LSD: Psychedelic Thrill or Optimism Pill?

If you’re in a room with ten adults, chances are two of them are going to develop a mental illness –- and only one of them will receive proper treatment.  Depending upon the psychiatric condition, common treatments include psychotherapy, cognitive behavioral therapy, and pharmacotherapy.  It is widely known that pharmacological treatment for psychiatric disorders such as depression and anxiety are marginally successful, at best.  The use of antidepressants as a treatment for depression are only efficacious in certain circumstances (namely, severe cases) and usually need to be combined with other forms of behavioral treatment in order to be most effective.  In fact, one controversial study found that in patients with mild or moderate depression, antidepressants were no more effective in treating symptoms than a placebo!  The National Center for Health Statistics reported that the rate of antidepressant use in the United States increased by 400% between the 1980s and early 2000s, which some psychiatrists believe is due to overprescription.  Since traditional antidepressants only seem to work in a subset of individuals who need treatment, it’s time we start considering alternative therapies to treat depression and other psychiatric illnesses.  The results from one new study are pointing to an unsuspecting candidate to treat psychiatric illness: LSD.

When most people think of LSD (lysergic acid diethylamide), they think of hallucinating hippies at Woodstock.  What many don’t know is that its original use was intended for psychotherapeutic application.  Several studies were done in the 1960s, and one in particular found that LSD reduces depression, anxiety, and pain in patients with advanced cancer.  Improper use by overexcited drug-users in the late 1960s halted research on LSD, but in recent years, there has been a resurgence of interest in its potential therapeutic benefits.  One recent clinical trial found that in a controlled supervised medical setting, the administration of LSD to patients with severe anxiety alleviated their anxious symptomatology.  In this double-blind, active placebo-controlled study, patients with anxiety-associated life-threatening diseases were given various dosages of LSD in addition to psychotherapy treatments.  Those in the experimental LSD group showed reductions in anxiety levels with no adverse effects from the LSD persisting beyond one day of treatment.  Now, a new study by a research group at the Imperial College London suggests that some of these therapeutic effects of LSD might last longer than we originally thought.

First, some history about LSD: Albert Hofmann, a Swiss chemist, was the first to synthesize LSD in 1938.  He accidentally discovered its hallucinogenic effects after unintentionally ingesting 250 μg (a very large dose!), before his evening commute home.  Being the good scientist that he was, he recorded a detailed account of his experience in his notebook.  His initial, paranoia-filled reaction was followed the next day by a blissful experience, in which

“everything glistened, and sparkled in a fresh light.”

Leaders of the aforementioned current study wished to re-explore some of these late-onset positive effects of LSD.  This placebo-controlled, within-subjects study included twenty participants who were recruited by word-of-mouth.  They were all over the age of 21, had no history of psychiatric illness, and all had at least one previous experience with a psychedelic drug (LSD, psilocybin, etc.).  This is an important consideration, and was done to minimize any unexpected adverse responses to the drug.  Each subject visited the testing center twice: once to receive LSD, and once to receive a placebo.  The order in which these individuals received the experimental condition was random.  During their visit, the participants were intravenously given a small dosage of LSD (or a placebo) by the study physician.  These individuals reported detection of an effect of the LSD as quickly as ten minutes after the infusion — which lasted a total of nearly eight hours.  Several hours into the dosing, they were asked to answer a series of questions regarding their psychological well-being.  Note that the dose given in this study (75 μg) was lower than the average dosage taken by recreational users.  Participants remained in the research center for the remainder of the day with a psychiatrist until they were functioning normally.  In order to determine longer-term effects, they filled out the same questionnaires two weeks later.

Shortly after taking the drug, participants who received LSD reported increased psychomimetic symptoms (feelings of psychosis-like symptoms), which the researchers had expected.  Symptoms included visual hallucinations, spiritual experiences, and paranoia. Interestingly, they were more likely to feel positive, and even “blissful” emotions, as compared to negative, and “anxious” feelings, sometimes associated with psychedelic drugs.

What was even more striking was that two weeks after taking LSD, these individuals reported increased optimism and trait openness, as compared to those who received the placebo.  Interestingly, high levels of optimism are well-known to be associated with both socioeconomic and physical health outcomes.

How can a drug with such acute psychomimetic effects lead to such pronounced long-term optimism?  This is a mostly unanswered question, but researchers think it has something to do with the serotonin 2A receptor (5-HT2AR).  This receptor is expressed all over the brain, particularly in regions associated with cognitive functions and social interactions. Stimulation of this receptor has been directly linked to cognitive flexibility, enhanced imagination, and creative thinking.  Disorders in which the 5-HT2AR is thought to be involved include schizophrenia, depression, obsessive compulsive disorder and attention deficit-hyperactivity disorder, indicating that variation in the number, affinity, and function of this receptor is largely involved in psychiatric illness.  It turns out that LSD functions by binding to and stimulating 5-HT2AR in the cerebral cortex, which is thought to regulate an enzyme called phospholipase C, and eventually leads to psychoactive effects.  In fact, blockage of this receptor has been linked to a remediation of the hallucinatory effects of LSD in rats.  The physiology that results in these distinct behavioral and perceptual feelings from LSD binding to 5-HT2AR is still a mystery.  The idea put forth by the authors of this paper is that once LSD binds to the receptor, it’s possible that the initial “blast” of stimulation results in more intense, acute psychotic-like symptoms, whereas the longer-term effects produce a “loosening” of network dynamics, and a general increase in optimism and well-being.

In a separate study, these same researchers used functional magnetic resonance imaging (fMRI) to measure neural activity in the participants’ brains, in order to further explore the mechanisms by which LSD might have an effect on behavior.  fMRI is a method that measures the blood-oxygen-level dependent (BOLD) signal in the brain, thought to be a proxy for how “active” certain regions of the brain are at any given time.  They found that not only was activity in the visual cortex (appropriately named as the region of the brain that’s responsible for the processing of visual information) increased in individuals while on LSD, but visual cortex activity showed increased “functional connectivity” (fMRI lingo for the tendency of one part of the brain to be active at the same time as another part of the brain, implying a functional relationship) to regions thought to be involved in emotion and self control.  On top of this, self-reported magnitude of visual hallucinations from the participants showed a strong correlation with this functional connectivity seen in the visual cortex.  The higher the ratings of complex visual imagery experienced during LSD, the more the visual cortex was engaged with other parts of the brain.  These findings indicate that LSD might lead to changes in the relationships between various parts of the brain, and even more so in individuals with especially vivid hallucinations.  While the researchers did not report an fMRI finding specifically related to measures of optimism, their results imply that there are clear neural correlates for some of the behavioral effects of taking LSD.

While we’re not suggesting that you illegally consume LSD in an attempt to increase long-term optimism and change the neural activity in your brain, we do think that this study raises important questions.  Could LSD one day be used to treat maladies like major depressive disorder?  Would the short-term psychological discomfort of giving an individual therapeutic LSD be worth the potential long-term benefits?  Would the positive effects of LSD persist longer than two weeks?  What is the physiological cascade that begins with LSD binding to 5-HT2AR activation and ends with psychological effects such as increased optimism?  Would the neural changes observed by taking LSD in this study hold up in patients with psychiatric disorders?  Is there a way to synthesize a compound that would take advantage of the beneficial aspects of LSD, while minimizing the negative effects?  There’s only one way to find out — more scientific experiments!

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Written by Rachel Jonas.

Images made by Jooyeun Lee and from Nature.

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References:

Carhart-Harris, R. L., et al. “The paradoxical psychological effects of lysergic acid diethylamide (LSD).” Psychological medicine 46.07 (2016): 1379-1390.

Zhang, Gongliang, and Robert W. Stackman Jr. “The role of serotonin 5-HT2A receptors in memory and cognition.” Frontiers in pharmacology 6 (2015).

Additional sources:

Mental Health By the Numbers by the National Alliance of Mental Illness.

National Center for Health Statistics. Health, United States, 2010: With Special Feature on Death and Dying. Hyattsville, MD. 2011.

Colpaert, F. C., and P. A. J. Janssen. “The head-twitch response to intraperitoneal injection of 5-hydroxytryptophan in the rat: antagonist effects of purported 5-hydroxytryptamine antagonists and of pirenperone, an LSD antagonist.” Neuropharmacology 22.8 (1983): 993-1000.

Egan, Christina T., et al. “Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors.” Psychopharmacology 136.4 (1998): 409-414.

Fournier, Jay C., et al. “Antidepressant drug effects and depression severity: a patient-level meta-analysis.” Jama 303.1 (2010): 47-53.

Gasser, Peter, et al. “Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases.”The Journal of nervous and mental disease 202.7 (2014): 513.

Kast, Eric C., and Vincent J. Collins. “Study of lysergic acid diethylamide as an analgesic agent.” Anesthesia & Analgesia 43.3 (1964): 285-291.

Passie, Torsten, et al. “The pharmacology of lysergic acid diethylamide: a review.” CNS Neuroscience & Therapeutics 14.4 (2008): 295-314.