A sub-set of psychoactive effects may be critical to the behavioral impact of ketamine on cocaine use disorder: Results from a randomized, controlled laboratory study.

Efforts to translate sub-anesthetic ketamine infusions into widespread clinical use have centered around developing medications with comparable neurobiological activity, but with attenuated psychoactive effects so as to minimize the risk of behavioral toxicity and abuse liability. Converging lines of research, however, suggest that some of the psychoactive effects of sub-anesthetic ketamine may have therapeutic potential. Here, we assess whether a subset of these effects - the so-called mystical-type experience - mediates the effect of ketamine on craving and cocaine use in cocaine dependent research volunteers. We found that ketamine leads to significantly greater acute mystical-type effects (by Hood Mysticism Scale: HMS), dissociation (by Clinician Administered Dissociative States Scale: CADSS), and near-death experience phenomena (by the Near-Death Experience Scale: NDES), relative to the active control midazolam. HMS score, but not the CADSS or NDES score, was found to mediate the effect of ketamine on global improvement (decreased cocaine use and craving) over the post-infusion period. This is the first controlled study to show that mystical-type phenomena, long considered to have therapeutic potential, may work to impact decision-making and behavior in a sustained manner. These data suggest that an important direction for medication development is the identification of ketamine-like pharmacotherapy that is selectively psychoactive (as opposed to free of experiential effects entirely), so that mystical-type perspectival shifts are more reliably produced and factors lending to abuse or behavioral impairment are minimized. Future research can further clarify the relationship between medication-occasioned mystical-type effects and clinical benefit for different disorders. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial.

Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Converging evidence suggests a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine may work to correct these neuroadaptations and restore motivation for non-drug rewards. Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs money later, we found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 h post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. These findings signal new directions in medication development for substance use disorders.

Therapeutic infusions of ketamine: do the psychoactive effects matter?

BACKGROUND: Sub-anesthetic ketamine infusions may benefit a variety of psychiatric disorders, including addiction. Though ketamine engenders transient alterations in consciousness, it is not known whether these alterations influence efficacy. This analysis evaluates the mystical-type effects of ketamine, which may have therapeutic potential according to prior research, and assesses whether these effects mediate improvements in dependence-related deficits, 24h postinfusion. METHODS: Eight cocaine dependent individuals completed this double-blind, randomized, inpatient study. Three counter-balanced infusions separated by 48h were received: lorazepam (2mg) and two doses of ketamine (0.41mg/kg and 0.71mg/kg, with the former dose always preceding the latter). Infusions were followed within 15min by measures of dissociation (Clinician Administered Dissociative Symptoms Scale: CADSS) and mystical-type effects (adapted from Hood's Mysticism Scale: HMS). At baseline and 24h postinfusion, participants underwent assessments of motivation to stop cocaine (University of Rhode Island Change Assessment) and cue-induced craving (by visual analogue scale for cocaine craving during cue exposure). RESULTS: Ketamine led to significantly greater acute mystical-type effects (by HMS) relative to the active control lorazepam; ketamine 0.71mg/kg was associated with significantly higher HMS scores than was the 0.41mg/kg dose. HMS score, but not CADSS score, was found to mediate the effect of ketamine on motivation to quit cocaine 24h postinfusion. CONCLUSIONS: These findings suggest that psychological mechanisms may be involved in some of the anti-addiction benefits resulting from ketamine. Future research can evaluate whether the psychoactive effects of ketamine influence improvements in larger samples.

Differential response to alcohol in light and moderate female social drinkers.

Individuals who are moderate drinkers are at increased risk to abuse alcohol. Moreover, women are more vulnerable than men to the adverse consequences of alcohol consumption and recent data indicate that the drinking pattern in women is becoming more similar to that of men. However, few studies have determined whether female moderate drinkers (MD) show a differential response to the subjective and performance effects of alcohol, compared to female light drinkers (LD). Fifteen female MD who consumed an average of 34.7 drinks/month were compared to 15 female LD who consumed an average of 6.7 drinks/month. None of the participants had a first-degree family history of alcoholism or substance abuse. The acute effects of alcohol (0, 0.25, 0.50, 0.75 mg/kg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using a full range of performance measures, subjective-effects questionnaires and observer ratings. Alcohol impaired performance in a dose-related manner on all performance tasks for both groups of females. However, MD were less impaired than LD on balance and Digit Symbol Substitution Test (DSST). This reduced response was also evident from the observer ratings, with MD being viewed as less impaired by alcohol than LD. While ratings of Drug Liking increased in both groups of women on the ascending limb of the breath alcohol curve, alcohol was disliked by LD on the descending limb and LD reported increased ratings of Bad Drug Effects following the high dose of alcohol. The reduced performance impairment, coupled with the positive subjective effects and relative absence of adverse subjective effects, suggestive of behavioral tolerance, could result in a progression towards increased alcohol consumption among moderate female social drinkers.

The effects of alprazolam and buspirone in light and moderate female social drinkers.

Individuals who are moderate/heavy drinkers are at increased risk to abuse benzodiazepines and this risk is increased in women compared to men. However, no studies have determined whether female moderate drinkers (MD) show a differential response to the subjective and performance effects of benzodiazepines compared to female light drinkers (LD). Fourteen female MD who consumed an average of 36 drinks/month were compared to 14 female LD who consumed an average of 4.2 drinks/month. None of the participants had either a first- or second-degree family history of alcoholism. The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg) and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using a full range of performance measures and subjective-effects questionnaires. Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. There were few differences between LD and MD with respect to subjective response or performance impairment following either alprazolam or buspirone. Although MD reported greater ratings of Good Drug Effect and Drug Liking than LD, this was neither dose-related, nor specific to alprazolam. The results of the present study suggest that female MD without a family history of alcoholism experience the same level of performance impairment as female LD, although they tend to report greater positive subjective effects from alprazolam.

Attention deficit hyperactivity disorder (ADHD) and substance use disorders.

Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder that often continues to manifest symptoms into adulthood. In children and adults, this condition may contribute to addictive vulnerability. Several factors are common to the developmental psychopathology of these conditions, suggesting an underlying deficit in behavioral regulation as an explanation for this comorbidity. Developmentally, faulty learning processes or attempts to self-medicate dysfunctional behavior may contribute to the pathogenesis of substance use disorders. Substance abuse itself also may contribute to the development of attentional deficits and behavioral dysregulation through direct (eg, prenatal or self-inflicted exposures to neurotoxic substances) and indirect (eg, poverty, neglect, abuse) mechanisms. Because ADHD can be identified prior to the peak onset of substance use, effective treatment of this common disorder may reduce the development of substance use disorders. Adult ADHD may also contribute to the development and maintenance of substance use disorders Substance abuse patients may particularly benefit from treatment of this comorbidity.

Effect of flupenthixol on subjective and cardiovascular responses to intravenous cocaine in humans.

The effects of oral flupenthixol and intramuscular (i.m.) flupenthixol decanoate in combination with intravenous (i.v.) cocaine were evaluated in male cocaine abusers. Participants resided at an inpatient research unit for 27 days followed by an 11-day outpatient period. Oral flupenthixol (2.5 or 5.0 mg; p.o.) followed by flupenthixol decanoate (10 or 20 mg; i.m.) and placebo were investigated in individuals who were randomly assigned to one of three groups under double-blind conditions (placebo, low or high dose flupenthixol). During the inpatient period, participants had four fixed cocaine dosing sessions; each session they were administered four doses of i.v. cocaine (approx. 48 mg/70 kg), spaced 14 min apart. These sessions occurred once before medication (baseline phase), once following oral medication (oral phase), and twice following intramuscular medication (IM phase). Out of 23 participants, 18 completed the study; 4 of the 5 non-completers were in the high dose flupenthixol group. Overall, there were few subjective, cardiovascular, or cocaine pharmacokinetic differences between the placebo group and the low dose flupenthixol group, indicating that the low dose of flupenthixol was well tolerated, but ineffective. In the high dose flupenthixol group, two out of seven individuals (29%) experienced a dystonic reaction following oral flupenthixol and were medically discharged. Taken together, these findings indicate that flupenthixol is not a good candidate for treating cocaine abusers.

Psychotherapy of adults with comorbid attention-deficit/hyperactivity disorder and psychoactive substance use disorder.

Psychotherapy for comorbid attention-deficit/ hyperactivity disorder (ADHD) and psychoactive substance use disorder (PSUD) is described. The authors suggest that relapse prevention is an appropriate initial treatment because it is well suited to manage both substance abuse and comorbid symptomatology such as impulsivity, distractibility, and avoidance associated with ADHD. Clinical vignettes describe typical interactions between patients and their therapists, highlighting opportunities for therapists to focus on overlapping symptoms. ADHD is one of the most common comorbid diagnoses with PSUD, and it is important that efficacious psychotherapies be developed to complement psychopharmacological approaches. Clinicians should consider psychotherapy as part of a multimodal treatment approach that includes medication and perhaps family therapy. Additional contributions from clinicians who have experience conducting psychotherapy with this population are needed in order to develop effective treatments.

Increased sensitivity to alprazolam in females with a paternal history of alcoholism.

RATIONALE: Few studies have directly examined the effects of benzodiazepines in individuals with a family history of alcoholism, particularly women, to determine whether they are differentially sensitive to their effects. OBJECTIVES: To determine whether females with a confirmed paternal history of alcoholism (FHP; n=14) were differentially sensitive to the mood and performance effects of alprazolam and buspirone compared with females without a first-degree family history of alcoholism (FHN; n=14). METHODS: The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg), and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect, and subjective ratings of mood, drug strength, and drug liking. RESULTS: Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. The highest dose of alprazolam impaired the response to the digit symbol substitution test (DSST), digit recall, and word memory more in FHP females than in FHN females. Further, performance on the DSST and immediate word recall was able to accurately predict family history status. Correspondingly, FHP women reported greater increases in "difficulty concentrating" and "unmotivated" and greater decreases in items such as positive mood following alprazolam than FHN women. In contrast, alprazolam produced similar dose-related increases in subject-rated and observer-rated drug strength ratings in both groups of females. Lastly, there was no evidence of an increase in ratings of drug liking in either group following alprazolam. CONCLUSIONS: In contrast to many previous findings with FHP males, these results suggest that FHP females may be more sensitive to the performance-impairing effects and negative subjective effects of alprazolam.

Posttraumatic stress disorder and short-term outcome in early methadone treatment.

The aim of this study was to determine treatment adherence relative to frequency of violence and posttraumatic stress disorders (PTSD) among new methadone patients. Ninety-six opiate-abusing patients were evaluated for childhood physical and sexual abuse (CPSA), adulthood exposures to violence (ADVIOL), PTSD, and treatment adherence. Overall, 43% of the subjects dropped out of treatment within 3 months of intake. Occurrence of trauma or PTSD did not predict drop-out rates. A 2 (Gender) x 2 (PTSD) analysis of covariance (ANCOVA) with severity of other drug use on admission as a covariate, however, revealed a main effect for PTSD, F(4, 71) = 7. 69, p < or =.01, such that those patients with current PTSD revealed significantly more ongoing drug use at 3 months (M = 24.3, SD = 20. 9) than those without (M = 8.9, SD = 11.8). Examination of ongoing cocaine use using a 2 (Gender) x 2 (PTSD) ANCOVA also revealed a main effect for PTSD, F(4, 17) = 8.24, p < or = .005, such that those patients with current PTSD revealed significantly more ongoing cocaine use at 3 months postadmission (M = 51.6, SD = 37.6) than those without (M = 24.3, SD = 20.9). For both genders, CPSA and ADVIOL were associated with higher rates of PTSD, which in turn predicted poorer treatment adherence as measured by ongoing co-occurring drug abuse 3 months postadmission. Results underscore the need for routine assessment and targeted treatment of trauma in methadone patients.

Venlafaxine treatment of cocaine abusers with depressive disorders.

OBJECTIVE: There appears to be a link between depression and cocaine that is both complex and elusive. The purpose of this study was to examine the effect of venlafaxine, a broad spectrum antidepressant, in the treatment of 13 patients who were diagnosed with cocaine dependence and comorbid major depressive disorder (MDD). METHOD: The majority of the patients in the study were part of a larger double-blind trial using desipramine. This subgroup consisted of people who had failed to respond to desipramine or could not tolerate its side effects. Thirteen patients were enrolled, 10 men and 3 women. Of the patients, 11 completed the 12-week study. All of the patients had a Hamilton Depression (HAM-D) score greater than 14 at baseline, and each had used at least $20 worth of cocaine per week in the 4 weeks prior to entering the study. In addition, all of the patients received weekly relapse prevention therapy throughout the study. The median dose of venlafaxine was 150 mg/day. RESULTS: The 11 patients who completed the study had significant reductions in mood symptoms by the end of the study. The average total HAM-D score at baseline was 18.0 +/- 3.2; at Week 2, it was 1.9 +/- 0.94; and at the end of the study, it was 1.4 +/- 1.8. The majority of patients reported reductions of cocaine use short of abstinence. All subjects reported a greater than 75% reduction in cocaine use compared to baseline. There were no serious side effects. CONCLUSIONS: The results of this small study indicate that venlafaxine may be a safe, well-tolerated, rapidly acting, and effective treatment for patients with a dual diagnosis of depression and cocaine dependence.

Pergolide mesylate for cocaine abuse: a controlled preliminary trial.

A small, controlled study was conducted to assess whether pergolide mesylate has clinical promise as a treatment for cocaine abuse prior to embarking on a larger, randomized, double-blind, controlled trial. Fourteen individuals were placed on placebo for 2 weeks, followed by a 24-week single-blind study in which they were placed on pergolide for 12 weeks, followed by placebo for 12 weeks. Another 14 patients received single-blind placebo for two weeks and then were randomized into a 24-week double-blind, placebo-controlled, multiple baseline design. Initially, patients enrolled in the study were placed on risperidone (n = 9) or placebo (n = 5). During the first 12 weeks, retention was worse for those receiving pergolide compared to risperidone or placebo. Neither risperidone nor pergolide were more efficacious in reducing cocaine use than placebo. Although earlier open studies found pergolide to show promise as a treatment for cocaine abuse, this study did not support these earlier findings. Comparing an agent to both an active control and placebo group may better predict whether a promising new agent will have clinical utility compared to the standard open trial.

Dissociative identity disorder and substance abuse: the forgotten relationship.

The treatment and research of dissociative disorders, particularly dissociative identity disorder (DID), are hampered by professional skepticism and diagnostic uncertainties. Almost always associated with severe and sustained childhood trauma, its chief manifestations are at least two distinct and separate identities which have an independent manner of existing in the world. It is also associated with a high degree of psychiatric comorbidity. Among the most frequent diagnoses found in patients with DID are substance use and dependence. For a variety of reasons there has been little dialogue among the disciplines that study patients with trauma and those that study and treat substance abuse. Clinicians dealing with a primarily substance-abusing population are likely to encounter but not recognize these patients. The authors present several representative cases illustrative of features of patients with DID. The epidemiology, phenomenology and presentation of DID, as well as its relation to posttraumatic stress disorder are discussed. Little systematic investigation exists on the treatment of DID in general, and substance abuse in DID in particular. The authors draw upon the existing literature, and their experience to discuss treatment strategies aimed at treating patients with both diagnoses. Ignoring either diagnosis is likely to be detrimental to patients; both disorders and their coexistence need to be addressed.

Use of standardized patients to evaluate the physicians in residence program: a substance abuse training approach.

The purpose of this study was to evaluate the efficacy of the Physician in Residence (PIR) program at the Hazelden Residential Program of New York City as a substance abuse training approach using standardized patients (SP) and self-report ratings. Using an objective rating scale, two experienced drug counselors evaluated four videotaped interviews carried out by housestaff pre- and post-enrollment in the PIR program. In addition, housestaff completed self-report ratings regarding their knowledge, attitudes, and skills of substance abuse. Of the 23 housestaff who completed both pre- and post-PIR program videotape sessions, significant improvements were noted in both observer and self-reported ratings. Overall, self-report ratings showed a greater percent improvement than the counselor ratings. The PIR program may be an efficacious approach to teach substance abuse clinical skills to housestaff.

Smoked cocaine self-administration in females and voucher incentives for abstinence.

UNLABELLED: There are three purposes for this study: (1) To extend the laboratory study of heavy smoked cocaine use to women, (2) to assess cocaine withdrawal symptoms and (3) to assess the utility of voucher incentives for achieving and maintaining cocaine and other drug abstinence in female cocaine abusers. METHODS: Ten non-treatment seeking female cocaine smokers resided inpatient for 4-5 days and could smoke up to 6 doses of cocaine base (50 mg each) twice a day (at 1200 h and again at 1600 h) for 2 consecutive days. During the following 2-week outpatient phase, women were given US $40 in merchandise vouchers if urinalysis indicated lower drug levels from the previous day. RESULTS: Women self-administered 20.4 out of 24 possible doses. Compared to the 1200 session, heart rate and blood pressure, but not subjective effects, were still significantly increased prior to the 1600 session. Nine women completed the outpatient phase, attending 98% of their appointments. Using the One-Half Rule, 56% of urines indicated no new cocaine or other drug use. IMPLICATIONS: Although a US $40 voucher incentive for a "clean" urine was not sufficient to eliminate cocaine use, the possibility of earning the voucher was sufficient to maintain nearly perfect attendance.

Mood and performance changes in women with premenstrual dysphoric disorder: acute effects of alprazolam.

This study determined if women with premenstrual dysphoric disorder (PMS) showed impaired mood and performance when they were experiencing their premenstrual symptoms, and if the effects of alprazolam varied as a function of menstrual cycle phase. Under double-blind conditions, the acute effects of placebo and alprazolam (0.25, 0.50, 0.75 mg) were tested during both luteal and follicular phases. Women with confirmed PMS experienced substantial changes in mood as a function of menstrual cycle phase. However, under controlled laboratory conditions, acute doses of alprazolam did not improve negative premenstrual mood, but rather increased negative mood in the follicular phase. Alprazolam impaired task performance, although this impairment was generally similar in both phases when baseline phase differences were taken into consideration. Consistent with the failure of alprazolam to improve mood premenstrually, subjective measures indicative of abuse liability were not increased following alprazolam. Taken together, these data suggest that acute administration of alprazolam doses are not clinically useful for the treatment of PMS.

Prevalence of adult attention-deficit hyperactivity disorder among cocaine abusers seeking treatment.

In this study, 281 cocaine abusers seeking treatment were assessed for adult attention-deficit hyperactivity disorder (ADHD). Structured assessments included the SCID for DSM-IV, a SCID-like module for ADHD, and a pattern of drug use questionnaire. The sample consisted of 82% men, 67% African-Americans, 19% Hispanics, and 14% Caucasians identified at several treatment sites. Average age was 33.7 +/- .4 years. Twelve percent (n = 34) of the sample met DSM-IV criteria for childhood ADHD. Of the entire sample, 10% (n = 27), or 79% of the patients diagnosed with childhood ADHD, had adult ADHD. A history of conduct disorder and antisocial personality disorder were prevalent among those with adult ADHD (63% and 52%, respectively). This subpopulation of cocaine abusers may be one of the most difficult-to-treat cocaine-abusing groups, particularly if the ADHD remains undetected. To provide effective treatment for cocaine abusers, clinicians may need to identify subpopulations of patients, such as those with ADHD, and target both pharmacologic and nonpharmacologic interventions for these groups.

Flupenthixol treatment for cocaine abusers with schizophrenia: a pilot study.

Cocaine use is common among individuals with schizophrenia and schizoaffective illness, with a prevalence ranging from 15-60% of patient samples. It is hypothesized that some schizophrenic cocaine abusers may use cocaine as an attempt to improve anhedonic symptoms or combat neuroleptic side-effects. Flupenthixol (FLX) has the distinct advantage of being both a neuroleptic medication and a potential treatment for cocaine abuse. We evaluated the efficacy of FLX in this dually diagnosed population in an open pilot study consisting of a 4-week inpatient phase and a 6-week outpatient phase. Eight individuals were initially cross-tapered off their neuroleptic medication and were given FLX in a dose of 40 mg of the decanoate every 2 weeks. Psychiatric symptomatology was assessed weekly, using the Positive and Negative Symptom Scale (PANSS) and the Beck Depression Inventory (BDI). Medication side-effects were monitored weekly, using the Simpson Neurological Rating Scale and the Abnormal Involuntary Movement Scale (AIMS). Substantial improvement in psychiatric symptomatology was noted when preadmission scores were compared to scores obtained during the last week of study enrollment. On the PANSS, positive symptom scores and negative symptom scores decreased by 31% and 29%, respectively. Similarly, BDI scores decreased by 57%. Comparing preadmission urine results to those for the last 6 weeks of enrollment in the study showed that cocaine-positive urines decreased by 28%, although most of the patients had a reduction of >75%. Missed clinic visits decreased by 26%. Thus, FLX was well-tolerated by schizophrenic cocaine abusers, suggesting that FLX may be useful for the treatment of this dually diagnosed population.

Methylphenidate treatment for cocaine abusers with adult attention-deficit/hyperactivity disorder: a pilot study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is common among cocaine abusers seeking treatment. This open trial was carried out to assess the efficacy of sustained-release methylphenidate for the treatment of cocaine abuse among individuals with ADHD. METHOD: Twelve patients who met DSM-IV diagnostic criteria for adult ADHD and cocaine dependence were entered into a 12-week trial of divided daily doses of sustained-release methylphenidate ranging from 40 to 80 mg. In addition to the pharmacotherapy, patients also received individual weekly relapse prevention therapy. Individuals were assessed weekly for ADHD symptoms; vital signs and urine toxicologies were obtained 3 times a week. RESULTS: Of the 12 patients entered, 10 completed at least 8 weeks of the study and 8 completed the entire study. Using both a semistructured clinical interview and a self-report assessment, patients reported reductions in attention difficulties, hyperactivity, and impulsivity. Self-reported cocaine use and craving decreased significantly. More importantly, cocaine use, confirmed by urine toxicologies, also decreased significantly. CONCLUSION: These preliminary data suggest that under close supervision, the combined intervention of sustained-release methylphenidate and relapse prevention therapy may be effective in treating individuals with both adult ADHD and cocaine dependence.