A Case Report: Good Effect of Psilocybin Even with No Psychedelic Effects
Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023
Marisa Leon-Carlyle reported on a 43 yr. old man with chronic treatment refractory depression who was given psilocybin 25mg (a 5HT2A agonist) at 8:00 AM after receiving trazodone 200mg HS (which should be enough to block 80% of 5HT2A receptors). He had an excellent antidepressant response, was able to feel emotion and new love for his wife, and finally felt that doing one’s best is good enough. Obviously further systematic study is needed.
High Response Rate to Psilocybin in Bipolar II Depression
Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023
Scott Aaronson gave 15 medication-free BP II patients (off all medications) 25mg of psilocybin with extensive therapeutic support. He saw rapid onset and persistent AD effects, such that at the end of 12 weeks 12 of the 15 patients were still in remission. Quality of life increased and suicidal ideation decreased. He indicated that others found that serum BDNF increased 1000 fold greater than baseline.
Antidepressant Effects of Psilocybin in Unipolar Depression
Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023
Alan Young reported on 233 patients with treatment refractory depression who were given 10mg then 25mg of psilocybin, 1 week apart.
There was intensive therapeutic support before, during, and after the ingestions. Patients experienced it as a waking dream. Response was rapid in onset and 20% response persisted at least through week 12.
An Open Label Study of Synthetic Psilocybin in Bipolar Type II Depression
Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego
Scott Aaronson reported on patients receiving a single dose of synthetic psilocybin. All subjects had three preparatory sessions prior to dosing and three integration sessions post dosing and were followed for 12 weeks.
“At the three week primary outcome measure, 11 of 14 participants (78.6%) met remission criteria.” They concluded: “Most subjects reported significant improvement in chronic depressive symptoms without hypomania or suicidality and durability lasting for three months follow-up.”
Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomized clinical trial
von Rotz et al reported in eClinical Medicine (the Lancet) that a single dose of psilocybin produced a huge AD (anti-depressant) effect compared to placebo. A dose of 0.215mg Kg (about 15mg for a 70kg person) had a rapid onset AD effect that persisted for at least 14 days. Music was played and in a living room like environment. Psychological support was provided on 3 visits pretreatment and on days 8 and 14 for a total of 14 hours
Psilocybin Comparable to Escitalopram in the Treatment of Depression
Four randomized, controlled clinical trials have established that psilocybin, the hallucinogenic compound in “magic mushrooms,” has anti-depressant effects. Recently, a phase 2 clinical trial compared the effects of psilocybin to a US Food and Drug Administration (FDA)–approved treatment for depression, the selective serotonin-reuptake inhibitor (SSRI) escitalopram. The study by Robin Carhart-Harris and colleagues was published in the New England Journal of Medicine in 2021.
The 59 participants in the 6-week study, which took place in the United Kingdom, had longstanding moderate-to-severe major depressive disorder. They were randomized to two groups. The psilocybin group received two separate doses of 25 mg of psilocybin 3 weeks apart, plus 6 weeks of daily placebo. The escitalopram group received two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram. (The small doses of psilocybin administered to the escitalopram group were assumed to have negligible psychiatric effects.) All participants were told they would receive psilocybin (though not the dose) in order to standardize their expectations.
In addition to the drug treatments, all participants also received psychological support, which consisted of monitoring immediately after the administration of the drugs (given the expectation that the 25mg dose of psilocybin would produce an “altered quality of conscious experience”), psychological debriefings, and an active listening session.
Psilocybin improved depression symptoms to a greater extent than escitalopram did. Among the participants, 70% of the psilocybin group responded to the treatment, compared with 48% of the escitalopram group. Remission occurred in 57% of the psilocybin group compared with 28% of the escitalopram group. These differences in the outcomes for the two groups were not statistically significant.
The FDA has designated psilocybin a “Breakthrough Therapy” for severe depression, which indicates that the therapy may be a substantial improvement over existing therapies for a serious condition. The designation is intended to speed up the drug development and review process.
The state of Oregon legalized psilocybin-assisted therapy in 2020.
Psilocybin May Improve Treatment-Resistant Depression
Psilocybin mushrooms
A small, uncontrolled study in the journal Lancet Psychiatry suggests that psilocybin, an ingredient in hallucinogenic mushrooms, relieved depression symptoms for up to three months in seven of 12 participants with unipolar depression that had not responded to at least two antidepressant medications.
Psilocybin has a different mechanism of action than typical treatments for depression. It activates 5HT2A serotonin receptors.
The participants, who had moderate to severe depression, were given two oral doses of psilocybin, a low dose (10mg) to establish the safety of the intervention, and a higher dose (25mg) seven days later. Psychedelic effects (anxiety, confusion, nausea, and headache) peaked within two to three hours and had dissipated by six hours after the intervention.
Depression began to improve within 24 hours after the 25mg dose. Depression symptoms were significantly improved by one week after the intervention. Eight of the 12 participants had a complete remission of their depression after one week, and this lasted the full three months in five participants. By the end of the three months, a total of seven of the 12 participants met the criteria for response to psilocybin.
The study’s authors, led by Robin L. Carhart-Harris, suggest that their preliminary results warrant more systematic investigation of psilocybin, but because there was no comparison group in this study, a large placebo effect cannot be ruled out.
“Epigenetic Changes After Trauma May Be Adaptive, Contribute to Resilience”
Originally From Psychiatric News Update
In recent years, research throughout the scientific and medical community has suggested a link between trauma and epigenetic changes, chemical modifications that affect gene activity without actually changing the gene’s DNA sequence. The assumption has been that epigenetic changes in the context of trauma are inherently bad, a form of damage that gets passed from generation to generation. But according to Rachel Yehuda, Ph.D., Endowed Professor of Psychiatry and Neuroscience of Trauma at the Icahn School of Medicine at Mount Sinai, these changes may also be adaptations that promote resilience.
“Sometimes the biological changes in response to trauma or intergenerational trauma are there to help deal with the problem of trauma, not compound its effects,” Yehuda said. “The survival advantage of this form of intergenerational transmission depends in large part on the environment encountered by the offspring themselves.”
Yehuda described this phenomenon as a paradox.
“Parental or ancestral trauma may heighten vulnerability to mental health challenges, but epigenetic adaptations may simultaneously facilitate coping mechanisms,” she said. “Trauma increases susceptibility for psychological distress, but also produces adaptations that help us cope with them.”
Yehuda described research she and her colleagues have conducted to tease out how trauma in parents can affect offspring in the context of the biology of posttraumatic stress disorder (PTSD) in Holocaust survivors and their children. As the research unfolded, Yehuda and colleagues found that survivors’ adult children were more likely to have mood disorders, anxiety disorders, and PTSD than Jewish people whose parents did not directly experience the Holocaust. This was especially true of children of Holocaust survivors who had PTSD. The researchers also found that many children of Holocaust survivors had low levels of the stress hormone cortisol, particularly if their parents had PTSD.
Yehuda and colleagues then conducted a series of studies that looked at the role of glucocorticoid receptors — the proteins to which cortisol must bind to exert its effects — and found evidence that these receptors were more sensitive in people with PTSD.
“In practical terms this means that even though someone with PTSD might have lower circulating levels of cortisol in their blood, their cells might react more strongly to the cortisol that is present,” Yehuda said.
Yehuda said that epigenetics provided further insight on the relationship between hypersensitive glucocorticoid receptors, cortisol, and PTSD. She explained the potential role of methylation, which is a chemical reaction in the body in which a small molecule called a methyl group gets added to DNA or DNA-associated proteins.
“Increased methylation generally impedes RNA transcription, whereas less methylation enhances gene expression,” Yehuda said.
In 2015, Yehuda and colleagues conducted a study involving combat veterans who had PTSD and found lower methylation on an important region on the participants’ glucocorticoid receptor gene. The changes were associated with cortisol and glucocorticoid receptor sensitivity in the study participants, suggesting a potential epigenetic explanation for the association between the trauma of combat and PTSD.
Yehuda said that stress-related epigenetic changes may be reversible. For example, one of the studies conducted by her team revealed that combat veterans with PTSD who benefited from cognitive-behavioral psychotherapy showed treatment-induced changes in the methylation of a gene that regulates glucocorticoid receptor sensitivity. Yehuda said that this finding confirmed that healing is also reflected in epigenetic change.
“That we can transform to meet environmental challenge is a superpower. That is resilience,” Yehuda said.” ?
Yehuda then went on to describe the striking and lasting effects of the psychedelics psilocybin and MDMA in trauma and in helping patients confront their fears in a positive and hopeful fashion. These agents which are given with intensive psychotherapeutic support are not yet FDA approved, but preliminary data suggest that they can have dramatic therapeutic effects in trauma and depression. They can help patients change their attitudes to themselves and the world.
NEW DATA ON EXTENDING THE EFFFECTS OF IV KETAMINE: Implications for countering the effects of stigma.
John Krystal of Yale U. in an article in Proceedings of the National Academy of Sci. (2023) gave new information about the anatomical and physiological effects of ketamine and about how to extend its effects. Ketamine in animals acutely (in a matter of hours) increases spines, synapses, and dendrites and physiological connectivity in neurons in the prefrontal cortex. Data now support these findings in humans with depression, but AD effects of ketamine tend to dissipate over a period of 3 to 5 days and require repeated infusions to maintain the improvement. Synaptic density can be measured with SV2A and this can be enhanced with a Navitor Pharmaceuticals drug acting on mTORC1. Surprisingly low doses of rapamycin, an inhibitor of mTOR1, extends the duration of AD effects of ketamine, increasing the response rate at 2 weeks of 13% to 41%. Ketamine restores only the spines that have been reduced in depression and rapamycin is thought to extend the duration of the restored spines. It may do this by increasing the neurotropic effects of microglia. The tripartite synapse of pre and post synaptic neurons and astrocytes, may now be better described as the tetrapartite synapse with the inclusion of microglial.
Adding psychotherapy to the effects of ketamine in PTSD increases and extends efficacy.
AD effects of ketamine can be extended with cognitive behavioral therapy. Thus, ketamine increases synaptic efficacy, synaptic density, glutamate homeostasis, and experience-dependent neuroplasticity. Extending the persistence of these effects by various chemical and psychotherapeutic mechanisms may give new ways of enhancing and prolonging the therapeutic effects of this rapidly acting agent.
Interestingly, Kaye at Yale U. reports that in contrast to transient effects of ketamine, the AD effects of therapy-assisted psilocybin appear to be very long lasting and the associated increases in spines persist for longer than 37 days. Another psychedelic MDMA that is effective in PTSD causes large increases in spines, although they are less persistent and are gone by 34 days.
Editors Note: As we have previously highlighted in the BNN, these data on ketamine and other psychedelics reversing the anatomical and physiological deficits in prefrontal neurons of depressed animals and humans (spines, dendrites, synapses and intercellular communication), give a new view of the real, reliable, and replicable neurological defects accompanying depression. The rapid correction of these neural abnormalities in conjunction with the rapid induction of antidepressant effects are not only paradigm shifting from a treatment perspective, but have major implications for the assertion that there is a neurobiological basis of depression and its treatment.
As such, these data should do much to counter the continuing stigma too often accompanying the term “mental” illness that it is somehow not as real as other medical and neurological conditions, and as it is often asserted that “it is just all in one’s head.” This picks up on the unfortunate associations and definitions of “mental” as imaginary, all in the mind, and evanescent and that mental illness can readily be countered with effort and will power such as “pulling oneself up by the bootstraps,” (the latter of which is in itself a logical impossibility.)“Pharmacotherapy of Bipolar Depression”
Roger McIntyre gave a talk on the “Pharmacotherapy of Bipolar Depression” at the International Society for Bipolar Disorders Conference in Chicago, June 22-25, 2023
He pointed out that, contrary to the many approved agents for mania, there were few FDA-approved drugs for depression in patients with Bipolar Disorders. These approved drugs included: cariprazine (Vraylar); lumateperone (Caplyta); lurasidone (Latuda); quetiapine (Seroquel); and the olanzapine-fluoxetine combination (Symbyax). Other non-approved agents include: lithium, lamotrigine, antidepressants, MAOIs, pramipexole, carbamazepine, ketamine, bupropion+dextromethorphan, amantadine, memantine, and possibly minocycline and celecoxib. Surprisingly, more than 3,000 bipolar depressed patients have been reported to be taking ketamine and that this was not associated with the induction of hypomania or mania.
McIntyre reported on the antidepressant (AD) effects of intra-nasal (i.n.) insulin. The insulin receptor sensitizer metformin had AD effects, but only in those who converted to insulin sensitivity.
McIntyre reported on the mixed effects of the GLP-1 agonists in the prevention of depression (Cooper et al J. Psychiatric Res, 2023). This is of interest in relationship to the bidirectional relationship of diabetes mellitus and depression.
Liraglutide appeared to have an anti-anhedonia effect. Semaglutide had AD and antianxiety effects in animal models of depression.
Recent studies have explored the antidepressant effect of psilocybin. Small studies have indicated that it has rapid onset of AD effects, and, in contrast to ketamine where rapid onset AD and anti-suicidal effects are short lived, the AD effect of psilocybin may be more prolonged.
Ketamine repairs structure and function of prefrontal cortical neurons via glutamate NMDA receptor blocking action, while psilocybin and other psychedelics act via stimulating 5HT2A receptors. One single case study suggested that blocking 5HT2A receptors with trazodone could achieve a rapid onset of AD effects of psilocybin without the psychedelic effects, a very interesting finding that requires replication.
