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

This oft-cited (457+) opinion/review article by Vollenweider & Kometer gives an overview of the neurobiology of psychedelics and where research stood in 2010.

Abstract

“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.”

Authors: Franz X. Vollenweider & Michael Kometer

Summary

Psychedelic drugs have been used by indigenous cultures for centuries, but research into them began in the 1950s after the discovery of LSD. Dissociative anaesthetics such as ketamine and PCP also produce psychedelic-like effects.

Psychedelic drugs produce a wide range of experiential states, from feelings of boundlessness, unity and bliss to anxiety-inducing experiences of loss of ego-control and panic. These experiences have been used as research tools for unravelling the neuronal basis of psychotic disorders.

LSD was observed to enhance self-awareness and facilitate the recollection of emotionally loaded memories. This property appealed to psychiatrists, but LSD was placed in Schedule i in many western countries in the 1960s and 1970s, leaving many avenues of inquiry unexplored.

Since the 1990s, interest in basic and clinical research with psychedelics in humans has steadily increased. This Perspective reviews early and current findings and evaluates the potential use of psychedelics in therapy.

OpiniOn

Ketamine, an NMDA-antagonist, was found to have a rapid antidepressant effect in seven medication-free patients with major depression. This rapid effect was sustained for at least 72 hours and may have high therapeutic value for patients who are suicidal.

All but 2 patients relapsed within 2 weeks after a single dose of ketamine. Moreover, biomarkers rooted in psychopathology, neuropsychology and/or genetics might help to predict whether ketamine therapy will be appropriate for a given patient with depression.

Ketamine therapy is being tested for the treatment of bipolar disorder and addiction. It showed positive results in the first 2 years of treatment.

Studies with classic hallucinogens are emerging slowly, perhaps because they are placed in Schedule 1, which has higher regulatory hurdles. A recent study showed that psilocybin, a psychedelic drug, decreased symptoms of OCD in patients who were previously treatment resistant. The relief of symptoms was prolonged and not related to the dose of the drug or the intensity of the psychedelic experience. The chronicity and disease burden of OCD and the well tolerated nature of psilocybin suggest further studies into the treatment of OCD.

Psilocybin and LSD have been shown to improve mood and reduce anxiety in patients with terminal cancer, and to abort attacks, terminate the cluster period or extend the remission period in people suffering from cluster headaches.

neurobiology of psychedelic drugs

The mechanisms of action of psychedelics are now better understood, and new hypotheses have been postulated regarding their use in the treatment of depression and anxiety.

Classical hallucinogens are comprised of three main chemical classes: tryptamines, phenethylamines and ergolines. They all interact with 5-HT 2 receptors, but also with other receptors.

Evidence suggests that classical hallucinogens produce their effects in animals and possibly in humans primarily through agonistic actions at cortical 5-HT 2A receptors. This view is supported by studies that demonstrate that 5-HT 2A receptor antagonists abolish psilocybin-induced subjective effects in humans.

Several studies have demonstrated that activation of 5-HT 2A receptors by classical hallucinogens or serotonin leads to an increase in glutamatergic synaptic activity in pyramidal neurons in the prefrontal cortex. This increase can be abolished by specific 5-HT 2A antagonists, AMPA receptor antagonists, and selective antagonists of the NR2b subunit of NMDA receptors.

Activation of 5-HT 2A and 5-HT 1A receptors in the medial PFC increases serotonergic and dopaminergic activity, resulting in increased release of 5-HT in the mPFC and of dopamine in mesocortical areas in animals and humans.

In rats, 5-HT 2A receptor activation seems to underlie the acute psychedelic effects of hallucinogens and may also lead to neuroplastic adaptations in the extended prefrontal – limbic network. Hallucinogens have been shown to reduce the density of 5-HT 2A receptors in the prefrontal cortex and to increase the density of 5-HT 2A receptors in the amygdala, which might explain the therapeutic effects of hallucinogens in the treatment of depression, anxiety and chronic pain.

Fronto-limbic 5-HT 2A receptor density is correlated not only with anxiety but also with an individual’s difficulties in coping with stress. This suggests that down-regulation of prefrontal 5-HT 2A receptors by classical hallucinogens might underlie some of the effects of hallucinogens on depression and anxiety.

Dissociative anaesthetics, such as ketamine, PCP and MK-801, block NMDA receptors in the mPFC, which results in increased glutamate release and increased firing rate of pyramidal neurons. The psychoactive effects of ketamine and PCP can be blocked by administration of AMPA receptor antagonists.

Non-competitive NMDA receptor antagonists increase extracellular prefrontal and mesolimbic dopamine and prefrontal serotonin levels in rats, and these effects may contribute to the psychotic symptoms of NMDA antagonists.

Ketamine increases glutamate release by blocking NMDA receptors, and this increases AMPA receptor activation, which is crucial for the antidepressant-like effects of ketamine and CP-101,606 in animals.

There is accumulating evidence that hallucinogens and dissociative anaesthetics both modulate glutamatergic neurotransmission in the prefrontal – limbic circuitry that is implicated in the pathophysiology of mood disorders. The normalization of this dysregulated network might be important in the recovery from depression.

We propose that psilocybin and ketamine increase extracellular glutamate levels in the prefrontal – limbic circuitry in rats and that this increases the level of brain-derived neurotropic factor (bDNF). This increase in bDNF levels is associated with the sustained antidepressant effects of both drugs.

Conclusions and future directions

The clinical findings and current understanding of the mechanisms of action of psychedelics suggest that they could be useful in the treatment of major depression, anxiety disorders and OCD.

Psychedelics and dissociative anaesthetics alter glutamatergic neurotransmission in prefrontal- limbic circuitries, and this leads to neuroplastic adaptations, presumably through enhancement of AMPA receptor function. These adaptations may explain some of the shared and relatively sustained antidepressant effects observed in clinical studies with ketamine and psilocybin.

To optimize the clinical benefits of psychedelics and reduce their unwanted side effects, a deeper understanding of the molecular mechanism of action is necessary. This may help to develop novel ligands for 5-HT 2A or NMDA receptors that display antidepressant properties but have fewer dissociative effects. Psychedelic therapy was initially based on the premise that the drug-induced psychological experience had an essential, facilitatory effect on the psychotherapeutic process. However, it has been shown that the drug-induced psychological experience and its integration in the psychotherapeutic process is the crucial mechanism that enables neuroplasticity and behavioural changes.

Drugs targeting glutamatergic neurotransmission in prefrontal – limbic circuitries may provide promising new treatment approaches for affective disorders.

Psychoanalytically oriented psychotherapy is based on Freudian psychoanalysis and involves bringing unconscious conflicts into consciousness to create insight for the resolution of problems.

Transference

A double-blind, placebo-controlled dose-effect study of psilocybin in healthy humans was conducted by Hasler, Grimberg, U., Benz, M. A., Huber, T. & Vollenweider, F. X.

Dittrich, A., Pletscher, A., Ladewig, D., Fischer, R., Marks, P. A., Hill, R. M. & Rockey, M. (1994).

Hallucinogenic drugs resemble acute endogenous psychoses, according to a study by Gouzoulis-Mayfrank et al., Geyer, M. A. & Vollenweider, F. X., and Nichols, D. E.

The dissociative anesthetics ketamine and phencyclidine reduce excitation of central mammalian neurons by N-methyl-D-aspartate.

LSD is used as a therapeutic tool, but there are acute adverse reactions to LSD in clinical and experimental use in the United Kingdom.

LSD is used in psychotherapy and alcoholism, and has been used with terminal cancer patients. Glutamate-based antidepressants are also used, and are 20 years on from their introduction.

Ketamine, an N-methyl-D-aspartate antagonist, has been shown to be effective in the treatment of depression.

Ketamine has been shown to be effective in treating treatment-resistant depression, and has been shown to have neurobiological markers that predict rapid antidepressant response to ketamine. Ketamine is also being used in the treatment of heroin addiction. LSD, psilocybin, and phenethylamines have been shown to relieve symptoms of obsessive-compulsive disorder, cluster headache, and schizophrenia, and ketamine has been shown to activate a network of fast-spiking interneurons in the orbitofrontal cortex. 46 studies have shown that cognitive therapy versus medication for depression has different treatment outcomes and neural mechanisms. 47 studies have shown that serotonin induces excitatory postsynaptic potentials in apical dendrites.

Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of the prefrontal cortex by an asynchronous mode of glutamate release. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior, and serotonin 2A receptor agonists induce schizophrenia-like psychosis in humans via a serotonin 2A receptor agonist action. Aghajanian, G. K., Zhang, C., & Marek, G. J. (2009) model psychosis in vitro by inducing disordered neuronal network activity. Several studies have shown that the metabotropic glutamate receptor subtype 2 plays an important role in hallucinogenic drug-induced psychosis. Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain, and behavioral tolerance to LSD is associated with reduced serotonin-2A receptor signaling in rat cortex.

Studies have shown that 5-HT2A receptors are increased in postmortem prefrontal cortex in major depression and are associated with reduced activity of protein kinase, A. Antisense inhibition of 5-HT2A receptors induces an antidepressant-like effect in mice. In early life, social isolation causes social anxiety-like behavior. Antagonism of corticotropin-releasing factor receptors reduces this behavior. The CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling, the frontolimbic serotonin 2A receptor is associated with personality risk factors for affective disorder, and the medial prefrontal cortex determines how stressor controllability affects behavior and the dorsal raphe nucleus. Phencyclidine affects prefrontal cortex neurons by increasing firing rate and decreasing burst activity. A group II metabotropic peptide reverses these effects.

Ketamine’s antidepressant effects are mediated by NR2B subunit selective N-methyl-D-aspartate receptor antagonists, which are also mediated by -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Jentsch, Tran, Taylor, J. R. & Roth, R. H. found prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system. M100907, a serotonin 5-HT 2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in sprague-dawley and wistar rats, and attenuates the effects of phencyclidine on object recognition in the rat prefrontal cortex. Vollenweider, F. X., Leenders, K. L., Oye, I., Hell, D. & Angst, J. Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis and the psilocybin model of psychosis. PET studies have shown that psilocybin, 3,4-methylenedioxyethylamphetamine and d-methamphetamine alter glutamatergic metabolism in healthy volunteers.

Researchers have found that the prefrontal cortex of depressed patients has reduced glutamate/glutamine and gamma-aminobutyric acid levels, and that the amygdala has an increased response to sad faces. Ketamine is a new generation of antidepressants with a rapid onset of action, and it is regulated by 5-HT2A receptors. Ketamine treatment reverses behavioral and physiological alterations induced by chronic mild stress in rats, and psilocybin treatment induces long-term subjective effects in healthy humans. LSD was used in therapy for alcoholics, and was found to have positive effects. Psilocybin was also found to be helpful in the treatment of alcoholics. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance, according to Griffiths, Richards, McCann, and Jesse.

There are many papers on the use of LSD in psychotherapy, such as Osmond, H., Kurland, A., Abramson, H., Hollister, L. E., Shelton, J. & Krieger, G., and Savage, C. & McCabe, O. L.

Ketamine is used in psychiatry to treat depression and anxiety. Its brain mechanisms are not fully understood.

As the field of human neuroscience has matured, it has become possible to identify the underlying cognitive and affective systems that are influenced by socioeconomic status (SES). This knowledge will enable the design of more specific and powerful interventions to prevent and remediate the effects of low childhood SES.

Other recent reviews have discussed the effects of SES on neurocognitive development in children, adolescents and young adults. This Perspective discusses possible mediators of these effects.

SES effects on mental health and cognition

SES is a complex construct that includes household income, material resources, education and occupation, as well as related neighbourhood and family characteristics. SES affects emotional and cognitive development to varying degrees, and the strongest effects are often seen in people with the lowest levels of SES.