Landmark trial compares LSD and psilocybin trips, finds few differences

A new study published in the journal Neuropsychopharmacology has reported the results of the first modern clinical investigation to compare the acute effects of psychedelics LSD and psilocybin. The landmark study reveals little subjective difference between the two psychedelic drugs beyond the effects of LSD lasting longer than psilocybin.

Clinical research on the therapeutic uses of psychedelic drugs continues to move forward at an incredible pace. Scientists are currently investigating how psychedelics can be used to treat everything from depression and anxiety to cluster headaches and Alzheimer’s disease.

But something that hasn’t been clinically investigated, beyond blurry late-night college dorm room conversations, are the differences between LSD and psilocybin. And understanding these differences will be important as psychedelic researchers begin to focus on the best ways to therapeutically utilize these previously taboo substances.

Anecdotally, the differences between LSD and psilocybin (the psychedelic substance found in magic mushrooms) often hinge on a natural versus synthetic binary. Mushrooms are natural, so they lead to mystical, organic and introspective experiences while LSD is synthetic, generating electric, jagged and sci-fi experiences. But setting aside recreational contexts and zooming in on the acute effects of the specific drugs, there has been very little research directly comparing the two psychedelics.

One of the earliest studies directly comparing the effects of LSD and psilocybin was conducted in 1959 by controversial pharmacologist Harris Isbell. Isbell’s work on psychedelics began in the late 1950s, reportedly at the request of the CIA, and was mostly conducted using African American prisoners in jail for narcotic offenses. Interestingly, his initial findings indicating the two drugs generate similar experiential effects echo the findings of this newly published research.

The new study, led by Matthias Liechti from the University of Basel, recruited 28 healthy participants, around half of whom had never taken a psychedelic drug before. Each subject completed five different test sessions: placebo, LSD (100 and 200 micrograms) and psilocybin (15 and 30 milligrams). The sessions were double-blinded, randomized and each separated by at least 10 days.

A number of physiological and subjective measures were used to track the effects of each psychedelic experience. As well as blood pressure, heart rate, and body temperature, the researchers took regular blood samples tracking hormones such as cortisol and oxytocin. Levels of a molecule called brain-derived neurotrophic factor (BDNF) were also tracked as prior studies have indicated it could be a useful marker for neurogenesis.

“Subjective effects that were induced by both doses of LSD and the high 30 mg dose of psilocybin were largely comparable, whereas 15 mg psilocybin exerted clearly weaker effects,” the researchers write in the study. “Ratings of the high 30 mg psilocybin dose were nominally between the 100 and 200 µg doses of LSD, indicating that 30 mg psilocybin corresponds to 150 µg LSD base, a dose that was not tested herein.”

Across a number of scales used to measure subjective altered states of consciousness, the differences between the two psychedelics were mostly dose dependent. The highest psilocybin dose tested led to slightly lower subjective effects compared to the highest LSD dose.

Physiologically the effects of the two drugs were slightly different. Psilocybin seemed to lead to greater increases in arterial blood pressure, while LSD resulted in elevated heart rate. Overall, however, the researchers indicate these differences were somewhat negligible.

“When combining elevations of heart rate and blood pressure into the rate-pressure product, the high dose of psilocybin (30 mg) and both doses of LSD (100 and 200 µg) exerted overall similar cardiovascular stimulation, whereas the 15 mg dose of psilocybin exerted overall weaker effects,” the researchers wrote.

Perhaps most interestingly, the study reported highly effective blinding. This means very few subjects correctly picked which drug and dose they had been administered, apart from when they were given a placebo.

“Generally, both the low and high doses were more likely to be confused with each other rather than the high dose being exclusively mistaken for the low dose,” the researchers write. “Interestingly, this was still the case at the end of the study, despite the clear differences in effect durations between LSD and psilocybin that could be expected to unmask the blinding between substances.”

These findings of course do not mean there are no differences between psilocybin and LSD. The researchers are cautious to note the study was conducted in healthy subjects using a very highly controlled setting. So there still may be therapeutic differences between the two drugs depending on the conditions they are being used to treat.

Plus, the study used controlled doses of synthesized pure psilocybin. Some people have argued the holistic effect of magic mushrooms can be influenced by the broader interactions between different compounds in the whole plant. This idea, dubbed the entourage effect, has yet to be investigated rigorously in terms of comparing the subjective experience of whole magic mushrooms versus pure psilocybin.

Ultimately, the researchers suggest the findings can inform dose finding for future psychedelic-assisted therapy trials. The findings also point to the power of mindset and environment in affecting the characteristics of psychedelic experiences. Considering the long-held anecdotal narrative of the differences between these two psychedelics, this study offers the provocative suggestion that maybe these two drugs are more similar than many would like to think.

“These findings further support the view that alterations of states of consciousness that are induced by LSD and psilocybin are more likely dose-dependent rather than substance-dependent and that the differences in their pharmacological profiles do not relevantly influence subjectively experienced effects,” the researchers concluded.

The new study was published in the journal Neuropsychopharmacology.