A paper published in Current Biology has confirmed the importance of the 5-HT2A receptor for
LSD.
Part of the paper looked at the drug's subjective effects, especially on the generation of personal
meaning.
The pharmacological side of the study involved LSD and ketanserin, a 5-HT2A antagonist.
Participants were given questionnaires to measure the subjective effects.
They were also studied using fMRI to measure LSD's impact on different regions of the brain.
All of the core subjective effects were measured, but the study had a specific focus on measures
of personal meaning and relevance.
To study this, they used music that was designated as meaningful, neutral, or meaningless for
each participant.
They then measured how LSD changed the impact of the music.
In a double-blind, randomized, crossover style, participants experienced three conditions.
Placebo
Placebo followed by LSD
And Ketanserin followed by LSD
100 micrograms of LSD and 40 mg of ketanserin were used.
The trials were completed with two weeks in between.
fMRI was employed to measure activity using the BOLD signal.
Data from the fMRI results was paired with subjective scores.
To measure the subjective effects of music, participants provided six songs they considered
personally meaningful.
They were also scanned while receiving meaningless and neutral music for comparison.
LSD led to greater scores on 9 out of 11 measures on the Altered States of Consciousness questionnaire.
It didn't have a significant effect on spiritual experiences or anxiety.
The lack of impact on spiritual experiences differed from prior research using 200 micrograms
of LSD.
It may have come from the dose, the clinical environment of the study, and from preexisting
differences with the participants.
LSD also significantly increased the personal meaning and relevance of music that was previously
deemed meaningless.
A greater BOLD signal was seen in multiple areas.
LSD led to greater activity in frontal and cortical midline regions associated with attaching
meaning to stimuli and to connecting stimuli to the overall view of the Self.
These include areas like the Dorsomedial Prefrontal Cortex, which has a connection to self activity.
Meaningless music elicited a greater response in the LSD condition compared to Ketanserin
plus LSD and compared to placebo.
This means that under the influence of LSD, otherwise meaningless stimuli can trigger
changes in brain activity associated with subjective measures of increased meaning.
There's a high density of serotonin 2A receptors in the relevant brain regions affected by
LSD.
And blocking that site with ketanserin was shown to practically eliminate the drug's
activity.
Most of the fMRI responses and subjective measures were negated with ketanserin.
Antagonizing the 2A site was shown to block LSD-induced activation of self-related brain
regions during the meaningless music condition.
This is suggestive of 2A being a very important receptor for LSD's effect.
It also suggests 2A may play a role in psychiatric illnesses, such as schizophrenia, that are
associated with problematic self-relevance and personal meaning mechanisms.
One of the few things not blocked by ketanserin was a greater BOLD signal in the Posterior
Cingulate Cortex relative to the Placebo condition.
We don't know why this was the case.
One possibility is that LSD's dopaminergic effects were responsible.
LSD is capable of increasing activity in brain regions associated with the sense of self
and the attachment of meaning to stimuli.
This same activity appears to result in otherwise meaningless music taking on personal meaning
under the influence of the drug.
When someone is exposed to both LSD and ketanserin, a 5-HT2a antagonist, most of the aforementioned
effects are blocked.
This suggests 2A is connected to LSD's ability to increase personal meaning.
It may also support the idea that the serotonin 2A system and the brain regions affected by
LSD have an important role in certain psychiatric disorders.