao1 transcription was associated with enrichment of permissive epigenetic marks on histone proteins in the hippocampus of male cocaine-sired progeny, some of which were enhanced near the Dao1 locus. Finally, hippocampal administration of d-serine reversed both the memory formation and synaptic plasticity deficits. Collectively, these results demonstrate that paternal cocaine exposure produces epigenetic remodeling in the hippocampus leading to NMDA receptor-dependent memory formation and synaptic plasticity impairments only in male progeny, which has significant implications for the male descendants of chronic cocaine users.

The effect of task difficulty on motor performance and frontal-striatal connectivity in cocaine users

BackgroundThere is growing recognition that chronic cocaine users have alterations in sensorimotor control that are positively related to low frontal-striatal connectivity within the motor system. These frontal-striatal motor circuits however, are modulated by circuits governing attention, which are also disrupted in cocaine users. This study’s aim was to determine if sensorimotor control deficits are positively related to the difficulty of a motor task or exist independent of the increasing cognitive demand. MethodsFunctional MRI data was collected from 40 individuals (20 non-treatment seeking chronic cocaine users, 20 age and gender matched non-drug using controls) as they mimicked an unpredictable finger-tapping sequence at various speeds. Dependent measures included task accuracy, percent BOLD signal change in sensorimotor regions of interest (ROIs), and functional connectivity (temporal correlations) between ROIs. ResultsIn both groups, as speed increased, the BOLD signal change increased in the primary motor cortex, supplementary motor area (SMA), cerebellum, and anterior cingulate cortex. Compared to controls, cocaine user SMA-Caudate and ACC-Putamen connectivity was lower at all speeds in the contralateral hemisphere. Furthermore, as speed increased there was a decrease in connectivity between additional ROI pairs among users. ConclusionsThese data support previous observations of sensorimotor performance deficits and dorsal frontal-striatal connectivity impairments among cocaine users. While previous studies demonstrate these deficits when performing a finger-tapping task at a single speed, we show that these same impairments exist at multiple levels of task difficulty. These data suggest that previously observed frontal-striatal connectivity in cocaine users during sensorimotor task performance are stable and not directly related to cognitive demands of the task.

Modeling Causal Relationships among Brain Areas in the Mesocorticolimbic System during Resting-State in Cocaine Users Utilizing a Graph Theoretic Approach.

ObjectiveWhile effective connectivity (EC, causal interaction) between brain areas has been investigated in chronic users of cocaine as they view cocaine pictures cues, no study has examined EC while they take part in a resting-state scan. This resting-state fMRI study aims to investigate the causal interaction among brain areas in the mesocorticolimbic system (MCLS), which is involved in reward and motivation, in cocaine users (vs. controls).MethodTwenty cocaine users and 17 healthy controls finished a structural and a resting-state scan. Mean voxel-based time series data were obtained from brain regions of interest (ROIs) from the MCLS, and were input into a Bayesian search algorithm called IMaGES.ResultsThe causal interaction pattern was different between the two groups. The feed-forward pattern found in cocaine smokers, between 7 ROIs of the MCLS during resting-state [ventral tegmental area (VTA)→hippocampus (HIPP)→ventral striatum (VenStri)→orbital frontal cortex (OFC), medial frontal cortex (MFC), anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC)], was absent in controls. That is, the subcortical VenStri area had a causal influence on four cortical brain areas only in cocaine users.ConclusionsDuring the resting-state scan, the VTA of cocaine smokers abstinent for at least 72 hours, but not controls, begins causal connections to limbic, midbrain, and frontal regions in the MCLS in a feed-forward manner. Following replication, further studies may assess if changes over time in EC during resting-state predict cocaine treatment efficacy and outcome.

Sleep Perception and Misperception in Chronic Cocaine Users During Abstinence.

During abstinence, chronic cocaine users experience an objective worsening of sleep that is perceived as qualitatively improving. This phenomenon has been termed "occult insomnia." The objective of this study was to determine whether chronic cocaine users experience positive sleep state misperception during abstinence. Forty-three cocaine-dependent persons were admitted to an inpatient research facility for 12 days and 11 nights to participate in a treatment study of modafinil. Polysomnographic sleep recordings were performed on study nights 3, 4, 10, and 11, when participants were on average 1 and 2 weeks abstinent from cocaine. Participants also completed sleep diary questionnaires every evening before bed and every morning upon awakening. Polysomnographic and sleep diary measurements of total sleep time, sleep latency, time awake after sleep onset, and time in bed after final awakening were compared. Chronic cocaine users accurately reported total sleep time after 1 week of abstinence but overreported total sleep time by an average of 40 min after 2 weeks of abstinence. Underestimating sleep latency and time spent awake after sleep onset were responsible for this difference. Positive sleep state misperception is revealed in chronic cocaine users after 2 weeks of abstinence and is consistent with the previously identified "occult insomnia" in this population.

Effective Connectivity within the Mesocorticolimbic System during Resting-State in Cocaine Users.

Objective: Although effective connectivity between brain regions has been examined in cocaine users during tasks, no effective connectivity study has been conducted on cocaine users during resting-state. In the present functional magnetic resonance imaging study, we examined effective connectivity in resting-brain, between the brain regions within the mesocorticolimbic dopamine system, implicated in reward and motivated behavior, while the chronic cocaine users and controls took part in a resting-state scan by using a spectral Dynamic causal modeling (spDCM) approach.Method: As part of a study testing cocaine cue reactivity in cocaine users (Ray et al., 2015b), 20 non-treatment seeking cocaine-smoking (abstinent for at least 3 days) and 17 control participants completed a resting state scan and an anatomical scan. A mean voxel-based time series data extracted from four key brain areas (ventral tegmental area, VTA; nucleus accumbens, NAc; hippocampus, medial frontal cortex) within the mesocorticolimbic dopamine system during resting-state from the cocaine and control participants were used as input to the spDCM program to generate spDCM analysis outputs.Results: Compared to the control group, the cocaine group had higher effective connectivity from the VTA to NAc, hippocampus and medial frontal cortex. In contrast, the control group showed a higher effective connectivity from the medial frontal cortex to VTA, from the NAc to medial frontal cortex, and on the hippocampus self-loop.Conclusions: The present study is the first to show that during resting-state in abstaining cocaine users compared to controls, the VTA initiates an enhanced effective connectivity to NAc, hippocampus and medial frontal cortex areas within the mesocorticolimbic dopamine system, the brain’s reward system. Future studies of effective connectivity analysis during resting-state may eventually be used to monitor treatment outcome.

Mobilization of Medial and Lateral Frontal-Striatal Circuits in Cocaine Users and Controls: An Interleaved TMS/BOLD Functional Connectivity Study.

The integrity of frontal-striatal circuits is an area of great interest in substance dependence literature, particularly as the field begins to develop neural circuit-specific brain stimulation treatments for these individuals. Prior research indicates that frontal-striatal connectivity is disrupted in chronic cocaine users in a baseline (resting) state. It is unclear, however, if this is also true when these circuits are mobilized by an external source. In this study, we measured the functional and structural integrity of frontal-striatal circuitry involved in limbic arousal and executive control in 36 individuals-18 cocaine-dependent individuals with a history of failed quit attempts and 18 age-matched controls. This was achieved by applying a transcranial magnetic stimulation to the medial prefrontal cortex (Brodmann area 10) and the dorsolateral prefrontal cortex (lateral Brodmann 9) while participants rested in the MRI scanner (TMS/BOLD imaging). Relative to the controls, cocaine users had a lower ventral striatal BOLD response to MPFC stimulation. The dorsal striatal BOLD response to DLPFC stimulation however was not significantly different between the groups. Among controls, DLPFC stimulation led to a reciprocal attenuation of MPFC activity (BA 10), but this pattern did not exist in cocaine users. No relationship was found between regional diffusion metrics and functional activity. Considered together these data suggest that, when engaged, cocaine users can mobilize their executive control system similar to controls, but that the 'set point' for mobilizing their limbic arousal system has been elevated-an interpretation consistent with opponent process theories of addiction.

OC10_01 Analysis of Small Intramyocardial Vessels of the Heart in Chronic Cocaine Users After Sudden Death

OC10_01 Analysis of Small Intramyocardial Vessels of the Heart in Chronic Cocaine Users After Sudden Death

Risky Decisions in a Lottery Task Are Associated with an Increase of Cocaine Use.

Cocaine use disorder is associated with maladaptive decision-making behavior, which strongly contributes to the harmful consequences of chronic drug use. Prior research has shown that cocaine users exhibit impaired neuropsychological test performances, particularly with regard to attention, learning, and memory but also in executive functions such as decision-making and impulse control. However, to what extent cocaine users show impaired decision-making under risk without feedback has not yet been investigated systematically. Therefore, to examine risk-taking behavior, 31 chronic cocaine users and 26 stimulant-naïve healthy controls who were part of the Zurich Cocaine Cognition Study, performed the Randomized Lottery Task (RALT) with winning lotteries consisting of an uncertain and a certain prospect. Results revealed that risky decisions were associated with male sex, increased cocaine use in the past year, higher cocaine concentrations in the hair, and younger age. In addition, higher levels of cocaine in the hair and cumulative lifetime consumption were associated with risky decisions, whereas potentially confounding factors including cognition and psychiatric symptoms had no significant effect. Taken together, our results indicate that cocaine users who increased their consumption over a period of 1 year show deficits in the processing of risky information accompanied with increased risk-taking. Future research should analyse whether risky decisions could potentially serve as a prognostic marker for cocaine use disorder.

Shared neural basis of social and non-social reward deficits in chronic cocaine users.

Changed reward functions have been proposed as a core feature of stimulant addiction, typically observed as reduced neural responses to non-drug-related rewards. However, it was unclear yet how specific this deficit is for different types of non-drug rewards arising from social and non-social reinforcements. We used functional neuroimaging in cocaine users to investigate explicit social reward as modeled by agreement of music preferences with music experts. In addition, we investigated non-social reward as modeled by winning desired music pieces. The study included 17 chronic cocaine users and 17 matched stimulant-naive healthy controls. Cocaine users, compared with controls, showed blunted neural responses to both social and non-social reward. Activation differences were located in the ventromedial prefrontal cortex overlapping for both reward types and, thus, suggesting a non-specific deficit in the processing of non-drug rewards. Interestingly, in the posterior lateral orbitofrontal cortex, social reward responses of cocaine users decreased with the degree to which they were influenced by social feedback from the experts, a response pattern that was opposite to that observed in healthy controls. The present results suggest that cocaine users likely suffer from a generalized impairment in value representation as well as from an aberrant processing of social feedback.

HIV Infection Itself May Not Be Associated With Subclinical Coronary Artery Disease Among African Americans Without Cardiovascular Symptoms.

BackgroundThe key objectives of this study were to examine whether HIV infection itself is associated with subclinical coronary atherosclerosis and the potential contributions of cocaine use and antiretroviral therapies (ARTs) to subclinical coronary artery disease (CAD) in HIV‐infected persons.Methods and ResultsBetween June 2004 and February 2015, 1429 African American (AA) adults with/without HIV infection in Baltimore, Maryland, were enrolled in an observational study of the effects of HIV infection, exposure to ART, and cocaine use on subclinical CAD. The prevalence of subclinical coronary atherosclerosis was 30.0% in HIV‐uninfected and 33.7% in HIV‐infected (P=0.17). Stratified analyses revealed that compared to HIV‐uninfected, HIV‐infected ART naïve were at significantly lower risk for subclinical coronary atherosclerosis, whereas HIV‐infected long‐term ART users (≥36 months) were at significantly higher risk. Thus, an overall nonsignificant association between subclinical coronary atherosclerosis and HIV was found. Furthermore, compared to those who were ART naïve, long‐term ART users (≥36 months) were at significantly higher risk for subclinical coronary atherosclerosis in chronic cocaine users, but not in those who never used cocaine. Cocaine use was independently associated with subclinical coronary atherosclerosis.ConclusionsOverall, HIV infection, per se, was not associated with subclinical coronary atherosclerosis in this population. Cocaine use was prevalent in both HIV‐infected and ‐uninfected individuals and itself was associated with subclinical disease. In addition, cocaine significantly elevated the risk for ART‐associated subclinical coronary atherosclerosis. Treating cocaine addiction must be a high priority for managing HIV disease and preventing HIV/ART‐associated subclinical and clinical CAD in individuals with HIV infection.

Modafinil and sleep architecture in an inpatient–outpatient treatment study of cocaine dependence

ObjectiveTo determine whether the increase in slow-wave sleep associated with modafinil treatment in chronic cocaine users mediates improved clinical outcomes. Method57 cocaine dependent participants were randomized to receive modafinil 400mg or placebo daily during a period of inpatient treatment followed by six weeks of outpatient treatment. Participants underwent polysomnographic sleep recording during inpatient treatment prior to and after starting modafinil. Outpatient treatment consisted of weekly cognitive behavioral therapy. Contingency management was used to promote participation in treatment and research demands, including thrice weekly visits during the outpatient phase for urine toxicology screens and other assessments. The primary clinical outcome was the percent of urine toxicology screens that were negative for cocaine. ResultsModafinil treatment was associated with a higher mean percentage (52% vs. 26%) of cocaine-free urine screens (p=0.02) and an increase in N3 sleep time (p=0.002). The change in N3 sleep time mediated the higher rate of cocaine-free urine screens. Modafinil treatment was also associated with more consecutive days abstinent during outpatient treatment, greater survival of abstinence, higher daily rates of abstinence, and less sleep degradation typically associated with abstinence from chronic cocaine use. ConclusionsMorning-dosed modafinil improves slow-wave sleep in abstinent cocaine users in the inpatient setting, and this effect is a statistical mediator of improved clinical outcomes associated with continued modafinil treatment. The high rates of abstinence achieved in this trial suggest that promoting healthy sleep physiology in an inpatient setting may be important in the effective treatment of cocaine dependence.

Directed forgetting of memories in cocaine users.

Memory retrieval requires an effective recruitment of inhibitory control to successfully reject unnecessary memories. The use of cocaine is associated with poor cognitive control processes, but little is known about the impact of chronic and recreational use of cocaine on inhibitory control during intentional forgetting. We studied whether chronic and recreational users of cocaine show impairments on the mechanism responsible for intentional forgetting of memories. Two experiments were carried out on chronic cocaine users in rehabilitation (Experiment 1) and recreational cocaine polydrug users (Experiment 2) performing a directed forgetting (DF) task, an index of memory suppression. Participants were matched for sex, age, and intelligence (Raven's standard progressive matrices) with cocaine-free controls and compared on their performance on a DF procedure. Chronic cocaine users in rehabilitation and recreational cocaine polydrug users, as compared with controls, were not able to intentionally suppress the required information and they did not show a reliable DF effect. The consumption of cocaine appears to alter the control processes implicated in intentional suppression of nonrelevant memories in episodic memory. The use of cocaine, even for recreational purposes, seems to be associated with poor performance in effectively triggering this control mechanism. The inability to suppress interference in declarative memory may have repercussion for daily activities. (PsycINFO Database Record

Effects of Alcohol in Chronic Cocaine Abuse: A Follow Up Study

Alcohol is the substance most commonly abused in combination with cocaine. The present study sought to investigate the possible influence of alcohol abuse in memory improvement during abstinence among chronic cocaine users. Fortyeight subjects were selected and grouped as either cocaine only abusers (COC) or cocaine and alcohol abusers (CA). All subjects were undergoing treatment at a south Florida area residential drug rehabilitation program at the time of testing. Participants were tested at the second week of abstinence (early abstinence) and retested at 2 months (late abstinence). Findings demonstrated that cocaine participants exhibited a similar memory recovery profile in short term memory tasks independently of their history of alcohol abuse. However, significant group differences emerged in delayed memory tasks. On the Rey-Osterrieth Complex Figure (ROCF) delayed memory test the CA group performed significantly worse than the COC group with significantly less improvement in scores during abstinence as well. The reduced score enhancement during abstinence in the CA group was also observed in the California Verbal Learning Test (CVLT) delayed memory variables. The present study suggests that the use of alcohol in combination with cocaine may have an effect on memory recovery with specific impact over longterm memory tasks. These findings may have important treatment implications.

Biomarkers for Success: Using Neuroimaging to Predict Relapse and Develop Brain Stimulation Treatments for Cocaine-Dependent Individuals.

Cocaine dependence is one of the most difficult substance use disorders to treat. While the powerful effects of cocaine use on behavior were documented in the 19th century, it was not until the late 20th century that we realized cocaine use was affecting brain tissue and function. Following a brief introduction (Section 1), this chapter will summarize our current knowledge regarding alterations in neural circuit function typically observed in chronic cocaine users (Section 2) and highlight an emerging body of literature which suggests that pretreatment limbic circuit activity may be a reliable predictor of clinical outcomes among individuals seeking treatment for cocaine (Section 3). Finally, as the field of addiction research strives to translate this neuroimaging data into something clinically meaningful, we will highlight several new brain stimulation approaches which utilize functional brain imaging data to design noninvasive brain stimulation interventions for individuals seeking treatment for substance dependence disorders (Section 4).

Sleep Regulates Incubation of Cocaine Craving.

After withdrawal from cocaine, chronic cocaine users often experience persistent reduction in total sleep time, which is accompanied by increased sleep fragmentation resembling chronic insomnia. This and other sleep abnormalities have long been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here, we report that after prolonged withdrawal from cocaine self-administration, rats exhibited persistent reduction in nonrapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep, as well as increased sleep fragmentation. In an attempt to improve sleep after cocaine withdrawal, we applied chronic sleep restriction to the rats during their active (dark) phase of the day, which selectively decreased the fragmentation of REM sleep during their inactive (light) phase without changing NREM or the total amount of daily sleep. Animals with improved REM sleep exhibited decreased incubation of cocaine craving, a phenomenon depicting the progressive intensification of cocaine seeking after withdrawal. In contrast, experimentally increasing sleep fragmentation after cocaine self-administration expedited the development of incubation of cocaine craving. Incubation of cocaine craving is partially mediated by progressive accumulation of calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). After withdrawal from cocaine, animals with improved REM sleep exhibited reduced accumulation of CP-AMPARs in the NAc, whereas increasing sleep fragmentation accelerated NAc CP-AMPAR accumulation. These results reveal a potential molecular substrate that can be engaged by sleep to regulate cocaine craving and relapse, and demonstrate sleep-based therapeutic opportunities for cocaine addiction. Significance statement: Sleep abnormalities are common symptoms in chronic drug users long after drug withdrawal. These withdrawal-associated sleep symptoms, particularly reduction in total sleep time and deteriorating sleep quality, have been speculated to foster relapse and further drug addiction, but direct evidence is lacking. Here we show in rats that the sleep pattern was persistently changed long after withdrawal from cocaine self-administration, and demonstrate that sleep interventions can bidirectionally regulate cocaine craving and seeking after withdrawal. We further demonstrate that glutamatergic synapses in the nucleus accumbens are potential neuronal targets for sleep intervention to influence cocaine craving after withdrawal. These results provide a strong rationale supporting sleep-based therapies for cocaine addiction.

O036. Cocaine and headache: a 2-year follow-up study in chronic cocaine users and literature review.

As many as 14-21 million people worldwide (0.3-0.5% of the population, aged 15-65 years) use cocaine [1]. In Europe, cocaine consumption has shown a 2- to 3-fold increase during the last 2 decades [2,3]; in Italy, lifetime cocaine experience among adults corresponds to 6.6% [4]. Cocaine use and headache share some common characteristics: present heavy global burden, prevail among young individuals, cause more severe consequences in females, may lead to emergency department access and progress to chronification. The study of headache in chronic cocaine users (CCU) is of interest also from a pathophysiological point of view, given that chronic cocaine use causes decreased dopamine and serotonin synaptic levels, a typical migraine biochemical feature (“empty neuron” condition) [5,6]. In a previous study we encouraged clinicians to carry out a more in-depth investigation on cocaine use in all headache suffers, especially those with migraine, as headache occurs in a very high proportion of CCU (90%), mostly showing migraine or migraine-like characteristics, while cocaine-induced headache, as classified by the ICHD criteria [7], seems exceedingly rare (2.2%). Moreover, we pointed out that CCU sometimes use cocaine as an acute remedy for the headache attack, even though improvement occurs very rarely (17.2% of cases) [8]. Recently, it has been described that patients with intractable cluster headache who tried cocaine, being dissatisfied with conventional treatments in terms of efficacy and/or tolerability, referred a full or partial improvement in 30.8% of cases [9]. The present study was aimed to evaluate the modification of the clinical characteristics of headache in CCU after a 2-year follow-up period. We contacted by phone the 80 patients previously enrolled [8] attending the Cocaine Addiction Service of the Drug Addiction Service, 20th District, Rome. Of these 80 patients, 60 (still followed by the Drug Addiction Service) were enrolled and interviewed by the same physicians of the previous study. We studied the modifications of headache pattern and characteristics relative to their actual cocaine consumption in CCU patients previously subdivided into 3 groups: neither lifetime nor current headache (group 0); lifetime and current headache (group 1); and de novo headache, i.e. individuals in whom headache developed only after cocaine use began (group 2). The correlation between headache and cocaine is controversial and still understimated. Written informed consent to publish was obtained from the patient(s).