In 1938, Swiss chemist Albert Hofmann synthesized a derivative of alkaloid ergotamine, a natural compound found in a parasitic fungus called ergot. He had no way of knowing that as little as 20 micrograms of this substance would cause a psychedelic effect!

Back in the first half of the 20^th century, there were not many methods to characterize new chemical compounds, let alone to establish the structure of complex natural substances such as alkaloids. Doing a bit of self-experimentation in the form of examining the smell and test of newly synthesized chemicals was a well-established and routine practice. In fact, many scientific journals of that period reported, among other things, the smell and taste of new compounds. So it doesn’t come as a surprise that Albert Hofmann decided to taste a new compound, which he called LSD-25 (Lysergic acid diethylamide derivative 25), and put a tiny crystal on his tongue.

Since then, LSD became a source of fascination for scientists, psychologists, recreational users and spiritual enthusiasts alike.

Lysergic acid diethylamide was repeatedly abused in the 1960s by young adults as a hallucinogenic substance. Its effects on patients with mental disorders and when combined with alcohol therapy have been studied since it was first discovered to have psychoactive effects. The research studies eventually stopped due to the drug’s effects on the users: irritability, unpredictability, erratic behavior and violence which often lead to injury and sometimes self-harm.

LSD is a potent drug – the smallest amounts can stimulate the central nervous system, while its usual dose can induce psychedelic effects. The compound is classified as a Schedule I drug in the USA, which means that is illegal to buy and possess. The DEA considers that the drug has no legitimate medical use and a high potential for abuse. The research data from the UK, however, show that the use of LSD is associated with one of the lowest levels of personal and social harm compared to the other recreational drugs, nicotine and alcohol.

I think the interest in LSD results primarily from the strength of its effect on our brain. This is, in itself, a very interesting effect worth studying even if the practical applications of any findings remain nebulous. Knowing how LSD works can help us to understand how our brain works.

WHat LSD does in the brain

The hallucinogenic effects of LSD result from its antagonistic action to serotonin in the brain. LSD inhibits serotoninergic neurons in the raphe nuclei. Its direct inhibitory effect to the raphe neurons is due to its potent agonistic effect on the 5-HT_1a autoreceptors.

The strength of the hallucinogenic effect of LSD is dependent on its affinity to another subtype of serotonin receptor, 5-HT_2. This receptor subtype is present on the locus ceruleus and the cerebral cortex. The locus ceruleus is indirectly affected by LSD through other mechanisms. However, it is important to note that this nucleus receives synapses from a wide area of the brain. Majority of 5-HT₂ receptors are found in the cerebral cortex. Enhanced response of the neurons in the locus ceruleus brings about a perceptive experience similar to those caused by hallucinogens such as LSD. At the same time, persistent stimulation of 5-HT₂ receptors found in the cerebral cortex causes thinking and sensing distortions. Hallucinogens like LSD minimize the release of serotonin into the postsynaptic neurons by disallowing the somatodendritic 5-HT_1a receptors to activate serotoninergic neurons.

With the use of imaging modalities such as MRI, a recent study has shown that there is an increased flow of blood towards the occipital area, particularly the visual cortex, under the influence of LSD. This may be the reason why people on LSD have profound visual hallucinations.

The researchers also found that neurons that normally fire together in a non-hallucinating state fail to do so while under the influence of LSD, and at the same time some of the neurons which do not usually fire together become synchronized. The participants in this study felt a sense of connectedness with their own environment, or ego-dissolution, proportional to the decreasing ability of the neurons to fire together while on LSD. LSD and psychedelics allow the brain to function in a more cohesive manner such that it unites the person’s own thoughts with his/her environment. It is said that the brain resembles an infant’s mind and that the person on LSD becomes hyperemotional and imaginative.

Furthermore, another study has shown that under the influence of LSD there is an increased neuronal connectivity at the fronto-parietal cortex, the area of the brain responsible for self-consciousness. Increased connectivity also occurs from this region of the brain towards the areas of the brain responsible for sensory responses, hence producing the feeling of increased connectivity of a person to his/her environment.

Although it’s the visual cortex that mainly contributes to the hallucinations and associated feelings while under the influence of LSD, other parts of the brain also contribute to the visual hallucinations. The parahippocampal girus, the region of the brain that plays an important role in the memory encoding and retrieval, communicates more with the visual cortex under the influence of LSD, thus allowing this area to receive more information than usual.

Studies have shown that the use of LSD and other psychedelics is not a factor for the development of mental illness, even among chronic users. These discoveries have opened the way for LSD to be used for psychiatric conditions. Some experts believe that positive effects from LSD use outweigh the negative ones, such as momentary feelings of anxiety and confusion. Furthermore, long-term psychedelic use has not been associated with addiction disorders when the drug is used alone and with no other factors involved.

LSD was considered by many researchers for therapeutic use in the treatment of alcoholism. LSD maximizes the brain’s neural plasticity. The ability of the brain to be manipulated in an LSD-induced state can be utilized for psychotherapeutic methods as an intervention for addiction disorders by allowing new behavior patterns to be introduced to a patient. These findings have been manifested in a study conducted with a group of volunteers, who showed increased suggestibility and responsiveness to ideas being suggested, while on LSD. More resent analysis has shown, however, that the treatment with LSD produces no long-term effects.

It is clear that LSD causes serious changes in brain work. Further studies of this interesting substance may help us to gain the understanding of more enigmatic aspects of our mental functioning and information processing.

References

Aghajanian, G. (1994). Serotonin and the Action of LSD in the Brain Psychiatric Annals, 24 (3), 137-141 DOI: 10.3928/0048-5713-19940301-09

Carhart-Harris, R., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., Tagliazucchi, E., Schenberg, E., Nest, T., Orban, C., Leech, R., Williams, L., Williams, T., Bolstridge, M., Sessa, B., McGonigle, J., Sereno, M., Nichols, D., Hellyer, P., Hobden, P., Evans, J., Singh, K., Wise, R., Curran, H., Feilding, A., & Nutt, D. (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

Carhart-Harris, R., Kaelen, M., Whalley, M., Bolstridge, M., Feilding, A., & Nutt, D. (2014). LSD enhances suggestibility in healthy volunteers Psychopharmacology, 232 (4), 785-794 DOI: 10.1007/s00213-014-3714-z

Krebs, T., & Johansen, P. (2012). Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials Journal of Psychopharmacology, 26 (7), 994-1002 DOI: 10.1177/0269881112439253

Tagliazucchi, E., Roseman, L., Kaelen, M., Orban, C., Muthukumaraswamy, S., Murphy, K., Laufs, H., Leech, R., McGonigle, J., Crossley, N., Bullmore, E., Williams, T., Bolstridge, M., Feilding, A., Nutt, D., & Carhart-Harris, R. (2016). Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution Current Biology, 26 (8), 1043-1050 DOI: 10.1016/j.cub.2016.02.010

Taylor, M., Mackay, K., Murphy, J., McIntosh, A., McIntosh, C., Anderson, S., & Welch, K. (2012). Quantifying the RR of harm to self and others from substance misuse: results from a survey of clinical experts across Scotland BMJ Open, 2 (4) DOI: 10.1136/bmjopen-2011-000774

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