Lysergic acid diethylamide, commonly
known as LSD, is a mood-changing
chemical manufactured from lysergic acid, found in the ergot fungus, which is
combined with a non-organic chemical called diethylamide to produce crystals
that are converted to a liquid for distribution. It is odorless, colorless, and
has a slightly bitter taste and was first synthesized in 1938 by a Swiss
chemist, Albert Hofman, to treat respiratory depression.
LSD (also commonly referred to as
‘acid’) falls under the class of substances known as “hallucinogens” whose
primary effects include the alteration of sensory perception, mood, and thought
patterns. In 1943, Hofman accidentally discovered its hallucinogenic properties
when he absorbed some through his skin. An LSD ‘trip’ lasts anywhere between 8
to 18 hours based on the dosage and can include feelings of euphoria,
weightlessness, heightened awareness, and ‘ego dissolution’ or a
sense of being at one with the universe; as well as vivid visual and auditory
hallucinations.
In 1967, LSD was banned and
classified as a Schedule 1 drug with no acceptable medical use. Its popularity
has decreased since then and it remains illegal in the United States (U.S.) and
elsewhere. However, recent research on the neuropsychological properties of
hallucinogenic substances has illustrated an interesting tendency of LSD to
induce a short term neurobiological state that comes extremely close to that of
psychosis and a long term one that promotes optimism and well being.
In 2016, extensive research was
conducted on the impact of LSD on the brain which involved 20 physically and
psychologically healthy volunteers – each of whom received both LSD and placebo
– and all of whom had previously taken some type of psychedelic drug. During
carefully controlled and supervised experiments, each volunteer received an
injection of LSD, or a placebo. Their brains were then scanned using fMRI and
magneto-encephalography (MEG) enabling researchers to study brain activity by
monitoring blood flow and electrical activity. Clear neural correlates for some
of the behavioral effects of taking LSD were found, especially in the visual
processing circuit which showed increased “functional connectivity” (the
tendency of one part of the brain to be active at the same time as another part
of the brain, implying a functional relationship) to regions thought to be
involved in emotion and self control. In addition to this, self reported visual
hallucinations from the participants showed a strong correlation with this connectivity seen in the visual
cortex. (Carhart-Harris et. al., 2016)
These findings further indicated that
LSD potentially leads to changes in the relationships between various parts of
the brain, at least in the short term -
reducing connections between regions of the brain that govern cognitive
processes while simultaneously increasing connectivity in brain networks
associated with sensory functions. It is further believed that this almost
chaotic connectedness is what leads to the psychosis like symptoms seen in some
reported experiences with LSD; and indeed an important relationship between
both drug-induced and disorder-based psychotic states has been illustrated in
significant research, based on the serotonergic pathway in the brain (Geyer and Vollenweider, 2008). Psychomimetic
symptoms (feelings of psychosis-like symptoms), are often reported by
participants including visual hallucinations, spiritual experiences, and
paranoia. . Studies on
hallucinogenic drugs that function as agonists at serotonin-2A receptors have
concluded that disordered functioning of very similar receptor channels
interact with other monoaminergic and glutamatergic systems to modulate states
of consciousness and contribute to psychotic disorders such as several types of
schizophrenia.
On the other hand however, studies
have also been conducted pointing to the potential long term benefits of
hallucinogenic drugs in alleviating anxiety states. Arecent study
demonstrated the efficacy of LSD-assisted psychotherapy in patients of anxiety
associated with life-threatening diseases. After 12 months of finishing
clinically administered LSD psychotherapy, 10 participants were tested for
anxiety and participated in an interview to elaborate about LSD effects and
lasting psychological changes over the course of its administration. Significant benefits were sustained over a 12-month period
by the participants who reported reduction in anxiety and a rise in quality of
life. Evaluation of subjective experiences suggested an increased access to
emotions and confrontation of anxieties as well as intense emotional peak
experiences linked to restructuring of thought processes. (Gasser et. al. 2014)
Research is yet to arrive at a fully conclusive answer that explains the dichotomy in these effects produced by LSD, but studies conducted so far point strongly towards the role of the Serotonin 2A receptor - 5-HT2AR which is expressed particularly in brain regions associated with cognitive functions and social interactions. LSD binds to and stimulates 5-HT2AR in the cerebral cortex, which regulates an enzyme called phospholipase C, and eventually leads to psychoactive effects. A recent study using crystallography zeroed in on images of an LSD molecule inside a serotonin receptor which showed that when LSD binds to serotonin, it gets stuck within an inner pocket inside the receptor and can’t get out. The serotonin receptor’s protein structure then forms an extracellular ‘lid’ over the LSD molecule, further trapping it in, and leading to slow dissolution from the receptor itself (Wacker et. al, 2017). The idea is that once LSD binds to the receptor, the initial burst of stimulation results in a more intense, acute psychotic-like state of consciousness; however, the longer-term effects produce a contrasting “loosening” of neural network dynamics which may be linked to a general increase in optimism and well-being.
While the immediate implications of
these studies point to the clinical relevance of LSD’s long lasting effects and support
the idea of using LSD in the treatment of mood and anxiety disorders; they
also address the apparent paradox of psychedelics and the distinct effects
they produce. Further qualitative research must be carried out in order to
fully uncover the potential of LSD and other hallucinogenic substances both as
a model of, and yet a treatment for psychopathology
REFERENCES
Carhart-Harris, R. L.,
Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., . . .
Nutt, D. J. (2016). Neural correlates of the LSD experience revealed by
multimodal neuroimaging. Proceedings of the National Academy of
Sciences, 113(17), 4853-4858. doi:10.1073/pnas.1518377113
Gasser, P., Kirchner, K., &
Passie, T. (2014). LSD-assisted psychotherapy for anxiety associated with a
life-threatening disease: A qualitative study of acute and sustained subjective
effects. Journal of Psychopharmacology, 29(1), 57-68.
doi:10.1177/0269881114555249
Geyer, M., & Vollenweider,
F. (2008). Serotonin research: Contributions to understanding psychoses. Trends
in Pharmacological Sciences, 29(9), 445-453.
doi:10.1016/j.tips.2008.06.00
Wacker, D., Wang, S., Mccorvy, J.,
Betz, R., Venkatakrishnan, A., Levit, A., . . . Roth, B. (2017). Crystal
structure of the LSD-bound 5-HT2B receptor. doi:10.2210/pdb5tvn/pdb
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