Archive for December, 2010

The secret history of psychedelic psychiatry

December 15, 2010 Leave a comment

On August 15th, 1951, an outbreak of hallucinations, panic attacks and psychotic episodes swept through the town of Pont-Saint-Esprit in southern France, hospitalizing dozens of its inhabitants and leaving five people dead. Doctors concluded that the incident occurred because bread in one of the town’s bakeries had been contaminated with ergot, a toxic fungus that grows on rye. But according to investigative journalist Hank Albarelli, the CIA had actually dosed the bread with d-lysergic acid diethylamide-25 (LSD), an extremely potent hallucinogenic drug derived from ergot, as part of a mind control research project.

Although we may never learn the truth behind the events at Pont-Saint-Esprit, it is now well known that the United States Army experimented with LSD on willing and unwilling military personnel and civilians. Less well known is the work of a group of psychiatrists working in the Canadian province of Saskatchewan, who pioneered the use of LSD as a treatment for alcoholism, and claimed that it produced unprecedented rates of recovery. Their findings were soon brushed under the carpet, however, and research into the potential therapeutic effects of psychedelics was abruptly halted in the late 1960s, leaving a promising avenue of research unexplored for some 40 years.

The secret history of psychedelic psychiatry began in the early 1950s, about 10 years after Albert Hofmann discovered the hallucinogenic properties of LSD, and lasted until 1970. It was uncovered by medical historian Erika Dyck, who examined the archives from Canadian mental health researchers and conducted interviews with some of the psychiatrists, patients and nurses involved in the early LSD trials. Dyck’s work shows early LSD experimentation in a new light, as a fruitful branch of mainstream psychiatric research: it redefined alcoholism as a disease that could be cured and played a role in the psychopharmacological revolution which radically transformed psychiatry. But, despite some encouraging results, it was cut short prematurely.

At the forefront of early psychedelic research was a British psychiatrist by the name of Humphry Osmond (1917-2004), a senior registrar at St. George’s Hospital in South London, who began investigating the chemical properties of mescaline, the psychoactive ingredient of the peyote cactus, during the late 1940s. After experimenting with the drug for nearly two years, Osmond and his colleagues concluded that it “caused symptoms in normal people that were similar to the symptoms of schizophrenia.” Further investigation led them to believe that the chemical structure of mescaline closely resembled that of adrenaline. As a consequence, they came to regard schizophrenia as being caused by an overproduction of adrenaline. In doing so, they had formulated what Osmond believed to be the first biochemical theory of mental illness.

In 1951, Osmond moved to Canada to take the position of deputy director of psychiatry at the Weyburn Mental Hospital in Saskatchewan and, with funding from the government and the Rockefeller Foundation, established a biochemistry research program. The following year, he met another psychiatrist by the name of Abram Hoffer, and the two embarked on a long-term collaboration. Osmond expanded his research program, and started using LSD instead of mescaline, because it was readily available from the Sandoz Pharmaceutical Company’s Canadian branch in Toronto.

The pair hit upon the idea of using LSD to treat alcoholism in 1953, at a conference in Ottawa. After arriving at their hotel, they were unable to sleep, and stayed up late discussing problems in psychiatry. In the small hours of the morning the conversation moved on to the similarities between the effects of LSD and the delirium tremens often experienced by alcoholics during withdrawal, and they began to wonder whether LSD could be effective in treating alcoholism. Hoffer recalls that the idea “seemed so bizarre that we laughed uproariously. But when our laughter subsided, the question seemed less comical and we formed our hypothesis: Would a controlled LSD-produced delirium help alcoholics stay sober?”

On their return to Saskatchewan, Osmond and Hoffer decided to test their hypothesis, and treated two chronic alcoholics who had been admitted to the Saskatchewan Mental Hospital with a single 200 microgram dose of LSD. Osmond knew from earlier self-experimentation that much smaller amounts were sufficient to produce profound changes in consciousness, but used very large doses for a stronger effect, the idea being that it would induce a terrifying artificial delirium that might frighten the patient into changing their drinking behaviour. One of the patients stopped drinking immediately after the treatment and remained sober for the entire six month period of the follow-up study. The other continued to drink after the experiment, but stopped after six months. Osmond and Hoffer found these results somewhat confusing, but concluded that LSD had a 50% chance of helping alcoholics.

The next Saskatchewan LSD trial was conducted several years later by Colin Smith, who treated 24 patients and reported that 12 of them were “improved” or “much improved” afterwards. Encouraged by these initial results, others began using the drug to treat alcoholics. Meanwhile, Osmond and Hoffer continued with their own research. By 1960, they had treated some 2,000 alcoholic patients with LSD, and claimed that their results were very similar to those obtained in the first experiment. Their treatment was endorsed by Bill W., a co-founder of Alcoholics Anonymous who was given several sessions of LSD therapy himself, and Jace Colder, director of Saskatchewan’s Bureau on Alcoholism, who believed it to be the best treatment available for alcoholics.

Osmond also “turned on” Aldous Huxley to mescaline, by giving the novelist his first dose of the drug in 1953, which inspired him to write the classic book The Doors of Perception. The two eventually became friends, and Osmond consulted Huxley when trying to find a word to describe the effects of LSD. Huxley suggested phanerothyme, from the Greek words meaning “to show” and “spirit”, telling Osmond: “To make this mundane world sublime/ Take half a gram of phanerothyme.” But Osmond decided instead on the term psychedelic, from the Greek words psyche, meaning “mind”, and deloun, meaning “to manifest”, and countered Huxley’s rhyme with his own: “To fathom Hell or soar angelic/Just take a pinch of psychedelic.” The term he had coined was announced at the meeting of the New York Academy of Sciences in 1957.

LSD therapy peaked in the 1950s, during which time it was even used to treat Hollywood film stars, including luminaries such as Cary Grant. By then, two forms of therapy had emerged. Psychedelic (“mind-manifesting”) therapy was practised mostly in North America and involved intensive psychotherapy followed by a single megadose of LSD. It was thought that the transcendental experiences induced by such large doses, as well as heightened self-awareness, would enable the patient to reflect on their condition with greater clarity. Psycholytic (“mind-loosening”) therapy, on the other hand, was practised mostly in Europe, and involved regular low to moderate doses of the drug in conjunction with psychoanalysis, in order to release long-lost memories and reveal the unconscious mind.

The early LSD studies took place alongside trials of newly developed drugs such as the antipsychotic chlorpromazine and the tricyclic antidepressant imipramine. Together, these drug trials led to the emergence of the new field of psychopharmacology, and so caused a major paradigm shift that revolutionized psychiatry and “dragged it into the modern world”. The finding that psychedelics can induce schizophrenia-like symptoms bolstered the notion that psychiatric conditions are caused by chemical imbalances in the brain. And psychiatrists, faced with new evidence that mental disorders can be effectively treated with drugs, began to abandon the psychoanalytical approach in favour of new disease models based on brain chemistry.

LSD hit the streets in the early 1960s, by which time more than 1,000 scientific research papers had been published about the drug, describing promising results in some 40,000 patients. Shortly afterwards, however, the investigations of LSD as a therapeutic agent came to an end for two reasons. Firstly, some researchers pointed at the flawed methodology of the studies. Most lacked proper controls, so that the patients involved were not randomly assigned into groups that received the real treatment or a placebo. Today, the randomized, placebo-controlled double blind study is the gold standard for clinical trials. The patient does not know whether they have been given the treatment or the placebo. The researcher should not know either, so that she does not bias the results with her expectations. Back then, though, this experimental design still had not been universally accepted as the best method for evaluating the efficacy of new drug treatments.

The second – and more important – reason was the cultural and political climate of the time. By the mid-1960s, LSD had became a popular recreational drug, and was closely linked to the hippie counterculture and related phenomena – student riots and anti-war demonstrations, non-conformity and social disobedience. The mass media increasingly portrayed LSD as a dangerous drug of abuse that could cause, among other things, chromosomal damage and foetal abnormalities. Sandoz voluntarily stopped making and supplying the drug in 1966, and the American, British and Canadian governments first placed severe restrictions on its use in research, then banned its use altogether in 1970. The documents pertaining to the Saskatchewan LSD trials were locked away, and gathered dust in the archives until they were re-discovered by Dyck five years ago.

The mid-1990s saw renewed interest in the potential therapeutic benefits of psychedelics, a key figure being Franz Vollenweider, who co-authored the new Nature Reviews Neuroscience paper. As the article explains, the new research confirms that psychedelics are indeed effective therapeutic agents, at least when given in combination with behavioural therapy, and can alleviate the symptoms of various psychiatric disorders. Sophisticated new techniques such as functional magnetic resonance imaging (fMRI) are providing fresh insights into how they affect the brain, and revealing the brain mechanisms that might underly their therapeutic effects.

We now know, for example, that the classical hallucinogens (LSD, psilocybin and mescaline) exert their effects by activating the 5-HT2A serotonin receptor subtype expressed by pyramidal cells in the deep layers of the prefrontal cortex. Serotonin is involved in signalling within a widely distributed neural circuit that is implicated in mood and affective disorders. Activation of the serotonin receptors in turn alters signalling mediated by glutamate and dopamine, and may also induce synaptic plasticity, modifying the strength of the long-range connections between the circuit components. The therapeutic effects of psychedelics may therefore be due to their ability to modulate the neuronal activity within these circuits.

Other new research shows that ketamine, a dissociative anaesthetic with hallucinogenic properties that acts primarily on the glutamatergic transmitter system, can effectively alleviate depression, and can also reduce the frequency of suicidal thoughts in depressed patients. A recent clinical trial showed MDMA (‘Ecstasy’) is beneficial for patients suffering from post-traumatic stress disorder. And some of Vollenwieder’s own research shows that psilocybin can alleviate anxiety and pain in terminally ill cancer patients. Remarkably, this recent work shows that some psychedelics are effective after just one dose; this has obvious advantages over other drug treatments, which can take many months or even years. But despite these advances, much remains to be discovered about how the psychedelics act on the brain and why they are of therapeutic value.

The history of LSD experimentation could be of use to those who make decisions about drug policy, too. The criminalization of LSD in 1970 was evidently a knee-jerk reaction by governments to the sensationalist media reports about the dangers of the drug that occurred without proper debate. A similar situation arose earlier this year, when the British government banned mephedrone. Examination of the reasons why the early LSD trials were brought to an end so abruptly could therefore provide valuable lessons about how controversial drugs could be effectively incorporated into modern medicine.



Vollenweider F. X. &  Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat. Rev. Neurosci 11: 642-651. doi: 10.1038/nrn2884

Dyck, E. (2006). ‘Hitting Highs at Rock Bottom’: LSD Treatment for Alcoholism, 1950-1970. Soc. Hist. Med. 19: 313-219. [PDF]

Dyck, E. (2005). Flashback: Psychiatric Experimentation With LSD in Historical Perspective. Can. J. Psychiatry 50: 381-388. [PDF]

Smart, R. G. & Storm, T. (1966). The Efficacy of LSD in the Treatment of Alcoholism. Quart. J. Stud. Alcohol 25: 333-338. [PDF]

Ketamine for Depression: Yay or Neigh?

December 14, 2010 Leave a comment

Venn diagram of psychoactive drugs (up)


NOTE: This post is part of a Nature Blog Focus on hallucinogenic drugs in medicine and mental health, inspired by a recent Nature Reviews Neuroscience paper, The neurobiology of psychedelic drugs: implications for the treatment of mood disorders, by Franz Vollenweider & Michael Kometer. This article will be freely available, with registration, until September 23. For more information on this Blog Focus, see the Table of Contents.


Veterinary Anesthetic, Club Drug, or Antidepressant?
Club drug “Special K” (aka ketamine) is stepping out of the laser light into the broad daylight of mainstream psychiatry with the publication of a new review article by Vollenweider and Kometer (2010). Long used to anesthetize animals (and children), ketamine was classified as a “dissociative anesthetic” by Domino et al. (1965) for its combined effects of sedation/analgesia and hallucinations. Domino (2010) recently revisited his classic paper, which reported on a study in 20 volunteers incarcerated at the Jackson Prison in Michigan:

The first human was given ketamine in an intravenous subanesthetic dose on August 3, 1964. Guenter [Corssen, M.D.] and I gradually increased the dose from no effect, to conscious but “spaced out,” and finally to enough for general anesthesia. Our findings were remarkable! The overall incidence of side effects was about one out of three volunteers. Frank emergence delirium was minimal. Most of our subjects described strange experiences like a feeling of floating in outer space and having no feeling in their arms or legs.

The ego death of the “K hole” can be a terrifying experience for some (“I ceased to exist”) or transformative for others (“I witnessed myself as a part of the universal collective of strange energy”)1. In their Nature Reviews Neuroscience opinion piece, Vollenweider and Kometer considered ketamine a psychedelic, along with the traditional hallucinogens such as LSD, psilocybin, and mescaline. They noted that both classes of drugs may have psychotherapeutic effects through actions on the excitatory glutamate neurotransmitter system.

Ketamine is an antagonist of the glutamate NMDA receptor and is thought to work by blocking NMDA receptors on inhibitory GABA-containing interneurons, ultimately promoting glutamate release. In a scientific tour de force, Li and colleagues (2010) demonstrated that the mTOR (mammalian target of rapamycin) protein kinase pathway is rapidly activated by ketamine. This sets off a cascade of events including the formation of new synapses on dendritic spines. Using a combination of cellular, molecular, electrophysiological, behavioral, and phamacological techniques, ketamine was shown to exhibit antidepressant properties in animal models of depression and anxiety, perhaps via rapid induction of synaptic plasticity in the medial prefrontal cortex (PFC). Regions of the medial PFC in humans, particularly the ventral anterior cingulate cortex, have been implicated in the pathophysiology of major depression.

Human clinical trials of ketamine as a rapidly acting antidepressant aren’t especially new. A randomized, double-blind study in 2000 involved administration of saline or a single subanesthetic dose of ketamine (0.5 mg/kg intraveneously) to nine depressed patients, seven of whom completed the trial (Berman et al., 2000). Within 72 hrs, amelioration of depressive symptoms was observed. Half of the treated patients showed a 50% or greater improvement in depression scores. However, these therapeutic effects weren’t very long-lasting, returning to baseline levels in 1-2 weeks. In a larger study, 18 patients with major depression participated in a similar double-blind cross-over design where they received the 0.5 mg/kg dose of ketamine and placebo one week apart (Zarate et al., 2006). The patients were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days post-infusion on a number of clinical scales, including the Hamilton Depression Rating Scale (HDRS), the Brief Psychiatric Rating Scale (BPRS) positive symptoms subscale, and the Young Mania Rating Scale (YMRS).

The primary outcome measure was change in HDRS score, shown in Figure 2 below (top graph). Significant improvements began at the 110 min time point. Scores declined further from 1-3 days and remained below placebo levels for 7 days. However, unusual experiences were noted at 40 min, with substantial increases in scores for psychosis-like and mania-like symptoms. Other adverse events associated with ketamine included…

…perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness, and increased libido. … The majority of these adverse effects ceased within 80 minutes after the infusion. In no case did euphoria [YMRS] or derealization/depersonalization [BPRS] persist beyond 110 minutes (Figure 2, middle and bottom graphs).

Figure 2 (Zarate et al., 2006). Change in the 21-item HDRS, BPRS positive symptoms subscale, and YMRS scores over 1 week (n=18). Values are expressed as generalized least squares means and standard errors for the completer analysis. * indicates P<.05; †, P<.01; ‡, P<.001.


So here we have several research groups that say yay! to ketamine as an antidepressant. Are there any naysayers?

Although the immediate onset of symptom amelioration gives ketamine a substantial advantage over traditional antidepressants (which take 4-6 weeks to work), there are definite limitations (Tsai, 2007). Drawbacks include the possibility of ketamine-induced psychosis (Javitt, 2010), limited duration of effectiveness (aan het Rot et al., 2010), potential long-term deleterious effects such as white matter abnormalities (Liao et al., 2010), and an inability to truly blind the ketamine condition due to obvious dissociative effects in many participants.

At present, what are the most promising uses for ketamine as a fast-acting antidepressant? Given the disadvantages discussed above, short-term use for immediate relief of life-threatening or end-of-life depressive symptoms seem to be the best indications.

Suicidal Ideation
Acute ketamine treatment in suicidal patients presenting at the ER has the potential to provide immediate changes in the risk that a patient will harm herself when released, when accompanied by proper followup and appropriate long-term treatment. An open label study in 33 patients with refractory depression involved infusion of 0.5 mg/kg ketamine over a period of 40 min (DiazGranados et al., 2010). Those with high scores on the Scale for Suicide Ideation showed significant improvements at 40 min that were maintained for the 230 min duration of the study. Obviously, one would like to follow actively suicidal patients for a longer period of time than 4 hrs, and future clinical trials should take this into account.

Palliative Care
Watching a terminally ill loved one suffer from unbearably excruciating pain is one of the most emotionally wrenching experiences you’ll ever have. Anything, and I mean anything , that will relieve this sort of suffering should be freely administered without reservation or stigma. As discussed in The secret history of psychedelic psychiatry, psilocybin has been shown to alleviate anxiety and pain in cancer patients. Reports of psychedelic psychotherapy in the 60s and 70s suggested that many patients overcame their fear of death through LSD-facilitated sessions. More recently, an open label study in two hospice patients, each with a prognosis of only weeks or months to live, showed beneficial effects of ketamine in the treatment of anxiety and depression (Irwin & Iglewicz, 2010). A single oral dose produced rapid improvement of symptoms and improved end of life quality. To disentangle the pain relieving and antidepressant effects of ketamine, the authors emphasized the importance of conducting clinical trials for this particular indication.

Better Drugs for a Brighter Tomorrow
Newer NMDA antagonist drugs with fewer dissociative side effects (e.g., more selective antagonists such as NR2B receptor blocker EVT 101) are undergoing testing and development. Personalized medicine and pharmacogenomics may ultimately shift psychedelic experiences out of the realm of hippies and into the doctor’s arsenal.



aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ. (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 67:139-45.

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. (2000). Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351-4.

DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr. (2010). Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. Jul 13. [Epub ahead of print]

Domino EF. (2010). Taming the ketamine tiger. Anesthesiology 113:678-84.

Domino EF, Chodoff P, Corssen G. (1965). Pharmacologic Effects of CI-581, a New Dissociative Anesthetic, in Man. Clin Pharmacol Ther. 6:279-91.

Irwin SA, Iglewicz A. (2010). Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 13:903-8.

Javitt DC. (2010). Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci. 47:4-16.

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959-64.

Liao Y, Tang J, Ma M, Wu Z, Yang M, Wang X, Liu T, Chen X, Fletcher PC, Hao W. (2010). Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain 133:2115-22.

Tsai GE. (2007). Searching for rational anti N-methyl-D-aspartate treatment for depression. Arch Gen Psychiatry 64:1099-100; author reply 1100-1.

Vollenweider, F., & Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders Nature Reviews Neuroscience, 11 (9), 642-651 DOI: 10.1038/nrn2884

Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856-64.

Serotonin, Psychedelics and Depression

December 13, 2010 Leave a comment

Note: This post is part of a Nature Blog Focus on hallucinogenic drugs in medicine and mental health, inspired by a recent Nature Reviews Neuroscience paper, The neurobiology of psychedelic drugs: implications for the treatment of mood disorders, by Franz Vollenweider & Michael Kometer. That article will be available, free (once you register), until September 23. For more information on this Blog Focus, see the “Table of Contents” here.

Ketamine, an anesthetic with hallucinogenic properties, which is attracting a lot of interest at the moment as a treatment for depression.

Ketamine, however, is not a “classical” psychedelic like the drugs that gave the 60s its unique flavor and left us with psychedelic rock, acid house and colorful artwork. Classical psychedelics are the focus of this post.

The best known are LSD (“acid”), mescaline, found in the peyote and a few other species of cactus, and psilocybin, from “magic” mushrooms of the Psilocybe genus. Yet there are literally hundreds of related compounds. Most of them are described in loving detail in the two heroic epics of psychopharmacology, PIKHaL and TIKHaL, written by chemists and trip veterans Alexander and Ann Shulgin.

The chemistry of psychedelics is closely linked with that of depression and antidepressants. All classical psychedelics are 5HT2A receptor agonists. Most of them have other effects on the brain as well, which contribute to the unique effects of each drug, but 5HT2A agonism is what they all have in common.

5HT2A receptors are excitatory receptors expressed throughout the brain, and are especially dense in the key pyramidal cells of the cerebral cortex. They’re normally activated by serotonin (5HT), which is the neurotransmitter that’s most often thought of as being implicated in depression. The relationship between 5HT and mood is very complicated, and depression isn’t simply a disorder of “low serotonin”, but there’s strong evidence that it is involved.

There’s one messy detail, which is that not quite all 5HT2A agonists are hallucinogenic. Lisuride, a drug used in Parkinson’s disease, is closely related to LSD, and is a strong 5HT2A agonist, but it has no psychedelic effects. It’s recently been shown that LSD and lisuride have different molecular effects on cortical cells, even though they act on the same receptor – in other words, there’s more to 5HT2A than simply turning it “on” and “off”.

How could psychedelics help to treat mental illness? On the face of it, the acute effects of these drugs – hallucinations, altered thought processes and emotions – sound rather like the symptoms of mental illness themselves, and indeed psychedelics have been referred to as “psychotomimetic” – mimicking psychosis.

There are two schools of thought here: psychological and neurobiological.

The psychological approach ruled the first wave of psychedelic psychiatry, in the 50s and 60s. Psychiatry, especially in America, was dominated by Freudian theories of the unconscious. On this view, mental illness was a product of conflicts between unconscious desires and the conscious mind. The symptoms experienced by a particular patient were distressing, of course, but they also provided clues to the nature of their unconscious troubles.

It was tempting to see the action of psychedelics as a weakening of the filters which kept the unconscious, unconscious – allowing repressed material to come into awareness. The only other time this happened, according to Freud, was during dreams. That’s why Freud famously called the interpretation of dreams the “royal road to the unconscious”.

Psychedelics offered analysts the tantalizing prospect of confronting the unconscious face-to-face, while awake, instead of having to rely on the patient’s memory of their previous dreams. To enthusiastic Freudians, this promised to revolutionize therapy, in the same way that the x-ray had done so much for surgery. The “dreamlike” nature of many aspects of the psychedelic experience seemed to confirm this.

Not all psychedelic therapists were orthodox Freudians, however. There were plenty of other theories in circulation, many of them inspired by the theorists’ own drug experiences. Stanislav Grof, Timothy Leary and others saw the psychedelic state of consciousness as the key to attaining spiritual, philosophical and even mystical insights, whether one was “ill” or “healthy” – and indeed, they often said that mental “illness” was itself a potential source of spiritual growth.

Like many things, psychiatry has changed since the 60s. Psychotherapy is currently dominated by cognitive-behavioural (CBT) theory, and Freudian ideas have gone distinctly out of fashion. It remains to be seen what CBT would make of LSD, but the basic idea – that carefully controlled use of drugs could help patients to “break through” psychological barriers to treatment – seems likely to remain at the heart of their continued use.

The other view is that these drugs could have direct biological effects which lead to improvements in mood. Repeated use of LSD, for example, has been shown to rapidly induce down-regulation of 5HT2A receptors. Presumably, this is the brain’s way of “compensating” for prolonged 5HT2A activation. This is probably why tolerance to the effects of psychedelics rapidly develops, something that’s long been known (and regretted) by heavy users.

Vollenweider and Kometeris note that this is interesting, because 5HT2A blockers are used as antidepressants – the drugs nefazadone and mirtazapine are the best known today, but most of the older tricyclic antidepressants are also 5HT2A antagonists. Atypical antipsychotics, which are also used in depression, are potent 5HT2A antagonists as well.

So indirectly suppressing 5HT2A might be one biological mechanism by which psychedelics improve mood. However, questions remain about how far this could explain any therapeutic effects of these drugs. Psychedelic-induced 5HT2A down-regulation is presumably temporary – and if all we need to do is to knock out 5HT2A, it would surely be easiest to just use an antagonist…



Vollenweider FX, & Kometer M (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience, 11 (9), 642-51 PMID: 20717121