Research on the Uses of LSD in Medical Settings

Psychedelics and dissociatives have a profound impact on human consciousness. Lysergic acid diethylamide, or LSD, is a synthetic compound found in the psychedelic realm. This drug induces an altered state of consciousness by transfiguring brain activity (Dyck, 2015). LSD was first synthesized in 1938 by a Swiss chemist, Albert Hofmann, but its psychoactive properties were not discovered until 1943, where Hofmann accidentally absorbed crystals of LSD through the skin (Dyck, 2015). These psychoactive properties were accidentally discovered because Hofmann was working with a newly discovered chemical found in ergot, a fungus found in tainted rye, with the intent of discovering a compound that would stimulate the respiratory and circulatory system (Liechti, 2017). With this newly discovered compound, Hofmann began to engage in self experimentation to gain a better understanding of the drug and the associating hallucinogenic effects. After further exploration of the drug, and studies on the self, he had believed that LSD had immense potential in the neurological and psychiatric fields, and continued testing on both animals and humans (Liechti, 2017). Simultaneously, LSD was becoming immersed in Western civilization after the psychoactive properties were announced and illegally made available to the public.

LSD was heavily popularized in the 1960s to escape the restrictions of society. Influential individuals, such as Timothy Leary, played a significant role in the use and acceptability of LSD, encouraging people to “turn on, tune in, and drop out” (Kupferschmidt, 2014). Influencers, such as Leary, were very dominant in this newfound movement. So much so, that Leary founded a psychedelic religion, “League for Spiritual Discovery”, intended for meditation, insight, and spiritual understanding (Kupferschmidt, 2014). Nonetheless, the epicentre of the culture around LSD use was also influenced by the popular press, sexual experimentation, artistic freedom, and cultural upheaval. Albeit a new spiritual awakening in the public, the Western intelligence community saw LSD as a potential chemical weapon (Carhart-Harris, & Goodwin, 2017). In fact, the CIA conducted a project in 1953, MK Ultra, consisting of clandestine experiments to assess the potential use of LSD for mind control, information gathering, and psychological torture (Carhart-Harris, & Goodwin, 2017). Due to this growing political pressure following the uncontrolled recreational use, clinical research hit a stand still.

Although research into LSD was coming to a halt, largely because it had become synonymous with countercultural activities, hedonism, and drug abuse, this hallucinogenic drug was originally used in clinical settings (Dyck, 2015). For example, LSD was used as an alternative therapy to treat alcoholism (Das et al., 2016). Interestingly, some psychiatrists tried to induce a form of delirium tremens, in hopes to scare alcoholics into reforming themselves (Dyck, 2015). Further, European psychotherapy clinics capitalized on LSD as they began implementing a new approach to combat mental disorders, called psycholytic therapy. In this therapy, psychiatrists administered low doses of LSD, in consecutive sessions, while patients expressed themselves through creative means such as drawings (Stevens, 1987). A different approach, psychedelic therapy, consisted of patients taking very high doses of LSD, after periods of psychological preparation, to attempt to restructure personality problems by means of eliciting a spiritual awakening (Stevens, 1987). Nonetheless, both therapies were introduced as a treatment for ailments, such as those associated with mental illness. In sum, the connection between mental illness, and disturbances of neurochemistry, has been firmly cemented into place by the discovery of LSD.

LSD has a rich pharmacology, and as such, the pharmacokinetics of LSD have been well researched. In its original form, LSD is a white, water-soluble, crystal that can be crushed into a powder and dissolved. LSD is usually administered orally by a blotter paper, however, in some instances LSD can be administered intravenously, or by inhalation (Dolder et al., 2017). Once LSD enters the user’s system, absorption of LSD is relatively rapid in the digestive tract (Dolder et al., 2017). However, the absorption rate of LSD is heavily influenced by the stomach contents and pH of the stomach and duodenum (Passie et al., 2008). The effects of the drug are felt within 30-40 minutes from absorption, and the psychological and sympathomimetic effects continue for approximately 30-45 minutes thereafter, reaching their peak after 1.5 – 2.5 hours. In a recent study, Pharmacokinetics and concentration-effect relationship of oral LSD in humans, concentrations of LSD in circulation were maximal after 1.5 hours, and gradually declined to very low levels, observing first order kinetics of LSD up to 12 hours (Dolder et al., 2017).

LSD has more diverse receptor affinities compared to its psychedelic counterparts. As such, recent research has discovered that LSD binds to serotonin receptors (Wacker et al., 2017). Further, LSD acts as a serotonin autoreceptor agonist on 5‐HT1A receptors in the locus coeruleus, raphe nuclei, and the cortex (Das et al., 2016).

Additionally, Wacker et al. (2017) discovered that the crystal structure of LSD, in complex with 5-HT2B, demonstrate rearrangements to accommodate LSD. Therefore, LSDs actions on serotonin receptors is due to the this binding mode of LSD, providing a molecular explanation for these actions(Wacker et al., 2017). Further, when LSD binds to 5-HT2B, a lid of protein slides over the drug, inhibiting the reuptake, hindering the chemicals release, therefore, exacerbating the drug effects (Preller et al., 2017). Following the binding of LSD, it is metabolized rapidly by the liver to structurally similar metabolites: inactive 2-oxy-LSD and 2-oxo-3-hydroxy LSD (Das et al., 2016).

Since LSD works on influencing the receptors associated with serotonin, the control of behavioural and regulatory systems are impacted, producing a plethora of behavioral effects (Preller et al., 2017). These effects can range from psychosis and anxious behaviors, distortions of the senses, and increased visual and auditory hallucinations (Das et al., 2016). When these behavioural systems, such as sexual desire, are disrupted, distortions in the user’s reality is profound. For example, LSD can influence sexual behaviour by heightening awareness, causing a sense of dissolution of boundaries, bringing a spiritual dimension to sex, and heightening suggestibility. Interestingly, LSD seems to have a great effect on suggestibility, as in a recent study over half the participants were more suggestible while under the influence of LSD, when compared to the control group (Carhart-Harris et al., 2015). These altered perceptions frequently result in impulsive behaviour, and if the consumption of LSD produces traumatic emotional reactions, aggressive and violent behaviour can occur (Das et al., 2016). This is especially prevalent at high doses, as LSD can frequently lead to unusual and risky behavior, which can transpire into a negative affect (Das et al., 2016).

Altogether, LSD influences many brain networks that ultimately underly human behaviour. It does so by magnifying the disconnect between the brain and the subjective experience, which allows us to better understand the basic processes of the mind (Ly et al., 2018). As stated, LSD is known to cause changes in consciousness, characterized by a stimulation of affect, including 'ego-dissolution,' or a loss of the sense of self. Knowing LSDs pharmacological effects have profound impacts on consciousness, researchers have turned to this hallucinogenic to gain a better understanding of the brain and the associating neuropharmacology.

Recently, the core hypothesis of cognitive neuroscience theories of psychedelic effects, is that these drugs interfere with the integrity of neurobiological information-processing constraint mechanisms (Ly et al., 2018). As such, reactions to LSD suggest that areas of the brain can be turned on and off, or different levels of consciousness can be activated. For example, brain scans of individuals who have ingested LSD actually show more information flowing from the thalamus to the posterior cingulate cortex (Swanson, 2018). In disrupting the brains normal communication, which separates normal functions such as vision and movement, LSD unifies these functions creating a more integrated brain (Swanson, 2018).

Research is exploring the potential use of LSD to encourage alternative ways of thinking, altering the brains habitual patterns of thought. Albeit the lack of knowledge of the exact effects that LSD has on the brain, what is known is that LSD acts on multiple receptors, especially serotonin and dopamine, which can alter cognitive functioning (Das et al., 2016). Current research has begun investigating how exactly LSD, and other psychedelics, alter one’s state of thinking. Of particular interest, Carhart-Harris and Friston (2019) have cultivated an alternative model, relaxed beliefs under psychedelics (REBUS), explaining how LSD may better help our understanding of the brain. This model explores the idea that psychedelics work to relax the precision of high-level priors, or beliefs, allowing bottom-up information to have more influence on conscious experience (Carhart-Harris, & Friston, 2019). In utilizing LSD to ease pathological priors that dominate cognition and underlie common expressions of mental illness, one can attempt to liberate bottom-up information flow, leading to a revision of pathological priors (Carhart-Harris, & Friston, 2019).

In conclusion, LSD has been used in a variety of contexts throughout the years and continues to be a popular recreational drug. Research continues to investigate the future use for LSD in a medical setting, specifically in regard to reducing the effects brought on by mental illnesses, such as anxiety. The current findings, and new discoveries of LSD’s underlying influence on the brain, highlight the brains neuropharmacology (Swanson, 2018). Such information can gear future research in new directions relating to pharmacotherapy for psychiatric disorders such as depression, addictions, or phobias (Swanson, 2018).