LSD, Ecstasy, or Speed: Which Feels Better?

I found it astonishing that someone actually tried to find an answer to this question. A recently published study by a group in Switzerland indicates that scientists are becoming more willing to venture out of their comfort zones and ask novel questions that would have once gotten their research labeled as marginal or unacceptable. Their goal: to determine, using a head-to-head comparison, whether a prototypical hallucinogen (LSD), a popular empathogen (MDMA, ecstasy), and the world’s most popular psychostimulant (amphetamine) produce distinct psychological changes in humans.

Their choice of substances to study was not random. Lysergic acid diethylamide (LSD) is a classic hallucinogen that is thought to act at serotonin receptors (other neurotransmitter systems are involved at higher doses). LSD acutely induces marked alterations of waking consciousness. Scientists are interested in LSD because the way in which some patients respond to its psychedelic experience might predict long-term changes in mental health. Essentially, LSD may be able to unmask underlying psychological vulnerabilities and strengths. A similar logic is guiding research using the hallucinogen psilocybin as an adjunct to standard psychotherapies.

MDMA (ecstasy) was chosen for study because it acts in an intermediate manner between a hallucinogen, such as LSD, and a pure stimulant, such D-amphetamine. Human subjects claim that MDMA induces feelings of well-being, love, and empathy while producing rather mild perceptual alterations. MDMA’s effects are thought to be mediated by serotonin, dopamine, and norepinephrine. [Never forget: All drugs have two effects: the ones we know about and the ones we have not yet discovered.] MDMA also releases oxytocin; this may contribute to the mediation of its emotional effects that have led to its classification as an empathogen.

D-amphetamine primarily activates dopamine and norepinephrine function; unlike with MDMA or LSD, serotonin is only minimally involved. D-Amphetamine promotes stimulation, wakefulness, and concentration while producing euphoria.

The distinction in effects are not quite as precise as the preceding statements imply. LSD can also induce MDMA-like empathogenic effects such as increased closeness, openness, and trust—features that initially drew the attention of psychiatry over 40 years ago.

The current study compared the acute subjective, autonomic, and endocrine effects of LSD, MDMA, and D-amphetamine at doses that produce similar cardiovascular effects. (That choice was not arbitrary.) All three substances were given to each of the participants in random order. Such a within-subject design made it possible to directly assess the differences and commonalities of these drugs in the same brain.

Conducting this type of study is challenging and the authors took great care in the design and testing. The participants were healthy females and males; their average age was 28, with a range from 25 to 45. Each subject had a 10-day washout period between drugs. Participants younger than 25 were excluded, as were people over 50, pregnant, or with a personal or family history of major psychiatric disorders or the use of medications that might interfere with the study medications (almost too many to list) or those who abused similar-acting substances for a prolonged period of time. The choice of subjects was carefully considered; for the sake of brevity, I am ignoring many of the critical details.

The results were assessed using the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale and Mystical Experience Questionnaire (MEQ). The authors monitored plasma concentrations of oxytocin, the so-called "cuddle hormone” that plays a role in social bonding as well as brain-derived neurotrophic factor, a hormone that is linked to neurogenesis because psychedelics may have a brain-regenerative potential.

Only LSD induced significant alterations of consciousness on all 5D-ASC and MEQ subscales, and those alterations were significantly greater than observed for MDMA and D-amphetamine. MDMA only moderately increased a “blissful state,” “positive mood,” and “ineffability.” D-Amphetamine only weakly increased “positive mood.” LSD produced greater overall subjective effects, including both “good drug effects” and “bad drug effects,” as compared with both MDMA and D-amphetamine. Only LSD produced significant “bad drug effects” and “anxiety.” All of the drugs produced comparable ratings of “open” and “talkative,” and ratings of “drug high" and “drug liking.”

When MDMA was compared with LSD, it induced only minimal and comparatively weak alterations of consciousness. MDMA produced some comparable (although less pronounced) positive effects as compared with LSD, but with lower associated “bad drug effects” and anxiety. MDMA produced greater ratings of “good drug effect,” “drug high,” and “drug liking,” and greater ratings of “positive mood” than D-amphetamine. MDMA also induced greater impairments in “concentration” and “speed of thinking” compared with D-amphetamine. Plasma levels of the feel-good hormone oxytocin were increased by MDMA, but not by D-amphetamine or LSD. MDMA and D-amphetamine induced comparable increases in “open” and “talkative” and “well-being” and “extraversion,” and a lack of significant “bad drug effects” or “anxiety,” as compared to LSD. Thus, overall, the results of this preliminary study demonstrated that MDMA produces less unpleasant, and more positive, effects than LSD; this may favor its use in future therapeutic trials.

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© Gary L. Wenk, Ph.D. , author of Your Brain on Food, 3rd Edition, 2019.