History

On April 16, 1943, Albert Hofmann was synthesizing a compound called lysergic acid diethylamide, when he accidentally spilled some on his skin and end up documenting 4 hours of perceptual and cognitive distortions that he experienced because of this accident.  He had intended to generate a new circulatory and respiratory stimulant, but instead he experienced one of the most powerful mind altering drugs known.  5 years before, Hofmann synthesized this compound as the 25th substance in a series of amides produced from lysergic acid.  When he used animals for testing, they were extremely restless, but did not show responses that he was looking for, and so the substance was discarded from further testing.  5 years later, the failure still haunted Hofmann, which explained why he returned years later to study it further.

Professional research in the United States for LSD-25 began in 1949 in Boston under the trade name Delysid, and by the mid-60s, there had been more than 1000 clinical papers published, 40,000 patients tested, several dozen books printed, and 6 international conferences covering psychedelic drug therapy.  As it may appear that ‘hippies’ researched LSD, it was actually pursued by professional therapists seeking to treat their patients and answer questions about the human psyche.  In psychotherapy, patients were given a single, high dose of LSD-25 while being accompanied by close, trusted, and sober friends to help guide them through their therapeutic journey.  When an image became scary or frightening, their friends would encourage them to face it, and when they did, most reported having reached a euphoric or religious experience.

In the same decade, the CIA began a top-secret program called MK-Ultra, which studied LSD-25 as a potential mind control agent.  Nothing ever came of the program, but unsuspecting people were dosed and followed, mental patients were tested on and there were plans of taking secretly drugging Fidel Castro – all done for the preservation of national safety.

Toward the end of the 1960s, LSD-25 had made its way onto the streets, becoming known as “acid”, and in some states, like California and New York, it become a criminal offense to possess acid.  Into the 70s, research facilities were required to reapply for LSD-25 research licenses, with only a few being granted, and in 1974, the last of the human studies were conducted.

Two of the most significant figures to remember are Albert Hofmann and Timothy Leary.  Albert Hofmann is credited as the discoverer of LSD-25, and Timothy Leary became something of an evangelist for LSD and travelled America giving lectures and talking to influential people trying to impress on them the ways in which LSD allowed people to explore the realities of their lives by ‘reprogramming their brains.’  Leary has a very interesting story to tell, and I encourage you to find the book, “Turn on and Tune In: Psychedelics, Narcotics and Euphoriants” by John Mann to read a narrative about Leary’s travels.  One fun fact among many more is that Leary had a huge influence on the Beatle’s exposure to LSD.

Mechanism of Action

Since LSD-25 is classified as a Schedule 1 Drug there is little work into the neurochemistry on LSD action in humans.  The structure of LSD-25 is similar to serotonin, mescaline, and psilocybin, and it acts as a partial agonist to serotonin receptors in the brain, meaning it mimics serotonin for the same presynaptic autoreceptor sites, leading to the inhibition of regular serotonin levels.  In fact, LSD-25 binds with high affinity to at least 8 different 5-HT (5-hydroxtryptamine) serotonin receptor subtypes, with 5-HT2A being the most active.  LSD-25 down regulates the 5-HT receptors, where continual down regulation leads to the development of a tolerance to LSD, and after a few days of sequential use, the same dose has a minimized effect.

There are two hypotheses for how LSD-25 interacts with the neurons in the brain.  The first suggests that a dense cluster of norepinephrine-containing neurons in the pons, called the locus coeruleus, experiences a decrease in spontaneous neuron firing, yet also undergoes an increase in cellular excitation due to sensory stimulation.  The locus coeruleus, located in the fourth ventricle of the brain, receives and integrates inputs from all the major sensory systems, and it sends information to all areas of the cortex including the sensory cortex.  The receptors that have been slowed down and excited by LSD-25 are responsible for the decrease in firing and excitation of sensory stimulation, and it is proposed that this is the genesis of the exhilarating and hallucinogenic effects of LSD-25.

The second, alternative hypothesis suggests that the hallucinogenic effects are produced by a disruption of normal information processing in a circuit that includes the prefrontal cortex, striatum and thalum.  The drug interferes with the normal “gating” or screening of sensory information as it passes through the circuit, which results in an information overload at the cortical level.  This mechanism accounts for both perceptual distortion and cognitive disturbances that one experiences.

Synthesis/Structure/Uses

Lysergic acid diethylamide is one of many amide syntheses of the parent compound lysergic acid, which is the core structure in the fungal family of ergot alkaloids.  Ergot, known as Claviceps purpurea, has a darkened history due to ergotism, however, in 1875, ergotinine was isolated and proved to have a mixture of alkaloids.  One of the alkaloids synthesized was called ergotamine in the 1920s and was very successful in treating migraines.  The research facility that Albert Hofmann worked for, Sandoz, was interested in alkaloids obtained from ergot, because of its clinical potentials.  Furthermore, in 1921, where ergotamine was isolated from the fermented C. purpurea fungus, and many complex amide derivates of lysergic acid were generated through simple hydrolysis of the natural ergot alkaloid.

LSD-25 had structural similarities with diethylamide of nicotinic acid, which was a successful respiratory and circulatory stimulant, and so that is why it was research by Hofmann.   Additionally, Hofmann discovered through characterization that only the d enantiomer was active and any modification of the alkyl groups on the amide nitrogen caused a loss of activity.  Ergotamine tartrate can be transformed into lysergic acid easily, which encourages illegal production, and it is likely that LSD in the US comes from a few clandestine labs in San Francisco or on the East Coast with a few tanks of fermenting C. purpurea.

Effects while High

LSD-25 is an odorless, tasteless, and clear liquid that produces an intensification of perceptions at 25-50 µg, and full hallucinations at higher doses, qualifying it as one of most powerful psychoactive drugs known.  Also, intensity of effects is linearly proportional to dosage.  Symptoms include dilation of pupils, increase in blood pressure and body temperature, loss of appetite, heightened awareness of sensations, where mundane sensations become vivid and intense, one can experience macropsia or micropsia, which is when it appears that objects get big and small, visual afterimages may be prolonged and overlap with immediate visual images like that of a camera with long exposure lenses, memories are generally unimpaired, and a lessening of interpersonal boundaries occur, which is why people have such strong senses of union with the other people ‘tripping’ with them.  Most experience good trips, however, people can have ‘bad trips’ in a frightening atmosphere or setting.  This person’s trip can be overwhelmed with terrifying emotions and perceptions, like fire or demonic warpings of tangible objects.  In most cases though, the person can be talked down and reasoned back into a safer state of being.  LSD-25 is sensitive to UV light, oxygen, and chlorine, but can keep for years if stored away from light and air in cool temperature. Psychedelic effects begin at about the 2nd hour, reaching a peak during the 4th or 5th hr.  The half-life in the body is about 3 hours, where symptoms can be felt up to 8 hours, and the entire syndrome clears in 12 hours.

References:

Daniel M. Perrine. “The chemistry of mind-altering drugs: history, pharmacology, and cultural context.”  1996. American Chemical Society.

Griggs, E.A.; Ward, M., “LSD toxicity: A suspected cause of death,” Journal of the Kentucky Medical Association, 1977, 75, 172-172

Jerrold s. Meyer, Linda F. Quenzer.  “Psychopharmacoogy: drugs, the Brain, and Behavior.”  2005.  Sinauer Associates, Inc.

John Mann. “Turn on and Tune In” Psychedelics, Narcotis and Eurphoriants.” 2009. Royal Society of Chemistry

Marcello Spinella.  “The Psychopharmacology of Herbal Medicine: Plant drugs that alter mind, brain, and behavior.”  2001. MIT Press.