Jessica Pommy

Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses

Alcohol and drug addiction are major public health problems, and existing treatments are only moderately effective. Although there has been interest for over half a century in the therapeutic use of classic hallucinogens to treat addictions, clinical research with these drugs was halted at an early stage in the early 1970s, leaving many fundamental questions unanswered. In the past two decades, clinical research on classic hallucinogens has resumed, although addiction treatment trials are only now beginning. The purpose of this paper is to provide a targeted review of the research most relevant to the therapeutic potential of hallucinogens, and to integrate this information with current thinking about addiction and recovery. On the basis of this information, we present a heuristic model which organizes a number of hypotheses that may be tested in future research. We conclude that existing evidence provides a convincing rationale for further research on the effects of classic hallucinogens in the treatment of addiction.

Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders

Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity.

Psychological and neuropsychological assessment of regular hoasca users

BACKGROUND Hoasca (also called ayahuasca) is a N,N-dimethyltryptamine (DMT) - containing psychedelic brew originally used for magico-religious purposes by Amerindian populations of the Amazon Basin. Recently, Brazilian syncretic churches have helped spread the ritual use of hoasca to Western societies. The aim of this study was to evaluate substance use, and neuropsychological and psychological functioning of regular hoasca users within a religious setting. METHODS Assessment of socio-economic status, mood, personality traits, impulsiveness, drug use, quality of life, extrinsic and intrinsic religiosity, and neuropsychological function was performed on 30 volunteers from a U.S. branch of União do Vegetal (UDV), a Brazilian religion which uses hoasca ritually. We also assessed 27 non-hoasca-using control subjects matched by socio-demographic profile and church attendance. Mann-Whitney U, chi-squared and Fisher tests were used to analyze differences between groups. Spearmans association and simple logistic regression tests were used to analyze the impact of frequency of hoasca use on dependent variables. RESULTS Relative to the control group, the UDV group demonstrated lower scores for depression (p=0.043, r=.27) and confusion (p=0.032, r=.29) as assessed by the Profile of Mood States (POMS); higher scores on the instrument Big Five Inventory (BFI) for the personality traits agreeableness (p=0.028, r=.29) and openness (p=0.037, r=.28); higher scores on the quality life domain role limitations due to physical health as determined by the instrument Medical Outcomes Study Short Form-36 - SF-36 (p=0.035, r=.28); less recent use of alcohol (p<0.001, φc=.57), greater past use of alcohol to intoxication (p=0.007, φc=.36) and past use of cannabis (p=0.001, φc=.45) as measured by the Addiction Severity Index (ASI), 5th edition; better score on a measure of memory vulnerability to proactive interference as measured by the California Verbal Learning Test - CVLT (p=0.040, r=.27). Lifetime use of hoasca was positively correlated with role limitations due to physical health (p=0.032, rs=.39) and negatively associated with lifetime heavy alcohol use (p=0.034, OR=0.979). CONCLUSIONS The findings indicate that religious use of hoasca does not adversely affect neuropsychological functioning and may have positive effects on substance abuse and mood.

Genetic influences on cognitive endophenotypes in schizophrenia

BACKGROUND Cognitive deficits are prominent in schizophrenia and represent promising endophenotypes for genetic research. METHODS The current study investigated the importance of two conceptually distinct genetic aggregates, one based on copy number variations (uncommon deletion burden), and one based on single nucleotide polymorphisms identified in recent risk studies (genetic risk score). The impact of these genetic factors, and their interaction, was examined on cognitive endophenotypes defined by principal component analysis (PCA) in a multi-center sample of 50 patients with schizophrenia and 86 controls. PCA was used to identify three different types of executive function (EF: planning, fluency, and inhibition), and in separate analyses, a measure general cognitive ability (GCA). RESULTS Cognitive deficits were prominent among individuals with schizophrenia, but no group differences were evident for either genetic factor. Among patients the deletion burden measures predicted cognitive deficits across the three EF components and GCA. Further, an interaction was noted between the two genetic factors for both EF and GCA and the observed patterns of interaction suggested antagonistic epistasis. In general, the set of genetic interactions examined predicted a substantial portion of variance in these cognitive endophenotypes. LIMITATIONS Though adequately powered, our sample size is small for a genetic study. CONCLUSIONS These results draw attention to genetic interactions and the possibility that genetic influences on cognition differ in patients and controls.

Strategic Choices versus Maladapative Development

Del Giudice (this issue) provides a novel and compelling “general framework” as to how individual variations in life history strategies can inform our understanding of the structure of psychopathology. Like his adapative calibration model of individual differences in stress responses (Del Giudice, Ellis, & Shirtcliff, 2011), Del Giudice’s target article draws our attention to fast versus slow life history strategies and how these are moderated by sex. From any lofty vantage point, four of the most visible, deeply etched features of the epigenetic landscape are those representing the four combinations of male/female and fast/slow phenotypes. It would be surprising if these major suites of adaptive design features were not related to vulnerabilities for specific forms of psychopathology. The framework represents an exploration of the relevance of life history theory (LHT) for psychopathology, and perhaps personality, more than a model for all psychopathology. In this brief comment, we suggest Del Giudice’s fast–slow framework, and LHT in general, is incomplete without systematic consideration of a (mostly) independent dimension of individual differences related to neural integrity, and thus his framework illuminates some disorders better than others. Here we discuss one disorder that he did not focus on—substance abuse—and suggest that his approach has much to offer. We also discuss a group of disorders that he did focus on—neurodevelopmental disorders such as schizophrenia and autism—and suggest that here the LHT approach may provide fewer insights. It is important to recognize that sensitivity to environmental signals that direct life history strategies represents an adaptation, facilitating reproductive fitness across the different environments humans have frequently encountered. This cue-driven adaptive tuning is partly accomplished by stress and immune regulation systems, and one thing we know about these systems is that it they are malleable. Thus, a LHT approach is perhaps on firmest ground in elucidating those forms of psychopathology that have their roots in atypical stress system functioning, that is, those types of psychopathology that are most apt to wax and wane over time and circumstance. Perhaps unsurprisingly, a perspective built on successfully implemented adaptations may work better for “disorders” that have relatively little impact on fecundity. Specifically, we suggest that Del Giudice’s model has much more to say about those disorders not characterized by reduced neural integrity or by reduced fecundity, that is, internalizing and externalizing disorders such as depression, anxiety disorders, obsessive-compulsive disorder, substance abuse, and conduct disorders, than it does for neurodevelopmental disorders (NDDs) characterized by reduced neural integrity and reduced fecundity, such as schizophrenia and autism.