Lysergic acid diethylamide (LSD) is a classical hallucinogen originally synthesized by Albert Hoffman. He accidentally concocted the drug while making experimental substances from ergots to create circulatory and respiratory stimulants. The most pronounced effect on the animals allowed him to create a model for psychosis and study the induced temporary psychotic-like states. During the psychotic state, he also noted permitted recall and produced improved insight.[1][2][3]

In 1986, almost 400 patients received treated with LSD. The Danish LSD Damages Law was passed because of the crimes and deaths linked to LSD usage, where applicants received financial compensation for the harm resulting from the treatments. Many years afterward, patients still suffered from the side effects of being treated with LSD.

Regulations on hallucinogenic drugs started to be introduced in 1967 to limit the use of LSD and other hallucinogenic drugs to qualified practitioners. The hope was to eliminate or decrease risky behaviors and resulting in harmful consequences that were brought on by the drug. Despite these efforts, LSD-assisted treatments continued in some European countries in the 1970s. In Switzerland, psychotherapy and research were also conducted from 1988 to 1993 with special permission from their government.  

No approved indications for LSD-assisted therapy exist today. It has seen use in the past for non-FDA approved indications: depressive disorders including those with conversion phobia, neurosis, manic-depression, and reactive depression, cyclothymic (obsessional) and passive-aggressive (obsessional) compulsive sexual deviation addiction, psychoneurotic disorders, mixed, pan-neuroticism (including schizophrenia), borderline or latent and personality disorders (especially transient situational).[4][5]

Researchers continue to study the utility of LSD-assisted therapy. The following non-FDA approved indications show the most evidence for serotonin-based psychoactive agents: substance use disorders, especially in the treatment of chronic alcohol addiction, post-traumatic stress disorder, anxiety, and depression in patients suffering from life-threatening illnesses. Combining LSD with counseling, researchers were able to create a psychedelic "trip" for the terminally ill, thereby decreasing the anxiety refractory to conventional anxiolytic therapy, depression, and pain associated with the life-threatening diseases such as cancer. Sleep reportedly improved with terminally ill patients, and they were less preoccupied with death.

Research has also begun to look at LSD as a possible treatment for Alzheimer dementia and as a last resort for migraines or cluster headaches. This role is in part because patients have self-medicated using LSD off-label as an ablative therapy to treatment-resistant migraines and cluster headaches. Patients obtained the illicit psychoactive substances as a last resort. When patients use LSD as a treatment or a recreational drug, there are few if any reports of psychoactive effects. The effects were reportedly tolerable or avoided using minimal doses.  

LSD-assisted therapy has shown to enhance suggestibility without hypnotic induction. It has shown the most improvement in suggestibility in neurotic and schizophrenic patients but the least in depression. Neural plasticity in the cortex and cognitive flexibility are possibly necessary for demonstrable improvement in suggestibility.

The mechanism by which LSD works is mainly mediated by activation of serotonin receptors (namely 5HT2A receptors or 5hydroxytryptamine 2A receptor, 5-HT2AR) with modulation of the 5HT2C and 5HT1A receptors. The interactions between the receptor activation and the resulting impairment in cognition and induction of hallucinations are still poorly understood. One study suggests that LSD-induced 5-HT2AR activation leads to a breakdown of inhibitory processes in the hippocampal prefrontal cortex. Specifically, it has demonstrated to reduce brain activity in the right middle temporal gyrus, superior/middle/inferior frontal gyrus, anterior cingulate cortex, and the left superior frontal and postcentral gyrus and cerebellum. Studies also have shown activation of the right hemisphere, altered thalamic functioning, and increased activity in the paralimbic structures and the frontal cortex; this all leads to the formation of induced visual imageries.[5][6][7]

In substance abuse, it is well established that anxiety and stress are important triggers for relapse. It is possible that 5HT2A receptor downregulation by hallucinogens could help in stress-induced relapses. LSD may also have effects on the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor(GDNF). Both of these play critical roles in neurogenesis, synaptic plasticity, learning, and memory. There is some evidence that LSD can induce neuroplastic changes suggesting a basis for the persistent behavioral changes. LSD also induces remodeling of pyramidal cell dendrites.

LSD is a Schedule I drug in the United States. Its precursors, lysergic acid and lysergic acid amide, are Schedule III drugs. It is illegal to administer, manufacture, buy, possess, process, or distribute LSD without a license from the DEA.[8][9][10]

LSD is taken orally as a capsule or tablet. The moderate effect in most subjects is produced at 1 to 3 micrograms/kg body weight. The onset of effects usually begins within 30 to 60 minutes after taking the drug. The drug moves rapidly to the brain and is quickly distributed throughout the body, acting both on CNS and on autonomics. The drug disappears from the brain in 20 minutes, but the effects are prolonged and may last many more hours after it disappears from the brain. LSD has a first-order elimination. LSD lasts up to 12 hours in the body with dose-proportional pharmacokinetics. The effects following administration are related to the time course of concentration in the plasma. The subjective response between patients with similar concentrations of LSD and similar doses are unpredictable. Each patient may have a completely different experience.

More recent studies used 75 micrograms of LSD intravenously. Reported subjective effects began within 5 to 15 minutes. Effects peaked 45 to 90 minutes after intravenous dosing. The researchers reported no further details.

In one study, the administration of 200 micrograms of LSD in a safe setting reportedly produced subjective positive effects for the user, further described to be a long-lasting positive experience. There were significant reports of positive attitudes with self-esteem, mood, altruism, social skills, behavioral changes, and improved satisfaction in life. No reported negative changes in attitude, mood, social skills, or behavior were attributed to LSD.[10]

Adverse effects are extremely subjective, with significant variability and unpredictability. One patient may experience a positive effect filled with bright hallucinations sights and sensations, increased awareness owing to mind expansion, and marked euphoria. The positive spectrum of effects is colloquially called a "good trip." Another patient may experience the total opposite that is filled with increased anxiety becoming panic, fear, depression, despair, and disappointment. The negative spectrum is colloquially called a "bad trip." One patient can experience both the positive and negative spectrum at different times of use.

One of the more disturbing side effects of LSD is the flashback. Flashbacks can be induced by stress or fatigue and by using other drugs. Often a flashback of a "bad trip" can occur without warning, even if the patient was not currently under the influence of LSD. Eventually, long-term use leads to the patient developing tolerance to the drug. Abstinence for a few days allows the patient to return to baseline quickly, emotionally, physically, and mentally. Abstinence of the drug does not typically produce a craving. Debilitating flashbacks occurred in the patients compensated under the Danish LSD Damages law.[11][12]

Daily ingestion is almost impossible because it produces an absurd "good trip" or high, making abuse of LSD difficult. The dependence on LSD, therefore, is not from physical effects or cravings but psychological dependence or need. Patients want to keep re-experiencing the same good trips. There are concerns about increased antisocial behavior and abuse with unsupervised use of LSD. There also are concerns about the negative implications of increased suggestibility. There are possible dangers of creating false memories or instilling wrong beliefs. 

As a classic hallucinogen, LSD does not typically create compulsive drug-seeking behavior as is with most other drugs, but it can still be dangerous in non-clinical settings. Nonmedical use can precipitate prolonged psychiatric reactions in rare cases.

Absolute contraindications are physical conditions that have marked excitatory states like cardiovascular disease, pregnancy, epilepsy, paranoid personality, overt psychosis, and organic-toxic cerebral disorder. The teratogenic effects of LSD are controversial; they have been demonstrated by some but not confirmed by others.