Microdosing with lysergic acid diethylamide (LSD) is associated with improved mood and increased attention, early research suggests. However, at least one expert believes it's far too soon to tell and warns against endorsing patient microdosing. In a dose-finding exploratory study, three low doses of LSD were compared with placebo in healthy volunteers who were all recreational drug users. Adjusted results showed that the highest dose boosted attention and mood, although participants were aware of psychedelic effects, prompting researchers to conclude the results demonstrated "selective, beneficial effects." "The majority of participants have improved attention," study investigator Nadia Hutten, PhD, Department of Neuropsychology and Psychopharmacology, Maastricht University, the Netherlands, told Medscape Medical News. "So we think that patients with attention deficits might have more beneficial effects," she added, noting her team plans to study LSD microdosing in patients with attention deficit hyperactivity disorder. The study was presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic. Growing Interest Over the past 10 years there has been growing interest in psychedelic microdosing, which is defined as a dose that aims to enhance mood and/or performance but does not affect perception. However, there has been considerable debate over what constitutes a "microdose." One tenth of a "full" psychedelic dose is typically suggested, but users report a much wider dose range in practice, suggesting potential "individual variation in response to low doses," the researchers note. In the current dose-finding study, the researchers explored whether the effects of LSD on cognition and subjective measures differed between individuals. The study included 24 healthy recreational drug users and compared the acute effects of 5 µg, 20 µg, and 20 µg LSD with placebo on a computer-based psychomotor vigilance task (PVT) that measured attention and on a Digit Symbol Substitution Test (DSST). Participants also completed the 72-item Profile of Mood States (POMS) questionnaire, a visual analog scale (VAS) on mood, and the 94-item 5-Dimensional Altered States of Consciousness Rating scales (5D-ASC). Unadjusted results showed that the 20 µg LSD dose significantly reduced correct substitutions on the DSST vs placebo (P < .05), but had no effect on attentional lapses on the PCT or on positive mood on the POMS. Correcting the DSST score for the number of total responses revealed no dose effect of LSD. This suggested that participants were no less accurate when under the influence of LSD, even though they encoded fewer digits, the researchers note. Participants also reported that both the 10 µg and 20 µg dose of LSD increased subjective experiences on the VAS and alternated states of consciousness on the 5D-ASC compared with placebo. After stratifying the results by dose and participant, the effect of LSD differed between individuals. For example, both the 5 µg and 20 µg doses were associated with improvement in attention on the PVT (P < .05), but not the 10 µg dose. These results also indicated that the 20 mg dose was associated with a significant increase in the correct number of substitutions on the DSST and with a significant increase in positive mood on the POMS (P < .05 for both outcomes). The findings suggest that future studies in patient populations with impaired attention are needed, "including biological parameters involved in LSD receptor-binding and metabolism, in order to understand the inter-individual variation in response to LSD," the investigators note. In an educational session at the meeting, the study's lead researcher, Kim Kuypers, PhD, associate professor at Maastricht University, said research shows individuals are already self-medicating with psychedelic microdosing to treat a wide range of mental health problems, and rated it as significantly more effective than conventional therapy at alleviating symptoms and improving quality of life. Nevertheless, Kuypers noted there have been fewer than 20 published placebo-controlled studies examining psychedelic microdosing in humans — and much of the current evidence is anecdotal. However, there is some clinical research suggesting that low-dose LSD is associated with improved mood and cognitive performance and that it also has an effect on resting-state amygdala functional connectivity and acutely increases brain-derived neurotrophic factor plasma levels. Furthermore, said Kuypers, the evidence in healthy volunteers thus far suggests microdosing is "safe." Jumping Ahead of the Science? Commenting on the study for Medscape Medical News, Jeffrey A. Lieberman, MD, professor and chair of psychiatry at Columbia University, New York City, said he "gives the investigators credit for doing such a study" but does not believe anything can be gleaned from the findings. He said he is also concerned that the resurgence of psychedelic research is not congruent with "the methodologic rigor and scientific thinking that accompanies treatment development in other disease areas." Lieberman, who is also psychiatrist-in-chief at the NewYork-Presbyterian Hospital Columbia Medical Center and was not involved with the study, added that some of the research is also being conducted in individuals who are "true believers and not sufficiently dispassionate and objective." "If this was just a treatment…for some type of skin fungus, no one would pay any attention to it. But because these are such notorious and interesting compounds, they have attracted a lot of peripheral interest to promote and to disseminate; and the risk is that it will be done in the wrong way and there may be consequences," he said. Moreover, Lieberman noted that the psychedelic drugs may be used in practice ahead of strong evidence of safety and efficacy. As an example, he pointed to ketamine, a drug that was identified as a treatment for people with depression who had not responded to standard treatments, he noted. "But before you knew it, there were clinics being opened up all over the place by anesthesiologists or other people that were trying to make a quick buck," he said. "That was alarming because they were stretching the criteria for whom the treatment was appropriate; there were no protocols for dosing, for frequency of administration, and there was inadequate psychiatric follow-up," Lieberman added. Preliminary but Promising He agreed with Kuypers that cases of microdosing with psychedelics are largely anecdotal. "So in that context, when these investigators tried to put it to a test, which is commendable, the results in no way tell you whether it's good, bad, or indifferent," Lieberman said. In fact, the results are "disappointing in terms of suggesting any beneficial effect." Lieberman said more and larger studies are needed in order to determine whether LSD microdosing is beneficial. In response to Lieberman's comments, Kuypers told Medscape Medical News that the investigators tried to base their placebo-controlled research on previous anecdotal research. She emphasized that the "whole field is still in its infancy," including research on the use of "full" doses of psychedelics. "I sometimes think that the message is too positive. We should never forget to communicate that not a lot of research has been done." In addition, she agreed that researchers should "keep a balanced message." "All the data to date is preliminary, in my view, but promising," she stressed, "and the evidence is growing." Source
