Tuesday, December 28, 2010

Investigating MDA-Induced Visions in Human Subjects

Bradley Voytek Baggott MDA

It's cool to see people taking seriously the visions people experience while under the influence of hallucinogens, and this is the first study I have seen using MDA. The study is open access and full text is online, as well as available as a PDF for download.

You can read an excellent interview with one of the researchers here - very enlightening to hear his perspective on the process. Here is a brief passage from the interview, giving a little context for MDA, a chemical very similar to MDMA, but apparently more visually hallucinogenic.
MDA seems to be a drug with similarities to classical serotonergic hallucinogens (like psilocybin and LSD). But it also has many similarities to its chemical cousin, MDMA ("ecstasy"), which many people argue is not really a hallucinogen at all.

Unlike classical hallucinogens, MDMA has very consistent emotional effects, which many people describe as feelings of empathy and emotional closeness to others. In our study, MDA seemed to share some of these consistent emotional qualities. Dave Nichols has suggested the term "entactogen" (which basically means "touchy-feely", or "generating touching within" if you want to be precise about it) for drugs with these unusual emotional effects. We and others have evidence that these so-called entactogen effects are related to serotonin release. I take a state-space or dimensional approach to understanding these drugs. Instead of seeing them in discrete categories, I think it is helpful to consider them as having different amounts of underlying characteristics, although it is not yet clear how many of these characteristics or dimensions there are.
Some of the subjective effects include the following:
In a dosage from 40 to 150 mg, none of the subjects reported hallucinations, perceptual changes, impaired thinking or eyes closed imagery. Yet, the subjects reported that, at some point during the drug action, MDA brought about an intensification of feeling, a facilitation of insight, and heightened empathy. It was also reported that thc psychotropic effects of this compound reached a peak intensity within two hours, with some effects continuing for approximately eight hours.
You can read the whole original article from 1974 if you are interested. In 1976 a pilot study was conducted on MDA-assisted psychotherapy for "neurotic outpatients," with good results.

Investigating the Mechanisms of Hallucinogen-Induced Visions Using 3,4-Methylenedioxyamphetamine (MDA): A Randomized Controlled Trial in Humans

Matthew J. Baggott, Jennifer D. Siegrist, Gantt P. Galloway, Lynn C. Robertson, Jeremy R. Coyle, John E. Mendelson

Abstract

Background

The mechanisms of drug-induced visions are poorly understood. Very few serotonergic hallucinogens have been studied in humans in decades, despite widespread use of these drugs and potential relevance of their mechanisms to hallucinations occurring in psychiatric and neurological disorders.

Methodology/Principal Findings

We investigated the mechanisms of hallucinogen-induced visions by measuring the visual and perceptual effects of the hallucinogenic serotonin 5-HT2AR receptor agonist and monoamine releaser, 3,4-methylenedioxyamphetamine (MDA), in a double-blind placebo-controlled study. We found that MDA increased self-report measures of mystical-type experience and other hallucinogen-like effects, including reported visual alterations. MDA produced a significant increase in closed-eye visions (CEVs), with considerable individual variation. Magnitude of CEVs after MDA was associated with lower performance on measures of contour integration and object recognition.

Conclusions/Significance

Drug-induced visions may have greater intensity in people with poor sensory or perceptual processing, suggesting common mechanisms with other hallucinatory syndromes. MDA is a potential tool to investigate mystical experiences and visual perception.

Trial Registration

Clinicaltrials.gov NCT00823407

Citation: Baggott MJ, Siegrist JD, Galloway GP, Robertson LC, Coyle JR, et al. (2010) Investigating the Mechanisms of Hallucinogen-Induced Visions Using 3,4-Methylenedioxyamphetamine (MDA): A Randomized Controlled Trial in Humans. PLoS ONE 5(12): e14074. doi:10.1371/journal.pone.0014074

Copyright: © 2010 Baggott et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This project was supported by National Institutes of Health (NIH) DA016776 and NIH/National Center for Research Resources UCSF-CTSI UL1 RR024131. Baggott was supported by the Beckley Foundation. Robertson is supported by NIH EY016975 and a Merit grant from the Veterans Administration. None of those organizations had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Serotonergic hallucinogens —such as LSD, mescaline, and psilocybin— produce a bewildering variety of visual phenomena [1][7]. Visual changes include altered form and depth perception, prolonged afterimages, motion-processing impairments, vivid pseudo-hallucinations, and, only very rarely, actual hallucinations in which insight into the non-veridical nature of the experience is impaired [8][17]. Pseudo-hallucinations can occur both with the eyes closed (closed-eye visions, CEVs) and open (open-eye visions, OEVs). Few studies have attempted to address the mechanisms of these visual changes after hallucinogens.

In order to study drug-induced visual hallucinations, we administered 3,4-methylenedioxyamphetamine (MDA, tenamfetamine, “Love Drug”) to healthy drug-experienced volunteers. MDA is a hallucinogen [18] that acts as a serotonergic 5-HT2A receptor agonist [19] and releases monoamines by interacting with monoamine plasmalemmal transporters [20][22]. MDA has been used non-medically since the 1960s and was scheduled as a controlled substance in the US in 1970. Some of what is sold as “Ecstasy” contains MDA instead of MDMA. For example, in a sample of 107 illicit Ecstasy tablets, Baggott and colleagues [23] found that 6.5% contained MDA. Similarly, MDA was found in 0.6% of pills submitted to Forensic Science South Australia (FSSA) for testing by South Australia Police (SAPOL) over a 6-month period [24]. Despite appearing in illicit drug preparations, MDA has not been studied in humans in over 30 years [3], [25][29]. Early reports suggest MDA may have more consistent emotional effects than hallucinogens such as LSD [30] and animal drug discrimination studies confirm that MDA has both typical hallucinogenic (LSD-like) effects as well as unusual effects similar to those of 3,4-methylenedioxymethamphetamine (MDMA) [31], [32], which some consider to represent a novel class of pharmacological agent (“entactogen” [18]). Animal studies show that MDA shares with MDMA potential to cause long-term serotonergic neurotoxicity [33].

Hallucinations are usually explained by some combination of three factors, none of which are mutually exclusive: loss of sensory or perceptual ability, abnormally increased neural activity, or cognitive alterations [34][39].

The first factor that may contribute to drug-induced hallucinations is loss of sensory or perceptual ability. Poor vision and perceptual difficulties increase risk for visual hallucinations [40]. Visual risk factors include low-level visual difficulties such as reduced contrast perception [41][44] and higher-level visual form perception deficits [45][48]. Among many other deficits, impairments in contour detection are seen in individuals with schizophrenia [49][54] and in people under the influence of the NMDA antagonist hallucinogen ketamine [55].

A second factor potentially contributing to hallucinations is abnormally increased neural activity, as in the case of migraine aura or epilepsy [39], [56][59]. Hallucinations may sometimes arise from abnormal activity in the cortex [60][62], possibly involving abnormal interactions between brain areas [35]. Serotonergic hallucinogens likely alter the balance of excitation and inhibition in the cortex [63], changing activity of brain networks [64], by affecting 5-HT2A and other serotonergic receptors [65][68]. Resulting excitation, according to formal models of hallucination developed by Ermentrout and Cowan [63] and others [69][71], could lead to activation of spatially periodic patterns in the cortex, which could be perceived as visual phenomena.

A third factor that may contribute to drug-induced hallucinations is alterations in cognitive functions – such as altered balance of top-down and bottom-up information [37] or impairment in perceptual inference [72] – which could lead to increased acceptance of expectations as reality. This possible mechanism can be tested by providing top-down cues for recognizing images. Appropriate top-down knowledge can enable recognition of an object from an otherwise unrecognizable degraded image [73][75] and, more generally, context facilitates object recognition [76][78].

Hypotheses

We predicted that MDA would induce self-report hallucinogen effects and that self-report visual changes would be accompanied by changes in one or more perceptual tasks designed to measure factors potentially contributing to hallucinations.

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