From the mythical visions of church goers who took mushrooms in the infamous ‘Good Friday Experiment’ to the extreme self-reflection of those ‘tripping’ off the traditional South American hallucinogenic tea Ayahuasca (1,2), humans have been painting the extraordinary narratives of psychedelics for thousands of years in thousands of settings.

Put simply, psychedelics are a class of psychoactive drugs that can alter your thoughts and senses, inducing wild experiences not thought possible in your brain’s ground state (3). One of the most famous of these drugs is LSD. ‘Lucy in the Sky with Diamonds’ is said to have inspired entire Beatles albums and shown Steve Jobs “that there’s another side to the coin” of life (4,5). LSD is also a psychedelic that stands as an enigma in many regards. It is both naturally derived and synthetically created. It has been tested in psychological therapy and psychological warfare. Even the ‘trips’ experienced by its users entail both unexplainable hallucinations and scientifically proven phenomena. 

While being lesser understood, the stories of LSD’s enigmatic origins, uses and effects are just as interesting as those that come from its users. 

The Origins   

Lysergic Acid Diethylamide (LSD) or ‘acid’ for short is a semi-synthetic chemical compound with humble biological beginnings. LSD is derived from a class of alkaloid metabolite molecules that are naturally produced by the fungus commonly known as ergot. Ergot fungi are members of the parasitic genus Claviceps, which have been infecting staple crops and shaping society long before acid came to distort shapes in the eyes of its users (6). 

Epidemics of ergotism, a disease caused by these ergot alkaloids after ingesting contaminated crops, swept across Middle Age Europe and led to the deaths of tens of thousands of people (7). Despite credible arguments to the contrary, some historians have even suggested that the Salem Witch Trials may have been sparked by a form of this disease known as convulsive ergotism. Not only were the environmental conditions in 1691 Salem reported to be optimal for ergot growth in the town’s rye, but convulsive ergotism also induces distinct muscle contractions, paranoia and audiovisual hallucinations (8). These symptoms all would have given credit to the claims of bewitchment made by the young girls that instigated the accusations of witchcraft in the town.

Aside from death and dark magic, this fungus has also been used as an effective therapeutic across several eras of history. It’s use as a medication for childbirth was recorded as early as 1100 BCE in China, with midwives using ergot or it’s alkaloids to reduce bleeding during birth, expedite delivery or induce an abortion (6,7). It wasn’t until modern pharmacology advanced in the 20th century that scientists began to chemically characterise these ergot alkaloids and use them as the basis to create potent drugs.

The story of how LSD was first created and consumed is one that has been immortalised in history books and unofficial holidays. Dr Albert Hoffman, a Swiss biochemist working for the pharmaceutical company Sandoz, first synthesised LSD in 1938 as the 25th substance in a series of lysergic acid derivatives being evaluated by the company (9). Initial testing of this compound indicated it had no unique pharmacological uses beyond those of pre-existing ergot alkaloid derived drugs (9). 

However, Hoffman couldn’t shake the nagging feeling that LSD-25 had more to offer. After making another batch of the compound 5 years later, Hoffman’s suspicions grew stronger when he was forced to leave the lab early after entering a “dream-like state… [with] a kaleidoscope-like play of colours” (9). A few days later, in a moment that demonstrated both admirable scientific curiosity and blatant rejection of OH&S, Hoffman took a large dose of LSD himself and set in for a trip of a lifetime (9). Like all good scientists, he recorded his experience in a journal, writing at 3pm on 19 April 1943: 

“visual distortions, symptoms of paralysis, desire to laugh” (9). 

Hoffman’s notes for the day stopped there.

The Uses

April 19th has come to be celebrated as ‘Bicycle Day’, commemorating the seemingly endless and surreal bike ride home Hoffman undertook after this self-experimentation. However, a wacky trip was not the only thing that followed this discovery. After Hoffman distributed the drug to his superiors to try for themselves, LSD was sold on the market by Sandoz under the name Delysid. This drug was employed by psychiatrists throughout the 1950s as a treatment for alcoholism or simply ‘psychotherapy-in-a-pill’ for patients suffering psychological trauma (10,11). 

LSD not only garnered therapeutic interest from scientists but also more nefarious intrigue from the CIA. Seeking to get an upper hand in the department of mental warfare during the Cold War, the CIA bought up 40,000 doses of LSD from Sandoz and performed a variety of unethical experiments on unknowing prisoners, heroin addicts and even other CIA agents in an attempt to understand the drug’s potential for ‘mind control’ under the MKUltra project (12). 

Moving into the 60s, LSD’s use amongst budding leaders of the Hippie and Yippie movements gave the drug its countercultural status. Harvard Professor Timothy Leary, who was dismissed from his position due to experimenting (literally) with LSD, promoted the drug as an agent of revolution that allowed the youth of America to “turn on, tune in, drop out” (10) of repressive society. Due to its increasing association with these disruptive movements and eventual outlawing by the US government in 1966 (11), acid’s place in culture shifted out of labs and psychologist offices and into illicit recreational usage by experimental hippies and enlightened artists.

The Trip

Whether accompanied by an experienced monitor or listening to some soothing vinyl records yourself, the experience of taking LSD is predictably unpredictable. ‘Dropping acid’ is unique in that only micrograms of the drug are enough to elicit a palpable psychedelic experience (13), with most users diluting the dosage on tabs of blotting paper or sugar cubes (11). Following consumption, it takes as little as 1.5 hours for LSD to cross the blood-brain barrier, dilate the pupils and bring users to the peak intensity of the drug’s psychological effects (13). 

The bizarre experiences perceived by those ‘tripping’ on LSD is rooted in a now well-characterised receptor binding interaction in the brain. The nitrogen-based chemical groups of the LSD molecule first anchor themselves within the 5-HT2A serotonin receptors found in the synapses of neurons (14). While the serotonin neurotransmitter typically helps regulate brain activities like mood and memory, LSD binding instead causes the activation of distinct intracellular cascades within these brain cells (3). The importance of this interaction was demonstrated in experiments that proved blocking this receptor can cancel the acid trip all together (3). Recent studies that have further characterised the chemical structure of this interaction have also shown that 5-HT2A forms a lid-like structure that locks LSD into this receptor protein’s binding site and sets the user in for a long trip (14).

From these individual cellular interactions, LSD ignites a burst of brain activity. Modern brain scanning technology has revealed that LSD first disrupts the capacity of the thalamus to filter and pass on sensory stimuli from the body to the cortex of the brain. Upon injection of LSD, patient’s brains demonstrated both an overflow of information running between the thalamus and posterior cingulate cortex and restriction of signals going to the temporal cortex (15).      

Not only does LSD modify the brain’s ability to sort out important stimuli from the outside world, but this small molecule has also been found to temporarily form new connections between different parts of the brain. Hoffman’s recount of how “every sound generated a vividly changing image” (9) on the first Bicycle Day can be explained by the increased connectivity of the brain’s visual cortex on LSD. This causes areas of the brain responsible for other senses or emotions to become involved in creating the images perceived in the user’s head, causing visual hallucinations and geometric distortion that have no basis in real stimuli coming from the eyes (16).      

In contrast, Hoffman’s feeling of being “outside [his] body” (9) likely came from decreased connectivity between the parahippocampus and retrosplenial cortex, two regions of the brain responsible for cognition. This severance has been correlated with the greater meaning that those tripping on LSD find in objects, events or music along with their characteristic ‘ego dissolution’ (16). This is a phenomenon where users no longer see the world through the lens of their own ‘self’ and instead feel an increased sense of unity with everything around them (17). Very Hippie ideas with a very scientific explanation.

The Comedown and Beyond

The float back down from the peak of an LSD trip takes up to 10 hours and leaves its users with a variety of stories and outcomes. Contrary to the fearmongering of parents and politicians, LSD does not leave holes in the brain, does not lead to addiction and has not directly led to the death of anyone as a result of overdosage (3). While the risk of a ‘bad trip’ and the feelings of severe anxiety, fear and despair that come with it may be traumatic, these are typically experienced when taking LSD in unsupportive environments without proper mental preparation (13). In fact, when LSD is taken in a manner closer to the controlled ritual practices surrounding psychedelics of old (3), acid is suggested to have long-lasting positive impacts on the user’s attitude and personality (13).

It is these experiences that have rejuvenated the field of LSD research from its abrupt stop in the 60s. Modern investigations have picked up where these scientists left off and are evaluating the potential of utilising LSD-assisted therapy to alleviate anxiety and depression. Studies have focused particular attention on addressing these mental health conditions in those suffering from life-threatening illnesses like cancer (18). While some of these experiments lack the controls or data to make strong generalised conclusions, several studies have demonstrated that patients supplied with LSD reported lasting decreases in anxiety surrounding their condition, greater responsiveness to their families and improved quality of life (3,18).

All of this is not to promote LSD as a harmless wonder drug. While rare, LSD has been linked to Hallucinogen Persisting Perception Disorder, a condition in which people experience distressing ‘flashbacks’ to the effects and experiences of past psychedelic trips in a normal setting. Additionally, the changes in visual perception, emotion and thought while one is tripping can also cause users to make reckless decisions in dangerous situations (18). However, continuing to wage war against controlled experiments and supervised therapeutic trials with LSD only serves to limit the attempts of scientists in better understanding the balance between this drug’s risks and benefits. 

While our trip through the life of LSD may end here, there is still much to explore. The greater story of how we use it, how we view it and how it fits into our society is far from over.

References

1. Illing S. Vox. 2018 [cited 2024 Oct 23]. The brutal mirror: what the psychedelic drug ayahuasca showed me about my life. Available from: https://www.vox.com/first-person/2018/2/19/16739386/ayahuasca-retreat-psychedelic-hallucination-meditation

2. Majić T, Schmidt TT, Gallinat J. Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences? J Psychopharmacol. 2015 Mar 1;29(3):241–53.

3. Nichols DE. Psychedelics. Barker EL, editor. Pharmacol Rev. 2016 Apr 1;68(2):264–355.

4. Gilmore M. Beatles’ Acid Test: How LSD Opened the Door to “Revolver” [Internet]. Rolling Stone. 2016 [cited 2024 Oct 23]. Available from: https://www.rollingstone.com/feature/beatles-acid-test-how-lsd-opened-the-door-to-revolver-251417/

5. Hsu H. The Lingering Legacy of Psychedelia. The New Yorker [Internet]. 2016 May 17 [cited 2024 Oct 23]; Available from: https://www.newyorker.com/books/page-turner/the-lingering-legacy-of-psychedelia

6. Haarmann T, Rolke Y, Giesbert S, Tudzynski P. Ergot: from witchcraft to biotechnology. Molecular Plant Pathology. 2009 Jul;10(4):563–77.

7. Schiff PLJ. Ergot and Its Alkaloids. American Journal of Pharmaceutical Education. 2006 Oct 15;70(5):98.

8. Woolf A. Witchcraft or Mycotoxin? The Salem Witch Trials. Journal of Toxicology: Clinical Toxicology. 2000 Jan;38(4):457–60.

9. Hofmann A. How LSD Originated. Journal of Psychedelic Drugs. 1979 Jan 1;11(1–2):53–60.

10. Massari P. Harvard Griffin GSAS News. 2021 [cited 2024 Sep 28]. A Long, Strange Trip | The Harvard Kenneth C. Griffin Graduate School of Arts and Sciences. Available from: https://gsas.harvard.edu/news/long-strange-trip

11. Stork CM, Henriksen B. Lysergic Acid Diethylamide. In: Wexler P, editor. Encyclopedia of Toxicology (Third Edition) [Internet]. Oxford: Academic Press; 2014 [cited 2024 Sep 28]. p. 120–2. Available from: https://www.sciencedirect.com/science/article/pii/B9780123864543007442

12. Stuff You Should Know. Did the CIA test LSD on unsuspecting Americans? - Stuff You Should Know [Internet]. [cited 2024 Aug 25]. (Stuff You Should Know). Available from: https://www.iheart.com/podcast/1119-stuff-you-should-know-26940277/episode/did-the-cia-test-lsd-on-29468397/

13. Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A. The Pharmacology of Lysergic Acid Diethylamide: A Review. CNS Neurosci Ther. 2008 Nov 11;14(4):295–314.

14. Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, et al. Crystal structure of an LSD-bound human serotonin receptor. Cell. 2017 Jan 26;168(3):377.

15. Sample I. Study shows how LSD interferes with brain’s signalling. The Guardian [Internet]. 2019 Jan 28 [cited 2024 Nov 10]; Available from: https://www.theguardian.com/science/2019/jan/28/study-shows-how-lsd-messes-with-brains-signalling

16. Carhart-Harris RL, Muthukumaraswamy S, Roseman L, Kaelen M, Droog W, Murphy K, et al. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences. 2016 Apr 26;113(17):4853–8.

17. Sample I. LSD’s impact on the brain revealed in groundbreaking images. The Guardian [Internet]. 2016 Apr 11 [cited 2024 Nov 10]; Available from: https://www.theguardian.com/science/2016/apr/11/lsd-impact-brain-revealed-groundbreaking-images

18. Liechti ME. Modern Clinical Research on LSD. Neuropsychopharmacol. 2017 Oct;42(11):2114–27.