LSD: The Ultimate Guide

Overview: In 1938, Swiss chemist Albert Hofmann accidentally discovered LSD while researching ergot derivatives. It gained popularity but was eventually stigmatized due to its association with countercultural movements. LSD profoundly affects perception, cognition, emotion, and ego, often leading to mystical experiences but can also cause "bad trips." Despite its therapeutic potential observed in early studies, research was halted in the 1970s. Recent studies suggest LSD may have therapeutic benefits, particularly in reducing anxiety in patients with life-threatening illnesses, alcohol addiction, and generalized anxiety disorder.

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LSD: From Lab to Counterculture

In the year 1938, A Swiss chemist by the name of Albert Hofmann, working out of Sandoz Pharmaceuticals, became the first man to synthesize Lysergic Acid Diethylamide (LSD). Active at the microgram level (one-millionth of a gram), LSD is the most potent psychoactive drug known to humankind.
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It wasn't long after Hofmann’s discovery that LSD was being used by medical professionals to achieve behavioral and personality changes and to treat a variety of mental health conditions.

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However, it soon leaked from the lab, quickly gained mainstream popularity, and became associated with countercultural movements, anti-establishment sentiments, and challenges to conventional authority. Controversial public figures like psychologist Timothy Leary passionately advocated for their use as tools for personal and spiritual exploration, which clashed with prevailing social norms and government policies. This, in conjunction with sensationalist media reporting, provoked the drug’s classification as a schedule one substance in 1970. 
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The scheduling of psychedelic drugs, such as LSD, psilocybin, and DMT, has been subject to much debate and scrutiny. While official justifications often cited concerns about public health and safety, there is evidence to suggest that political and cultural factors played significant roles in their classification as Schedule I substances.

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Many argue that the decision to criminalize and tightly regulate these substances was influenced by a desire to suppress dissent and maintain social control rather than genuine concern for public health. The fear of psychedelics' potential to challenge established belief systems and societal structures — their ability to “dissolve opinion structures” — to quote the late, great, ethnobotanist and orator, Terence Mckenna, likely contributed to their stigmatization and legal prohibition.
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Leary and McKenna were known for their perspectives on psychedelics as catalysts for consciousness expansion and cultural transformation. They often criticized the political motivations behind drug prohibition and spoke about psychedelics' capacity to disrupt entrenched patterns of thought and behavior.

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There can be no doubt that when applied properly, LSD can induce a boundless variety of psychedelic experiences, from the awe-inspiring and spiritually insightful to the deeply meaningful and powerfully therapeutic . That said, the history of psychedelic use in the west teaches us that LSD is not a magic bullet cure-all, nor does it guarantee everlasting love and enlightenment.

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What is LSD?

Interested in derivatives of lysergic acid, an unnatural product of an ergot (Claviceps purpurea) alkaloid called ergotamine, Albert Hofmann was actually trying to obtain a central nervous system stimulant when he synthesized LSD.

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Unimpressed by its mild stimulative effects, Hofmann decided to shelve the psychedelic ergoline for 5 years. Then, in April of 1943, Hofmann experienced a “peculiar presentment” that LSD deserved to be re-investigated, and in synthesizing it for the second time, he accidentally ingested a small dose that had a compelling threshold effect.

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Noticing a pronounced alteration of his consciousness, Hofmann became enthralled by “unusual sensations”, which would soon develop into what he described in his autobiography, LSD, My Problem Child, as a “dreamlike state”, characterized by an “uninterrupted stream of fantastic pictures, extraordinary shapes with an intense, kaleidoscopic play of colors.”

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3 days later on April 19, at 4.20 pm, Hofmann ingested 250 micrograms, about 1.5 times the typical recreational dose (although false quantification of dosages is very common), and became the first man in history to intentionally trip on LSD. Hofmann somehow managed to safely make it home on his bicycle with the help of his lab assistant, whom he had asked to accompany him on the 5-kilometer ride home.

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Hofmann’s discovery of LSD’s effects is now commemorated on April 19, a.k.a. "Bicycle Day.”

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After enduring the first-ever “bad trip”, one that was dyed with a fear of impending death, Hofmann experienced an afterglow effect in the proceeding days, remarking that

‍“everything glistened and sparkled in a fresh light. The world was as if newly created.”

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Convinced that LSD had discovered him, rather than vice versa, Hofmann predicted that LSD could be used as an effective adjunct to psychotherapy.

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What Are the Effects of LSD?

LSD is known for its profound effects on perception, cognition, emotion, and sense of self, taking hold 20-60 minutes after ingestion and typically lasting for 8-12 hours. These effects can vary widely from person to person and depend on factors such as dosage, set and setting, and individual susceptibility.

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Here's a brief breakdown of how LSD can influence each of these aspects:

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• Perception: LSD can dramatically alter perception, leading to changes in sensory experiences such as visual distortions, enhanced colors, and heightened sensitivity to sounds and textures. These perceptual changes can manifest as colorful closed-eye visuals (often kaleidoscopic/geometric), surfaces and objects appearing as if they are "breathing," shifting, or changing form, and synesthesia (the blending of sensory experiences).

• Cognition: LSD can profoundly affect cognitive processes, including thinking, problem-solving, and memory. Users may experience changes in thought patterns, such as increased introspection, abstract thinking, and insightfulness. However, LSD can also impair cognitive functioning, leading to confusion, disorientation, and difficulty concentrating, particularly at higher doses.

• Emotion: LSD can evoke a wide range of emotional experiences, from euphoria and awe to anxiety and fear. These emotional states can be intensely felt and may fluctuate rapidly throughout the trip. Some users report feelings of profound connection, empathy, and love, while others may encounter challenging emotions or confront unresolved psychological issues.‍

• ‍Sense of Self (Ego): LSD can profoundly alter one's sense of self, often leading to ego dissolution. This involves a temporary loss of the boundaries that typically define the self, leading to experiences of unity, interconnectedness, and transcendence. Ego dissolution can be accompanied by feelings of ego transcendence, oneness with the universe, and a profound sense of insight and liberation. However, it can also provoke feelings of existential dread, identity confusion, or fear of losing control.

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Ego dissolution can be, understandably, very frightening but it can also be welcomed as something positive depending on the person’s mindset going into the experience and the environment in which it takes place.

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Experts suggest that the key to successfully navigating this precarious sensation is to confront the fear. “Trust. Let go. Be open” — the wise words of Johns Hopkins psychologist, Bill Richards, who has served as a therapist for hundreds of patients in their psychedelic journeys. Of course, this is easier said than done but speaks to the importance of having a therapist or trusted person to provide support for the duration of the experience.
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Once it isn’t resisted, ego dissolution may be accompanied by a transcending sense of being a part of something greater than oneself, a powerful feeling of “at-onement” with the wider universe, and mystical-type experiences. LSD-induced mystical experiences may be characterized by a deeply-felt positive mood, peace and joy, profound feelings of unity or interconnectedness, transcendence of space and time, a sense of sacredness, and a belief that the experience is a source of objective truth about the nature of reality.

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Mystical experiences have been associated with better therapeutic outcomes in clinical trials. The shift in perspective that follows an experience of being a part of something greater than oneself is often a catalyst for personal change.

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Bad Trips On LSD

While many people have positive and transformative experiences with LSD, it can also lead to challenging experiences colloquially known as a "bad trip."

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Several factors can contribute to the onset of a bad trip, including:

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• Preparation: Being mentally prepared involves having an understanding of what to expect from an LSD experience, including both the potential benefits and risks. This can include educating oneself about the effects of the drug, learning about harm reduction strategies, and cultivating a mindset of openness and acceptance. Without proper mental preparation, individuals may be more susceptible to feeling overwhelmed or disoriented during the trip.‍‍

• ‍Set and setting: The mindset and environment in which the LSD experience occurs can significantly influence its outcome. Negative emotions, pre-existing mental health issues, or being in an unfamiliar or uncomfortable setting can increase the likelihood of a bad trip.

• ‍‍‍Dosage: Taking a high dose of LSD can intensify its effects, increasing the likelihood of experiencing overwhelming sensations and emotions.

• ‍Personal susceptibility: Some individuals may be more prone to experiencing negative reactions to LSD due to underlying psychological factors or sensitivity to the drug's effects.

• ‍Drug interactions: Mixing LSD with other substances, including alcohol or certain medications, can amplify its effects and increase the risk of a bad trip.

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During a bad trip, individuals may experience intense feelings of anxiety, paranoia, confusion, and fear. These feelings can be overwhelming and distressing, potentially leading to a sense of loss of control or connection with reality.

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LSD experiences can bring into question some of our most basic assumptions of reality, ourselves, and the people in our lives. Once termed “non-specific amplifiers of mental processes” by the pioneering LSD psychotherapist and author Stanislav Grof, psychedelics tend to bring to the surface thoughts and memories that may have hitherto been ignored or repressed.

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It's important to note that while a bad trip can be distressing, it is usually temporary, and the effects of LSD typically wear off within several hours. Although such experiences can cause considerable distress, and may in rare cases have lingering psychological consequences, they are generally insightful and therapeutic. The majority of clinical trial participants and recreational users consider their challenging psychedelic experiences to be highly beneficial and personally meaningful.
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The therapeutic potential of challenging experiences is evidenced in a landmark study led by the late former Johns Hopkins researcher, Dr. Roland Griffiths, wherein one-third of participants who reported their psilocybin journey to be one of the most terrifying experiences of their entire lives, also reported it to be the most spiritually significant.

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However, individuals experiencing severe distress or psychological symptoms during a bad trip may benefit from professional support and guidance to help manage their experience. In a clinical context, challenging experiences may be necessary to help people break free from negative rumination and constricted worldviews. In the aftermath of a challenging experience, most patients  return to their lives with fresh perspectives and a state of consciousness more conducive to living a happy and healthy life.

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Following a psychedelic experience, positive or negative, integration becomes crucial. Integration refers to the process of making sense of and incorporating insights, emotions, and experiences gained during a psychedelic journey into one's everyday life. It involves reflecting on the psychedelic experience, identifying its significance, and finding ways to apply any lessons learned or insights gained to personal growth and development.

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LSD and The Brain

Marketing it as an effective model for psychosis, Sandoz pharmaceuticals sent supplies of LSD to mental health professionals all over the world who believed it could be used as a psychotomimetic (i.e. a drug capable of producing an effect on the mind similar to a psychotic state.)
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As a consequence, scientists, who up until that point were under the illusion that psychiatric disorders were the result of bad parenting, began to make the connection between brain chemistry and behavior — this connection may seem obvious now, but it was considered quite radical at the time.
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Then, in 1953, a biochemist by the name of Betty Twarog became the first person to isolate serotonin in the mammalian brain, much to the disbelief of her supervisor. It can be said that Albert Hofmann’s discovery of LSD sparked a revolution in neuroscience, led at least in part, by the determined Betty Twarog. 

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How Does LSD Produce its Effects? 

Pharmacologically rich, LSD is jokingly said to be a promiscuous molecule due to its activity at a whole host of brain receptors. Receptors are proteins located on nerve cells (neurons) that serve as docking sites for specific molecules, such as neurotransmitters or drugs. When a molecule binds to its corresponding receptor, it triggers a series of biochemical events within the cell, leading to various physiological responses.

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The most important of these to remember is the 5-HT2A serotonin receptor, which is the essential receptor for producing LSD’s psychedelic effects. When LSD enters the 5-HT2A receptor cell, it essentially gets trapped there and takes the place of serotonin. Unlike serotonin, LSD doesn't directly activate the receptor. Surprisingly, for such a potent compound, LSD is a rather weak agonist. 
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Responding to LSD, the receptor changes its form to accommodate the larger, more rigid LSD molecule, which then interacts with the exterior part of the cell and couples to signaling molecules. The specific signaling patterns subsequently stimulated are what mediate the psychedelic actions of LSD. 
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Signaling patterns are dependent on the nature of the chemical inside, and so LSD-induced signaling events are altogether different from those produced by serotonin and other drugs. This phenomenon (activation by different agonists leading to different signaling events) is known as functional selectivity.  
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Recent research indicates that the LSD-bound serotonin receptor may form a "lid" that keeps the LSD molecule inside the receptor for long stretches. The formation of this lid could provide a molecular explanation for LSD’s sticktoitiveness and long duration of action despite its weak agonism. 

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LSD also has an affinity to dopaminergic and adrenergic receptors, unlike other psychedelics. However, interaction with these receptors is thought not to play a significant role in LSD's effects. 

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Therapeutic Potential of LSD

Clinical studies conducted between the 1950s and 1970s investigating the therapeutic potential of LSD yielded positive outcomes up until research was strictly prohibited.
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During that period, three different LSD therapy approaches were employed in clinical trials: “psycholytic therapy”, wherein low doses of LSD were used in continuing therapy sessions, “psychedelic-chemotherapy”, which used high doses with limited therapeutic input, and plain old “psychedelic therapy”, in which a single high dose was administered to induce a mystical-type experience to be monitored by a therapist or nurse.
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LSD was observed to reduce pain, anxiety, and depression, and treat alcohol-use disorder, and heroin-use disorder. Other studies involving larger patient samples demonstrated LSD’s impressive safety profile (it does not entail physical dependency or exhibit physiological toxicity) and positive outcomes in terminally ill cancer patients.  These studies largely failed to meet the design criteria of contemporary clinical investigation. As a consequence, it is best to interpret this early evidence of LSD’s healing power as preliminary evidence of therapeutic efficacy.
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Now, however, LSD is regaining traction as a therapeutic aid. The first double-blind, randomized, active placebo-controlled study conforming to modern standards observed that LSD-assisted psychotherapy significantly reduced anxiety in patients with life-threatening diseases. Additionally, the clinical-stage biopharmaceutical company MindMed recently announced the results of their Phase 2 study of LSD-assisted psychotherapy for anxiety, also reporting significant and enduring reductions in symptoms. 

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The FDA has recently designated a form of LSD as a breakthrough therapy for the treatment of generalized anxiety disorder (GAD). This decision highlights the growing recognition of psychedelics' therapeutic potential in addressing mental health conditions. The designation signifies that the FDA recognizes the significant benefits of this form of LSD in treating GAD and aims to expedite its development and review process

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After a decades-long hiatus in LSD research, this fascinating compound is again showcasing its far-reaching potential.