Lysergic acid diethylamide (LSD) was used extensively for treating mood disorders in the pre-antidepressant era, before it was prohibited in the late 1960s. A review of 19 studies—many uncontrolled—concluded that approximately 80% of patients improved, according to the treating physicians.3 However, research on LSD was halted for several decades after it became illegal, and resumed in 2010. Neuropsychiatrists and neuroscience researchers are now employing advanced techniques, such as neuroimaging, molecular pharmacology, and connectomics, to study its therapeutic effects.4 LSD is not only being used for treatment-resistant depression but also anxiety, alcoholism, autism, and even schizophrenia. However, despite its potential uses for treating alcoholism and anxiety, enhancing creativity, or caring for terminally ill patients, using LSD requires expertise, caution, and adherence to ethical standards.5
In healthy individuals, the effects of LSD include visual hallucinations, audiovisual synesthesia, depersonalization and derealization, and a sense of well-being, happiness, closeness to others, and trust.
Biologic effects include increased heart rate and blood pressure, elevated temperature, dilated pupils, and increased serum cortisol, prolactin, oxytocin, and epinephrine. All effects subside within 3 days.6
Psilocybin, a component of some mushrooms that is known for its use during rituals in some cultures, has been discovered to have antidepressant, anxiolytic, and anti-addictive effects.7 Recent controlled studies at Johns Hopkins University reported that a single dose of psilocybin can relieve anxiety or depression for up to 6 months, which, if replicated, could lead to a remarkable paradigm shift in treating mood and anxiety disorders, especially if patients do not respond to standard antidepressants.3 Other emerging uses of both psilocybin and LSD are in treating addictions8 where psychiatry is desperately looking for innovative new therapies.
MDMA (3,4-methylenedioxymethamphetamine), also known as ecstasy, is widely regarded as a harmful party drug that produces euphoria, but not hallucinations. However, it has emerged as a useful treatment for posttraumatic stress disorder (PTSD). In one study of female sexual abuse victims, 80% of the patients who received MDMA with psychotherapy no longer met diagnostic criteria for PTSD after 2 months.9 Other studies showed no effects. Despite persistent skepticisms by many, the Multidisciplinary Association for Psychedelics Studies organization is investing millions of dollars into studying MDMA for PTSD in several countries.9,10 One hurdle is that it is difficult to conduct truly blind studies with psychedelic drugs because of their profound effects. MDMA releases cortisol, oxytocin—which are known to facilitate psychotherapy—and testosterone, but the debate about the risk–benefit ratio will continue.11 MDMA also is being studied for treating social anxiety in adults with autism.12
Ketamine is a weaker cousin of the potent psychotogenic phencyclidine (approximately one-fiftieth the potency) and is a well-known drug of abuse that causes dissociation and hallucinations. It is used as an anesthetic in veterinary medicine and in children undergoing surgical procedures. Until recently, its only use in psychiatry has been as an anesthetic during electroconvulsive therapy. However, over the past few years, IV ketamine has been in the spotlight as a breakthrough, rapid-onset antidepressant and anti-suicidal agent in several controlled studies.13 This drug is revolutionizing the management of treatment-resistant depression and suicidal ideation and generating new insights into the neurobiology of depression.