The neurobiology of psychedelic drugs : implications for the treatment of mood disorders, Franz X. Vollenweider and Michael Kometer, 2010

The neurobiology of psychedelic drugs : implications for the treatment of mood disorders

Franz X. Vollenweider and Michael Kometer

Perspectives,, 2010, 11, 642-651.



After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.


Psychedelic drugs have long held a special fascination for mankind because they produce an altered state of consciousness that is characterized by distortions of perception, hallucinations or visions, ecstasy, dissolution of self boundaries and the experience of union with the world. As plant-derived materials, they have been used traditionally by many indigenous cultures in medical and religious practices for centuries, if not millennia (1).

However, research into psychedelics did not begin until the 1950s after the breakthrough discovery of the classical hallucinogen lysergic acid diethylamide (LSD) by Albert Hofmann (2) (timeline). The classical hallucinogens include indoleam- ines, such as psilocybin and LSD, and phenethylamines, such as mescaline and 2,5-dimethoxy-4-iodo-amphetamine (DOI). Research into psychedelics was advanced in the mid 1960s by the finding that dissociative anaesthetics such as ketamine and phencyclidine (PCP) also produce psychedelic-like effects (3) (BOX 1). Given their overlapping psychological effects, both classes of drugs are included here as psychedelics.

Depending on the individual taking the drug, their expectations, the setting in which the drug is taken and the drug dose, psychedelics produce a wide range of experiential states, from feelings of boundlessness, unity and bliss on the one hand, to the anxiety- inducing experiences of loss of ego-control and panic on the other hand (4–7). Researchers from different theoretical disciplines and experimental perspectives have emphasized different experiential states. One emphasis has been placed on the LSD-induced perceptual distortions — including illusions and hallucinations, thought disorder and experiences of split ego (7,8) — that are also seen in naturally occurring psychoses (9–11). This perspective has prompted the use of psychedelics as research tools for unravelling the neuronal basis of psychotic disorders, such as schizophrenia spectrum disorder. The most recent work has provided compelling evidence that classical hallucinogens primarily act as agonists of serotonin (5-hydroxytryptamine) 2A (5-HT2A) receptors (12) and mimic mainly the so-called positive symptoms (hallucinations and thought disorder) of schizophrenia (10). Dissociative anaesthetics mimic the positive and the negative symptoms (social withdrawal and apathy) of schizophrenia through antagonism at NMDA (N-methyl-d-aspartate) glutamate receptors (13,14).

Emphasis has also been placed on the early observation that LSD can enhance self-awareness and facilitate the recollection of, and release from, emotionally loaded memories to psychiatrists as a unique property that could facilitate the psychodynamic process during psychotherapy. In fact, by 1965 there were more than 1,000 published clinical studies that reported promising therapeutic effects in over 40,000 subjects (17). LSD, psilocybin and, sporadically, ketamine have been reported to have therapeutic effects in patients with anxiety and obsessive– compulsive disorders (OCD), depression, sexual dysfunction and alcohol addiction, and to relieve pain and anxiety in patients with terminal cancer (18–23) (BOX 2). Unfortunately, throughout the 1960s and 1970s LSD and related drugs became increasingly associated with cultural rebellion; they were widely popularized as drugs of abuse and were depicted in the media as highly dangerous. Consequently, by about 1970, LSD and related drugs were placed in Schedule 1 in many western countries. Accordingly, research on the effects of classical psychedelics in humans was severely restricted, funding became difficult and interests in the therapeutic use of these drugs faded, leaving many avenues of inquiry unexplored and many questions unanswered.

With the development of sophisticated neuroimaging and brain-mapping tech- niques and with the increasing understand- ing of the molecular mechanisms of action of psychedelics in animals, renewed interest in basic and clinical research with psyche- delics in humans has steadily increased since the 1990s. In this Perspective, we review early and current findings of the therapeutic effects of psychedelics and their mechanisms of action in relation to modern concepts of the neurobiology of psychiatric disorders. We then evaluate the extent to which psychedelics may be useful in therapy — aside from their established application as models of psychosis (3,11).


Current therapeutic studies

Several preclinical studies in the 1990s revealed an important role for the NMDA glutamate receptor in the mechanism of action of antidepressants. These findings consequently gave rise to the hypothesis that the NMDA-antagonist ketamine might have potential as an antidepressant (24). This hypothesis was validated in an initial double-blind placebo-controlled clinical study in seven medication-free patients with major depression. Specifically, a significant reduction in depression scores on the Hamilton depression rating scale (HDRS) was observed 3 hours after a single infusion of ketamine (0.5 mg per kg), and this effect was sustained for at least 72 hours (25). Several studies have since replicated this rapid antidepressant effect of ketamine using larger sample sizes and treatment-resistant patients with depression (26–30). Given that 71% of the patients met response criteria (defined as a 50% reduction in HDRS scores from baseline) within 24 hours (26), this rapid effect has a high therapeutic value. In particular, patients with depression who are suicidal might benefit from such a rapid and marked effect as their acute mortality risk is not considerably diminished with conven- tional antidepressants owing to their long delay in onset of action (usually 2–3 weeks). Indeed, suicidal ideations were reduced 24 hours after a single ketamine infusion (28).

However, despite these impressive and rapid effects, all but 2 of the patients relapsed within 2 weeks after a single dose of keta- mine (26). Previous relapse prevention strategies, such as the administration of either five additional ketamine infusions (29) or riluzole (Rilutek; Sanofi-aventis) on a daily basis (30), yielded success only in some patients and other strategies should be tested in further studies. Moreover, the use of biomarkers that are rooted in psychopathology, neuro- psychology and/or genetics might help to predict whether ketamine therapy will be appropriate for a given patient with depression (31). In line with this idea, decreased activation of the anterior cingulate cortex (ACC) during a working memory task (32) and increased activation of the ACC during an emotional facial processing task (33), as well as a positive family history of alcohol abuse (27), were associated with a stronger antidepressant response to ketamine.

Ketamine therapy could be extended to other disorders in which NMDA receptors are implicated in the pathophysiology — for example, bipolar disorder34 and addiction (35). The use of ketamine for the treatment of bipolar disorder is currently being tested ( NCT00947791). Its poten- tial as a treatment for addiction is supported by results from a double-blind, randomized clini- cal trial in which 90 heroin addicts received either existentially oriented psychotherapy in combination with a high dose (2.0 mg per kg) or a low dose of ketamine (0.2 mg per kg). Follow-up studies in the first 2 years revealed a higher rate of abstinence, greater and longer-lasting reductions in craving, and a positive change in nonverbal, unconscious emotional attitude in subjects who had been treated with a high dose, compared with a low dose, of ketamine (36).

In contrast to the rapidly increasing number of clinical studies with ketamine, studies with classic hallucinogens are emerging slowly. This slow progress may be due to the fact that classic hallucinogens are placed in Schedule 1 and therefore have higher regulatory hurdles to overcome and may have negative connotations as a drug of abuse.

A recent study by Moreno and colleagues (37) evaluated case reports and findings from studies performed in the 1960s that indicated that psilocybin and LSD are effective in the treatment of OCD (22,38–40). They subsequently carried out a study show- ing that psilocybin given on four different occasions at escalating doses (ranging from sub-hallucinogenic to hallucinogenic doses) markedly decreased OCD symptoms (by 23–100%) on the Yale–brown obsessive compulsive scale in patients with OCD who were previously treatment resistant37. The reduction in symptoms occurred rapidly, at about 2 h after the peak psychedelic effects, and endured up to the 24-h post-treatment rating (37). This symptom relief was not related to the dose of the psychedelic drug or to the intensity of the psychedelic experience, and extended beyond the observed acute psychological effect of 4–6 h, raising intriguing questions regarding the mecha- nisms that underlie this protracted effect (37). Further research on how this initial relief of symptoms in response to psilocybin — and the subsequent return of symptoms — is linked to functional changes in the brain could contribute not only to a mechanistic explanation of the potentially beneficial effects of psychedelics but also to the development of novel treatments for OCD. The chronicity and disease burden of
OCD, the suboptimal nature of available treatments and the observation that psilocybin was well tolerated in OCD patients are clear indications that further studies into the duration, efficacy and mechanisms of action of psilocybin or of related compounds in the treatment of OCD are warranted.

Encouraged by early findings (BOX 2), several clinical centres have begun to inves- tigate the potential beneficial effects of psilocybin ( NCT00302744, NCT00957359 and NCT00465595) and LSD ( NCT00920387) in the treatment of anxiety and depression in patients with terminal cancer, using state of the art, double-blind, placebo controlled designs. One of these studies has recently been completed and revealed that moder- ate doses of psilocybin improved mood and reduced anxiety and that this relief variably lasted between 2 weeks and 6 months in patients with advanced cancer (C.S. Grob, personal communication). Finally, another recent study reported that psilocybin and LSD aborted attacks, terminated the cluster period or extended the remission period in people suffering from cluster headaches41. Taken together, these findings support early observations in the 1960s that classical hallucinogens have antinociceptive potential and may not only reduce symptoms but also induce long-lasting adaptive processes.


Neurobiology of psychedelic drugs

The enormous progress that has been made in our understanding of the mechanisms of action of psychedelics (12,42–45) and the neurobiology of affective disorders (34,46,47) has enabled us to postulate new hypotheses regarding the therapeutic mechanisms of psychedelics and their clinical applications. Here we focus on the glutamatergic and serotonergic mechanisms of action of psychedelics with regard to their most promising indications — that is, their use in the treatment of depression and anxiety.