This double-blind, placebo-controlled study (2010) found large individual variability in MDA-induced visions (n=12) and suggests that they could have similar mechanisms as other hallucinatory syndromes.
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.
Serotonergic hallucinogens such as LSD, mescaline and psilocybin produce a wide range of visual phenomena, from altered form and depth perception to vivid pseudo-hallucinations that may occur with the eyes closed (closed-eye visions, CEVs) or open (open-eye visions, OEVs). The mechanisms underlying these drug-induced visual changes remain poorly understood; prevailing explanations implicate (1) reduced sensory or perceptual fidelity, (2) abnormally increased cortical excitation, and/or (3) altered cognitive or top-down influences on perception. Previous work has linked visual hallucinations in other conditions to low-level visual deficits (for example, impaired contour detection), to abnormal excitation as in migraine or epilepsy, and to altered use of top-down cues for recognition. Baggott and colleagues set out to probe these putative mechanisms by administering 3,4-methylenedioxyamphetamine (MDA) to healthy, drug-experienced volunteers in a controlled laboratory experiment. The study tested whether MDA would produce self-reported hallucinogen effects (including CEVs and mystical-type experiences) and whether those visual reports would be associated with changes on perceptual tasks designed to index reduced sensory fidelity (contour integration and object recognition) and altered cortical excitability (tilt illusion). The authors therefore aimed to relate subjective visual phenomena to objective measures of perceptual organisation and early visual cortical processing.
Papers cited by this study that are also in Blossom
Nichols, D. E. · Journal of Psychoactive Drugs (1986)
Geyer, M. A., Vollenweider, F. X. · Trends in Pharmacological Sciences (2008)
Winter, J. C. · Psychopharmacology (2008)
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
The study used a double-blind, placebo-controlled within-subjects crossover design conducted at a clinical research centre. Twelve healthy participants with prior experience of MDA, MDMA, or other hallucinogens completed two consecutive dosing sessions (MDA and placebo, order counterbalanced). Safety screening included medical history, EKG and blood work; pregnancy and toxicology testing were performed before dosing. Racemic MDA was synthesised for the study and administered orally at 98 mg per 70 kg body weight; lactose capsules served as placebo. Participants stayed for a single three-evening admission and returned two weeks later for follow-up checks. Timed measures included physiological monitoring, blood draws for pharmacokinetics, repeated self-report instruments and three computerised visual tasks. Self-report measures comprised visual analog scales (VAS) for rapid time-course ratings of general drug effects and four closed-eye visual categories (patterns, things, beings, scenes), plus the Altered States of Consciousness (ASC) Visionary Changes subscales and the Hood Mysticism questionnaire, administered 7.5 hours after dosing. For rapidly changing measures the analysis used each participant's maximum post-dose change (Emax). The tilt illusion task probed putative changes in early visual cortical excitation by measuring shifts in perceived orientation of a central sine-wave grating when embedded in oriented surrounds. Points of subjective verticality (PSV) were estimated using interleaved staircases for multiple surround orientations and the tilt-illusion magnitude was computed as the difference between minimum and maximum PSV after baseline correction. The contour integration task assessed perceptual organisation using closed chains of Gabor elements embedded in background noise; difficulty was manipulated by orientation jitter and thresholds (75% accuracy) were estimated from psychometric functions. The object recognition task assessed recognition of phase-degraded images presented with true, false or no semantic cues; images were progressively deblurred until the participant reported recognition. Primary outcomes were recognition accuracy and the degradation level at identification, analysed separately by cue type. Statistical analyses used mixed-effects models in R with drug condition as a fixed effect and participant as a random effect. Sequence and sequence-by-condition terms were initially included to control for order effects. Repeated measures were reduced to Emax for analysis where appropriate. After omnibus F-tests, pairwise comparisons used Tukey post hoc tests. The authors report handling of a few missing or unusable data points arising from participant misunderstanding or technical errors in task runs.
MDA was generally well tolerated and produced robust subjective and physiological effects consistent with hallucinogen action. On VAS measures of general drug effects, MDA significantly increased maximum ratings for any drug effects (t = 18.624, p < 0.001), good drug effects (t = 9.769, p < 0.001), high (t = 13.35, p < 0.001) and, to a lesser extent, bad drug effects (t = 2.366, p = 0.0272). Approximately half the participants reported notable closed-eye visions during the MDA session; CEVs were largely absent under placebo. MDA significantly increased Emax for closed-eye patterns (t = 4.437, p < 0.001), closed-eye objects (t = 3.883, p < 0.001), closed-eye beings (t = 2.54, p = 0.019) and closed-eye scenes (t = 2.79, p = 0.011). Scores on the ASC main scales and the Hood Mysticism questionnaire were also significantly elevated after MDA, including all Visionary Changes subscales. On the tilt illusion task, a planned within-subjects analysis did not find a significant effect of dosing condition on illusion magnitude (F1,9 = 2.515, p = 0.147). However, the authors detected a significant sequence effect (F1,9 = 6.658, p = 0.030) and therefore analysed session-one data alone; in that between-subjects comparison dosing condition predicted a larger tilt illusion under MDA (F1,9 = 7.495, p = 0.023). The tilt-illusion magnitude did not correlate with peak CEVs. Contour integration thresholds were not predicted by dosing condition alone (F1,10 = 0.409, p = 0.537). When peak CEVs were included as a predictor, there was a significant main effect of CEVs (F1,9 = 9.385, p = 0.014) and a significant interaction between CEVs and dosing condition (F1,9 = 17.972, p = 0.022), indicating that individuals with larger CEVs had poorer contour-detection performance and showed greater MDA-related impairment. In the object recognition task there were main effects of cue type (F2,52 = 6.035, p = 0.004) and dosing condition (F1,52 = 6.058, p = 0.017) on accuracy, with true cues improving accuracy by an estimated 7.2% and MDA reducing accuracy by an estimated 4.9% relative to placebo. Adding image degradation level revealed that participants on MDA were more impaired by increased degradation (interaction F1,46 = 6.693, p = 0.013). Collapsing cue types, peak CEVs and dosing condition both predicted accuracy, with significant main effects of CEVs (F1,10 = 20.337, p = 0.001) and condition (F1,9 = 8.736, p = 0.016) and a significant interaction (F1,9 = 11.499, p = 0.008). The authors report that each percent increase in CEVs was associated with approximately a 0.2% decrease in accuracy on MDA and 0.1% decrease on placebo, and that these relationships were specific to visual effects rather than to general drug effects. Missing or unusable data affected a few runs (one participant excluded from contour analysis, one tilt session unusable, and one missing object-recognition session).
Baggott and colleagues interpret their findings as confirming that MDA produces prototypical hallucinogen effects in humans, including increases in closed-eye visual phenomena and indices of mystical-type experience on standard questionnaires. The authors regard MDA as a useful experimental tool for studying hallucinogen-induced visions, while noting its complex pharmacology and limited prior human research. A key observation was that larger CEVs were associated with poorer performance on measures of perceptual organisation (contour integration and object recognition), and that those with more intense CEVs showed greater MDA-related impairment. The researchers argue this pattern is consistent with the hypothesis that reduced sensory fidelity or impaired perceptual organisation increases susceptibility to drug-induced visual phenomena. They note that the acute contour-integration effects under MDA resemble prior findings with the NMDA antagonist ketamine, supporting a cross-drug link between impaired early visual processing and hallucination-like experiences. Evidence for increased occipital cortical excitation, as indexed by the tilt illusion, was equivocal. A between-subjects comparison limited to first sessions suggested a dosing effect, but planned within-subject analyses did not replicate this and the tilt-illusion change was not related to CEV magnitude or self-reported geometric visuals; the authors therefore consider the tilt-illusion result tentative and possibly influenced by residual drug effects. With respect to cognitive, top-down mechanisms, the object recognition task showed that true cues improved recognition and that MDA reduced overall accuracy and increased sensitivity to image degradation. However, the study did not find a significant interaction between cue type and dosing condition, and the task did not cleanly separate criterion shifts from sensitivity changes. Consequently, the investigators could not confirm or refute a role for strengthened top-down influences in producing MDA-induced visions. The authors acknowledge several limitations that constrain interpretation: participants were experienced users, which may affect expectancy and generalisability; dosing sessions occurred on consecutive days, producing sequence and possible residual effects that complicated within-subject comparisons; and some tasks could not disentangle certain perceptual from decisional factors. They recommend future studies using signal-detection paradigms or noise masking to partition sources of altered efficiency and suggest repeating these paradigms with other serotonergic hallucinogens such as LSD or psilocybin to clarify links between neuropharmacology and phenomenology. Overall, the study supports an association between visual hallucination-like experiences and impaired perceptual processing, while providing only limited evidence for increased cortical excitation or altered top-down efficacy as primary mechanisms.
The protocol for this trial, supporting CONSORT checklist, and CONSORT flowchart are available as supporting information; see Protocol S1, Checklist S1 and Figure.
Data were analyzed using mixed-effects models in R [103] with drug condition as a fixed-effect and participant as a random effect using a 2-tailed 0.05 level of significance. In order to control for possible sequence effects, linear models initially included a dummy-coded term for dosing sequence and a sequence-condition interaction term. When repeated measures were made (as in the case of self-report measures), data were transformed into maximum effects (Emax) for analysis. Summary statistics for the fixed-effects part of the model were calculated with the anova function in R. After a significant F-test, pairwise comparisons were made using Tukey's post hoc tests.
We conducted the first controlled study of the hallucinogen MDA in humans in over thirty years. Participants reported that MDA administration was followed by a number of prototypical hallucinogen effects, as indicated by significant increases in our visual change VAS items, ASC VC subscales, and the Hood Mysticism questionnaire. Along with perceptual and cognitive changes, the potential for mystical-type experiences has long been considered a characteristic of hallucinogens (e.g.,). However, to our knowledge, this is only the second published controlled experimentto assess a hallucinogen using a well-validated measure of mystical-type experience and the first such publication involving a hallucinogen other than psilocybin. These findings of prototypical hallucinogen effects support our approach of using MDA to understand hallucinogen-induced visions despite the caveat that MDA has complicated pharmacologyand is relatively unstudied. MDA had significant perceptual effects. Alles [106], who first studied MDA in self-experiments, reported experiencing visual percepts of smoke rings. However, subsequent researchers have emphasized the unusually consistent social and emotional effects of MDA rather than the visual changes. Given that drug-induced CEVs are more easily elicited than open-eye visual changes, one might speculate that MDA-induced extraversion decreases likelihood of closing eyes and experiencing visual percepts. Nonetheless, it seems likely that the visual effects of MDA are more subtle than those of hallucinogens such as mescaline and psilocybin, which often produce dramatic open-eye visual percepts. Magnitude of CEVs after MDA was associated with lower performance on the two measures of perceptual organization. In both cases, there was also a significant interaction with dosing condition, suggesting that individuals who saw more intense CEVs both had poorer overall performance on these tasks and also had greater MDA-induced changes in perceptual performance. This finding is consistent with evidence from other populations linking hallucinations to decreased sensory fidelity and impaired perceptual organization. Acute effects of MDA on the contour integration task also match acute effects previously reported for the NMDA antagonist hallucinogen ketamine. While decreased perceptual performance in MDA sessions could be partly due to nonspecific drug effects, we were not able to find a significant relationship between general self-report effects and impaired perceptual performance. The association of CEVs and uninebriated perceptual performance suggests those with poor perceptual organization may be more likely to experience hallucinations. Our study is not able to specify the underlying mechanism of this potential relationship. Further research will be needed to determine if this is the result of relatively low-level sensory fidelity changes (such as changes in gain control of thalamic or cortical neurons), perceptual organization effects, or higher-level cognitive changes. In addition to decreased perceptual ability, hallucinations have also been linked to abnormal excitation in a number of disorders, such as migraine and epilepsy. Although never previously studied during acute hallucinogen effects, increased occipital cortex excitation is predicted by Ermentrout and Cowan's model of geometric hallucinations. In keeping with this prediction, we detected some evidence of increased occipital cortex excitation using the tilt illusion. Specifically, the magnitude of the illusion was predicted by dosing condition in a between-subjects comparison using only participants' first sessions. However, we regard this finding as tentative. First, the effect did not seem related to magnitude of CEVs or self-report geometric visuals. Second, it was not robustly detectible in planned within-subjects analyses. We restricted our analysis of tilt illusion results to the first session because we saw a significant sequence effect in our analysis which we interpret as possible evidence of residual effects of MDA in the task. Residual effects of MDA in the tilt illusion are not unprecedented. While not previously reported with MDA, there have been previous reports of residual effects of MDMA in the closely related tilt aftereffectexcitability suggested by the tilt illusion results would provide a plausible mechanism for the geometric pattern hallucinations sometimes reported by such individuals. A third factor that might contribute to the mechanism of druginduced hallucinations is cognitive changes. Hallucinations have been hypothesized to be produced by increased influence of topdown factors on perception. We found that participants made effective use of true cues during their MDA session and, if anything, performance in trials with false or no cues may have been differentially impaired. However, we were not able to confirm a statistical interaction between cue type and dosing condition in the object recognition task. One limitation to the task is that it did not allow us to cleanly distinguish criterion shifts from changes in sensitivity, which may have decreased our ability to detect drug effects. Thus, we cannot confirm or deny the role of strengthened top-down factors in MDA-induced hallucinations. Furthermore, the object recognition task only manipulated one kind of top-down influence, with cues essentially functioning as semantic primes. Each cue would be expected to activate highlevel representations of the cued object, but -because the cue had 50% accuracy-would not create a strong response bias to indicate that the cue was correct. Nonetheless, it likely also minimized the type of top-down attentional changes that are normally measured, for example, in the Posner cuing task. In that task, top-down changes are typically created using spatially predictive cues. Tasks like the Posner task that manipulate the likelihood of different responses might also be useful in studying drug-induced hallucinations. There were several limitations to our tests of hallucination mechanisms that were imposed by the overall study design. To begin with, our participants were all experienced users of MDMA and hallucinogens. This was an ethical consideration intended to minimize risk of idiosyncratic reaction and facilitate informed consent. However, participants' expectations and drug use history may have influenced effects, limiting generalizability. Another limitation was that dosing sessions were on consecutive days in order to maximize measurement of the pharmacokinetics of a presumably long-half-life drug while minimizing blood loss in participants. Therefore, placebo measures may have been influenced by residual (next day) effects of MDA in half the participants. Although such trade-offs are a necessary part of clinical research with psychoac-tives, they may have limited our ability to detect the acute effects of MDA. Thus, further research with MDA will be needed in order to confirm and extend our findings. One potentially promising approach would be to use noise masking and signal detection theory to examine mechanisms of hallucinogen-induced visual changes. This would allow us to mathematically separate different sources of altered efficiency, such as increased internal noise or inefficient use of available information. Additionally, repeating these tasks with other serotonergic hallucinogens, such as LSD and psilocybin, might allow us to begin to better understand the relationships between neuropharmacology of hallucinogens and their complex phenomenology. In conclusion, we conducted the first study of the effects of the hallucinogen MDA in humans in over thirty years. We confirmed that the drug does induce mystical-type experiences and, in at least some individuals, CEVs. Magnitude of CEVs after MDA was associated with lower performance on measures of contour integration and object recognition, supporting a hypothesized link between hallucinations and impairments in sensory or perceptual processing. In contrast, we were unable to provide strong evidence for changes in efficacy of top-down influences on perception or acutely increased occipital cortex excitation.
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Griffiths, R. R. · Journal of Psychopharmacology (2008)
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