How Do Psychedelics Work in the Brain?

By understanding how these drugs work, researchers hope to design better and safer treatments that come with all the benefits of psychedelics, and few of the downsides. This recent pivot toward psychedelic drugs has been described by some as a “psychedelic revolution” in psychiatry, if not a “miracle cure” for mental health disorders in general. But many of the basic mechanisms of these drugs remain poorly understood, in a field of medicine that has barely begun to recover from decades of government-enforced stigmatization.

B. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Thalamus and Reticular Nucleus

Whether you take an opiate alone or with others, on a good day or a bad day, the high will pretty much be the same. It includes the people you trip with, tripping alone, your surroundings, your culture, whether the experience is guided or unguided, and the music you listen to during the experience. In contrast, people can take the same dosage of a psychedelic but have very different experiences. To better understand what psychedelics are, we need to compare and contrast them with other types of drugs. Indeed, there are certain aspects of psychedelics that make them quite different from many legal and illegal drugs. Because the term plant medicine excludes many psychedelic compounds, which may offer incredible healing to people, many find the term too restrictive.

Research on Psychedelic Drug Use

Nevertheless, higher doses of particular psychedelics may lead to activation of the 5-HT2C receptor, which often functionally opposes the effects of 5-HT2A receptor activation. For example, low doses of DOI increase locomotor activity in mice, whereas higher doses attenuate it, leading to an inverted are psychedelics addictive U type of dose-response curve. This effect has been attributed to activation of 5-HT2A receptors at low doses, but 5-HT2C receptor agonist activity at higher doses (Halberstadt et al., 2009). This interaction is explored more fully in the section in this review on the use of animal models.

A. General Issues of Safety and Mental Health in Psychedelic Users

Strachan et al. (2009) also showed that RSK2 was necessary for EGF-mediated heterologous desensitization of the 5-HT2A receptor, showing for the first time that a growth factor can heterologously desensitize 5-HT2A receptor signaling. Although there is a general public perception that psychedelic drugs are dangerous, from a physiologic standpoint they are in fact one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of LSD, psilocybin, or mescaline. Cohen (1967) and Jaffe (1985) have both stated that death due to direct LSD toxicity is unknown. For example, eight individuals who believed they had cocaine accidentally insufflated an extremely high dose of LSD.

• Prior to her freelance career, Marks was a supervising producer of medical programming for Ivanhoe Broadcast News.
• Indeed, Li et al. (2000) showed that SERT KO mice have reduced densities of 5-HT1A receptors, and Rioux et al. (1999) demonstrated reduced 5-HT2A receptors in SERT KO mice.
• Relative efficacies for AA release and IP accumulation varied within the series, and the substituted amphetamines had higher efficacy in both pathways.
• Although nonhuman primates might be the best animals to model the actions of psychedelics in humans, almost nothing has been published in the past decade using monkeys.
• Following the civil rights movement and the hippie counterculture of the 1960s, this was an era with a lot of political contention.

Study: Psilocybin Better Than SSRIs in Treating Depression

Doctors and veterinarians use ketamine as an anesthetic for humans and animals undergoing surgery. At lower doses, PCP can cause feelings of detachment from a person’s surroundings and self, slurred speech, and loss of coordination. DMT is a powerful chemical present in certain plant groups, including Phalaris, Delosperma, Acacia, Mimosa, and in the leaves of citrus plants. People can make a tea called ayahuasca, which is also known as hoasca, aya, or yagé, from the natural plant version. Psilocybin is the main active ingredient in “magic mushrooms,” which include a wide range of mushrooms found in tropical and subtropical regions of South America, Mexico, and the U.S.

What Are Psychedelic Drugs, and How Can They Help Treat Mental Health Conditions?

As this review was being finalized, Nichols and Martin (2015) reported that serotonergic hallucinogens preferentially activate subsets of cortical neurons, interneurons, and glial cells in the rat claustrum and induce rapid redistribution of 5-HT2A receptor protein within neurons. Sorted populations were processed for RNA extraction and subjected to quantitative RT-PCR for gene expression analysis. Only about 3% of total mPFC cells were activated in response to DOI; after identification, it was found that these activated cells displayed a 10-fold higher expression of 5-HT2A receptors than the nonactivated population. The highest 5-HT2A receptor expression and cellular activation was seen in these cells, which were identified as claustral cells, in which nearly one-half of the neurons were directly activated by DOI. Serotonin regulates amygdalar activity through activation of the 5-HT2 receptor family, which includes the 5-HT2A, 5-HT2B, and 5-HT2C receptors. In the deep nuclei of the amygdala, the 5-HT2A receptor is expressed on both excitatory (glutamatergic) pyramidal and inhibitory (GABAergic) nonpyramidal neurons, potentially playing a crucial role in the formation of emotional memories.

• Although the classic psychedelics have not been directly responsible for causing death, the judgment of users is certainly impaired while under the influence of these drugs.
• There were no significant differences found between groups in general intensity of drug effect, suggesting that mystical-type subjective effects, rather than overall intensity of drug effect, were responsible for smoking cessation.
• Griffiths et al. (2008) subsequently conducted a 14-month follow-up of the subjects from their earlier study.
• While intoxicated, PCP users may become violent or suicidal and are therefore dangerous to themselves and others.
• The number of dots successfully tracked was significantly reduced from placebo in both the psilocybin and psilocybin plus ketanserin pretreatment conditions; ketanserin alone had no effect.

G. Serotonin 5-Hydroxytryptamine 2A Receptor Expression in the Amygdala

While short-term positive and negative mood changes are common with psychedelic and dissociative drugs, more research is needed to better understand the long-term effects these substances may have on mental health. People with eating disorders often have other mental health symptoms, so psychedelic therapy might ease the symptoms that lead to disordered eating. A 2020 study of 28 people with a history of eating disorders found that psychedelics significantly reduced participants’ reported depression symptoms. Schizophrenia patients with predominantly negative symptoms exhibit reduced prefrontal activation compared with patients without negative symptoms. By contrast, schizophrenia patients with positive symptomatology have increased frontal metabolic rate of glucose. Soyka et al. (2005) used [18F]FDG PET in 10 unmedicated schizophrenia patients with vivid positive symptoms.

In addition, as will be discussed later, some of the newer highly potent synthetic phenethylamine hallucinogens have proven to be unexpectedly toxic. This section will detail studies indicating that psychedelics can be safely used under supervision, and that few documented serious adverse effects occur even after recreational use. The discussion will then turn to some generally recognized adverse reactions, followed by case reports of some more serious and even fatal reactions to psychedelics.

A. Evidence for Agonist or Partial Agonist Action at Serotonin 5-Hydroxytryptamine 2A Receptors

Transcript levels in the mouse somatosensory cortex 1 hour after agonist injection were compared by quantitative reverse-transcription (RT) polymerase chain reaction (PCR) to those from vehicle-injected controls. Thirteen transcripts showed significant changes after at least one agonist, with each agonist showing a unique and reproducible transcriptome fingerprints. Of the genes identified, only early growth response protein 1 (egr-1), early growth response protein 2 (egr-2), and period-1 were similarly activated by DOI and LSD but were unaffected by lisuride. Their data support the hypothesis that agonists acting at the same receptor in vivo can induce unique patterns of signaling, thereby eliciting different behavioral responses. Unique behavioral and signaling responses elicited by each agonist studied in vivo appear to result from agonist-specific differences in the activation of multiple signaling pathways coupled to the 5-HT2A receptor. Only the psychedelics DOI and LSD induced increased expression of egr-1, egr-2, and period-1 transcripts and were activated by changes in cortical signaling that appear to be specific effects of the two psychedelics, which correlate with the generation of the mouse HTR.

Can a Psychedelic Experience Improve Your Life?

• Because PCP can also have sedative effects, interactions with other central nervous system depressants, such as alcohol, can lead to coma.
• MDMA is an entactogen, which works by flooding the spaces between brain cells with serotonin, Johnson explains.
• R-DOI was found to block TNF-α–induced increases of these inflammatory markers in the vasculature (aortic arch).
• Grossman et al. (2010) characterized the behavioral and endocrine effects of LSD on adult zebrafish.

As far as we know, animals administered a psychedelic do not “hallucinate” or have the same sorts of sensory and cognitive effects that occur in humans. As with all animal models, the underlying assumption is that what happens in the animal system parallels, at least to a certain extent, what happens in the human. Fortunately, the key brain target for psychedelics, the serotonin 5-HT2A receptor, is a prominent player in the brain physiology of all mammalian species and its activation can produce measurable behaviors.