As mentioned above, LSD was synthesized in 1938 by Swiss chemist Albert Hofmann while he was working for Sandoz Pharmaceuticals in Basel, Switzerland.

Hofmann's original intention was to develop a circulatory and respiratory stimulant. Initially unimpressed by the modest effects observed in animal studies, Hofmann temporarily set LSD aside. However, five years later, on April 16, 1943, he had a strong intuition to revisit the synthesis of LSD.

As Hofmann was wrapping up his work, he was unexpectedly overcome by unusual sensations that prompted him to leave early and go home. There, his consciousness underwent a profound alteration, characterized by a cascade of vivid imagery with a kaleidoscope of extraordinary shapes and intense colors.

Believing that he had unintentionally ingested a very small yet potent amount of LSD, Hofmann proceeded to self-experiment with a 250-microgram dose (equivalent to a quarter-milligram) three days later. Unaware of the intensity of such a dose, Hofmann had intended to carefully document his experience. However, the overwhelming power of LSD's effects rendered this task impossible.

After the intense experience, Hofmann managed to jot down a brief trip report consisting of only 13 hastily scribbled words. With the assistance of his lab assistant, Susi Ramstein, he somehow made his way back home on his bicycle. There, he found solace in the care of a neighbor, who seemed somewhat witchlike to him in his altered state. As the effects gradually subsided, Hofmann was surprised to find that he could remember the entirety of his frightening experience.

After this LSD experience, Hofmann reported feeling refreshed and overcome with “a feeling of good fortune and gratitude.” The following morning, when he walked out into the garden after a rainfall, Hofmann remarked that “everything glistened and sparkled in a fresh new light. The world was as if newly created.” After experiencing the profound effects of LSD, he believed that it could have potential applications in psychotherapy.

Albert Hofmann’s discovery of the psychedelic experience produced by LSD is commemorated every year on April 19, colloquially known as "Bicycle Day”.

In addition to its central influences on culture, art, and music in the mid-20th century, many claim that the discovery of LSD was crucial to the advance of neuroscience and psychiatry. For example, reportedly inspired by the discovery of LSD, American biochemist Betty Twarog became the first person to isolate serotonin in the mammalian brain.

As mentioned above, LSD was also used as an aid in the psychotherapeutic treatment of many thousands of patients suffering from a variety of mental health conditions.

The gradual leakage of LSD from the laboratory, its subsequent widespread popularity as a recreational drug, its association with the counterculture movement of the 1960s, and sensationalist newspaper reporting led to LSD’s banning in 1968.
‍

The Ancient Roots of Psychedelic Use

Long before psychedelic research commenced in the West, many psychedelic substances had been ingested as part of sacred rituals and ceremonies for millennia by indigenous communities all over the world.

The sacred use of psychedelic substances and plant medicines continues to this day in shamanic rituals, particularly in South and Central America. Shamanic rituals are spiritual practices that involve a shaman, who is believed to have a connection with the spirit world, using various techniques such as psychedelic substances, chanting, drumming, and dancing to enter a trance-like state in order to communicate with the spirits and address spiritual or emotional concerns.

Indigenous communities take part in shamanic rituals for a variety of reasons, including connecting to spiritual, cultural, and ancestral traditions, healing, and gaining insights about the world around them and guidance from the spiritual realm.

For many indigenous cultures, shamanic practices are an important part of their way of life and belief systems. They provide a means of connecting with the natural world and the spirits that govern it. In shamanic contexts, psychedelic plant medicines, such as ayahuasca or peyote, are believed to have powerful healing and transformative properties.
‍

The Historical Use of Psilocybin Mushrooms 

Recent discoveries suggest that psilocybin-containing mushrooms have been used as part of religious and/or social rituals for 6000 years.

‍The Selva Pascuala mural, a cave painting near the town of Villar del Humo in Cuenca, Spain, represents the earliest reliable evidence of the use of psilocybin in Europe. This post-Paleolithic piece of rock art, which depicts the use of a species of magic mushroom called Psilocybe hispanica, dates back to 4000 BCE. The Selva Pascuala mural is part of a set of more than 12 cave art sites declared World Heritage Sites by UNESCO.

In addition, nine miniature mushroom stones and nine stone tools from the Verbena cemetery at Kaminaljuyu, Guatemala suggest sophisticated use of the Psilocybe mexicana dating back to 1000-500 BCE. These sculptures may have been associated with the religious ceremonies of the Maya civilization, a Mesoamerican civilization that existed from about 2000 BCE to 1500 CE and lived in parts of what are now Mexico, Guatemala, Belize, and Honduras.

In 1955, amateur mycologist (a person who studies fungi) R. Gordon Wasson traveled to Oaxaca, Mexico to take part in a traditional Mazatec mushroom ceremony with the highly regarded Mazatec healer, María Sabina, aka the “priestess of mushrooms.” The Mazatec are an indigenous group known for their rich cultural heritage and traditional use of entheogenic plants such as psilocybin mushrooms.

Wasson's detailed account and photographs of his mushroom ceremonies, published in Life magazine in 1957, brought widespread attention to the traditional indigenous use of psilocybin-containing mushrooms. This exposure sparked interest in psychedelics among scientists, researchers, and the general public, contributing to further exploration, study, and cultural influence of psychedelic substances.

Wasson persuaded renowned French mycologist Roger Heim to join him on a follow-up trip to Oaxaca. In 1958, having received some Psilocybe mexicana from Heim, LSD discoverer Albert Hofmann isolated psilocybin as the mushroom’s principal psychoactive ingredient. Hofmann also became the first person to artificially synthesize psilocybin soon after.

Psilocybin has since been detected in almost 200 species of psychoactive mushrooms worldwide.
‍

The Ancient Origins of Mescaline-containing Cacti Use in Shamanic Rituals: San Pedro and Peyote

Archaeological evidence from the Guitarrero Cave located in the Callejón de Huaylas valley in Yungay Province in the Ancash region of Peru suggests that San Pedro (Echinopsis pachanoi), a cactus that contains mescaline, has been used in shamanic rituals since prehistory. Here, remnants of San Pedro cactus were discovered alongside ceremonial artifacts dating back to 8200–6800 BCE.

Perhaps the most well-known representation of the ancient origins of San Pedro use is the “Raimondi Stele,” a Chavín stone carving from 1300 BCE located in the temple site of Chavín de Huántar in the Andean highlands of Peru. The Chavín civilization was an ancient civilization that flourished in the Andean highlands of Peru around 1000 BCE and is known for its distinctive art and architecture, which had a significant influence on subsequent Andean cultures.

Named after an Italian traveler by the name of Antonio Raimondi, who discovered this piece of art, the Raimondi Stele depicts a fearsome human-like figure known as the “Staff God” holding a staff in each hand that double as San Pedro cactus.

Like San Pedro, peyote (Lophophora williamsii) is another mescaline-containing cactus that has been used by indigenous tribes for thousands of years. Radiocarbon analysis of peyote effigies made from ground peyote and other plant material is suggestive of peyote use in the Shumla Caves in the Lower Pecos region of southwest Texas approximately 6000 years ago. Radiocarbon analysis is a method of determining the age of organic materials based on their content of carbon-14.

Mescaline was identified as the sought-after psychedelic component of peyote in 1897 by the German chemist, Arthur Heffter. In 1919, Austrian chemist Ernst Späth proposed that mescaline could be 3,4,5-trimethoxyphenethylamine, and in 1929, he successfully determined its complete chemical structure. Späth's groundbreaking synthesis sparked numerous scientific investigations into the drug's impact on the brain, body, and behavior.

Despite peyote’s Schedule 1 status under the US Controlled Substances Act, members of the Native American Church have religious exemption to consume peyote as part of their religion, which is the largest pan-Indian religion in North America.
‍

Exploring the History of Ayahuasca and its Main Ingredient, DMT

Ayahuasca, an entheogenic beverage mostly made by prolonged boiling of the leaves of the Psychotria viridis shrub and the Banisteriopsis caapi vine, has been used by indigenous Amazonian communities for centuries.

The term “entheogenic” refers to substances that are used to induce spiritual or mystical experiences, often in a religious or shamanic context, and are believed to help individuals connect with a higher power or divine realm. Entheogenic substances are sometimes referred to as “plant medicines” or “teacher plants.”

‍Psychotria viridis contains the classic psychedelic compound DMT, whereas Banisteriopsis caapi contains monoamine oxidase inhibitors (MAOIs). The MAOIs helps to prolong the effects of DMT by inhibiting the breakdown of the compound in the digestive system, allowing it to reach the brain and induce profound psychedelic experiences.

Anthropology studies (the study of humans, including their cultures, societies, and physical characteristics) have documented the traditional customs and purposes of ayahuasca use. This research indicates that indigenous shamanic healers facilitate ritual ceremonies in which they utilize the visionary properties of ayahuasca to diagnose, heal, communicate with spirits, engage in spiritual warfare, and acquire traditional healing songs called “icaros.”

‍Archaeological evidence demonstrates the presence of 1000-1500-year-old snuffing tablets and grave goods buried alongside preserved mummies. Gas chromatography-mass spectrometry (GC-MS) analysis, a type of analytical technique used to identify and quantify the components of a sample, identified constituents of the ayahuasca vine, Banisteriopsis caapi, in the mummies' hair samples, providing the earliest evidence of its use among ancient Andean communities.

That said, some anthropologists claim that indigenous communities of the Amazon have likely been using ayahuasca for at least 5000 years.

In recent years, ayahuasca ceremonies have become increasingly popular in the Western world, with many indigenous shamans traveling to North America and Europe yearly to offer the plant medicine. A significant number of individuals from Western countries also journey to the Amazon region to participate in multi-day retreats where they partake in the ceremonial consumption of ayahuasca. This is often referred to as “ayahuasca tourism.”

DMT is also present in the beans of Anadenanthera peregrina and Anadenanthera colubrina, perennial trees native to the Caribbean and South America. The beans, traditionally ground into a snuff called “yopo,” seem to have been used in ceremonial contexts for thousands of years by indigenous populations. Radiocarbon testing of pipes made of puma bone discovered in Argentina indicates that Anadenanthera beans may have been used as entheogenic substances since at least 2130 BC.

DMT was first synthesized in 1931 by German-Canadian chemist Richard Manske before Hungarian chemist Stephen Szára discovered its psychedelic effects in 1956. Interestingly, DMT has since been identified in human blood, urine, and cerebrospinal fluid, which has led to much speculation about where it is produced and what it does in the human body.
‍

Psychedelics and Adverse Effects: What You Need to Know

Despite the contrary perception of much of the public, psychedelics are known to be physically safe. They are not addictive, non-toxic, and are medically safe when taken at standard dosages. However, they can have potential adverse effects.

One of the most commonly reported adverse effects of psychedelics is a “bad trip,” which can be a distressing and frightening experience that may include a range of physical and psychological effects. Some characteristic effects of a bad trip may include anxiety, paranoia, feelings of despair, and confusion. These effects can vary depending on the individual's mental and emotional state, the dose and type of psychedelic used, and the environment in which the drug is taken.

It is important to note that not everyone who uses psychedelics will experience a bad trip, and that proper preparation, set and setting, and guidance can help minimize the risk of a negative experience.

Additionally, individuals with a personal or family history of psychotic disorders may be at risk of exacerbation or initiation of a psychotic reaction. Psychedelics can also have moderate cardiovascular effects, such as an increase in blood pressure and heart rate, which may be of concern for individuals with preexisting cardiovascular conditions.

People who have a personal or familial history of psychosis, are pregnant, have a cardiovascular condition, have epilepsy with a history of seizures, have insulin-dependent diabetes, are regularly taking a psychoactive prescription medication, are regularly taking any medications that have a primary centrally-acting serotonergic effect, or are more than 25% outside the upper or lower range of ideal body weight, are excluded from clinical research and are strongly advised to refrain from using psychedelics.

It is also important to be aware of medications that may be contraindicated when considering the use of psychedelics. The combination of psychedelics with certain medications, such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors, can potentially cause harmful or life-threatening interactions, such as serotonin syndrome.

It is important to consult with a healthcare provider and disclose all medications currently being taken before considering the use of psychedelics.
‍

The Future of Psychedelic-Assisted Therapy: Caution and Responsibility

Psychedelic substances remain stigmatized and legally restricted despite their seemingly favorable safety profile and therapeutic potential. Scientific use of psychedelics has been severely restricted since their placement into schedule 1 of the 1970 Controlled Substances Act, making it difficult to conduct research investigating their therapeutic and spiritual potential.

However, institutional review boards have loosened restrictions in recent years, opening the doors to regulated clinical investigations and facilitating the recent revival of interest and research in the use of psychedelic substances for therapeutic purposes.

Clinical trials sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS) have demonstrated MDMA’s clinical efficacy for post-traumatic stress disorder (PTSD), prompting the US Food and Drug Administration (FDA) to grant breakthrough therapy status to MDMA-assisted psychotherapy. The FDA has also recognized the potential of psilocybin in treating treatment-resistant depression and major depressive disorder (MDD) by granting it breakthrough therapy designation.

This designation signifies that MDMA and psilocybin, when used alongside supportive psychotherapy, have shown potential improvement over existing treatment options in clinical trials.

Psychedelics have shown promising potential as a therapeutic tool for treating a variety of mental health conditions and for spiritual exploration. However, like any medication, they also come with risks, including the possibility of adverse effects. It is important to conduct further research to better understand the risks and benefits of psychedelics, as well as to develop safe and effective protocols for their use in therapy.

As the psychedelic renaissance continues to unfold, it is critical to approach this promising area of research with caution and responsibility, and continue to strive towards developing evidence-based treatments that prioritize patient safety and well-being.