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Serotonergic Hallucinogens in Depression Treatment
Depressive disorder is a demanding and common condition affecting more than 264 million people worldwide . Despite many studies, the etiology of this disease remains unknown . Some psychedelics, especially psilocybin, demonstrated an ability to reduce depressive symptoms as measured by several psychological scales, which was often sustained for months after the last psychedelic session.
1.1. Depression in the General Population
Some factors are strongly associated with a higher risk of developing depression, including environmental factors like emotional, physical, and sexual abuse; genetic and epigenetic factors; and organic changes in the central nervous system, especially in the hippocampus. These factors can affect the neurobiological stress-responsive systems, resulting in neuroinflammation and altered neurotransmission . The biological dysfunctions produced by these factors can also have a great impact on physical health and are associated with a higher risk of developing various conditions, such as heart disease, disability, diabetes mellitus, obesity, and cancer . However, the most pressing clinical concern is suicide, a direct cause of death in patients with depressive disorders, as the pooled lifetime prevalence of suicide attempts in depressed patients is estimated to be 27–34%, which is almost 20 times greater than in general population .
1.2. Current Treatment Methods for Depression and Their Limitations
1.3. Serotonergic Hallucinogens as a Potential Treatment for Depression
2. Serotonergic Hallucinogens in Depression Treatment
|No.||Studies’ Authors, Year||Substance/Test Group||Substance/Control Group||Comorbid Condition||No. of Participants||Used Questionnaires to Measure Depressive Symptoms|
|1||Kraehenmann R et al., 2015 ||Psilocybin, 0.16 mg/kg||Lactose||Healthy volunteers||25||PANAS, STAI|
|2||Ross S et al., 2016 ||Psilocybin, 0.3 mg/kg||Niacin, 250 mg||Advanced cancer||29||HADS, BDI, STAI, MEQ 30|
|3||Griffiths RR et al., 2016 ||Psilocybin, 22 or 30 mg/70 kg||Psilocybin, 1 or 3 mg/70 kg||Advanced cancer||51||GRID-HAMD-17, BDI, HADS, STAI|
|4||Carhart-Harris R et al., 2021 ||Psilocybin, 25 mg versus Escitalopram, 10–25 mg||Psilocybin 1 mg, placebo||Major depressive disorder||66||QIDS-SR-16|
|5||Ot’alora G M et al., 2018 ||MDMA, 125 or 100 mg||MDMA, 40 mg||PTSD||28||BDI|
|6||Mithoefer MC et al., 2019 ||MDMA, 75–125 mg||MDMA, 0–40 mg||PTSD||103||BDI|
|7||Wolfson PE et al., 2020 ||MDMA, 125 mg||Lactose, 125 mg||Life-threatening illness||18||BDI, MADRS|
|8||Bershad AK et al., 2019 ||LSD, 6.5–26 μg||Lactose||Healthy volunteers||20||POMS|
The Ot’alora et al. study involved 28 patients with chronic PTSD, of which nearly half (42.9%) had been diagnosed with MDD and 25% with depression. The lifetime Suicide Severity Rating Scale (SSRS) showed that 27/28 (92.6%) patients had suicidal ideation, and 8/28 (28.6%) exhibited suicidal behavior. During two eight-hour sessions spaced a month apart, patients received either an active (125 or 100 mg) or a comparator (40 mg) dose of MDMA. Changes in depressive symptoms, as measured by the BDI, showed approximately equivalent decreases across the groups. However, after an additional third open-label session where all participants received 100 mg or 125 mg MDMA, there was a significant improvement in the BDI at the 12-month follow-up compared to the baseline (7.3 points vs. 27.8 points) .
2.4. Open-Label Studies
Five studies revealed that the administration of 10–25 mg psilocybin in patients with treatment-resistant MDD significantly reduced depressive symptoms and that this effect persisted for 5 weeks–5 months as measured by the QIDS, BDI, STAI-T and Snaith-Hamilton Pleasure Scale (SHAPS) . fMRI images also showed that the amygdala response to emotional stimuli increased after psilocybin intake, which can be related to an enhanced ability to face and work through negative emotions, an increase in functional connectivity between the amygdala and prefrontal cortex and the occipital-parietal cortices, and a revival of emotional responsiveness .
|No.||Studies’ Authors, Year||Substance||No. of Participants||Comorbid Condition||Results|
|1.||Carhart RL et al., 2016 ||Psilocybin,
1. dose: 10 mg,
2. dose: 25 mg
|12||Major depression disorder (MDD) (moderate to severe degree, treatment-resistant)||A significant reduction in depressive symptoms lasting up to 3 months after 2. dose, relative to the baseline, measured by:
QIDS (10.0 vs. 19.2)
BDI (15.2 vs. 33.7)
STAI-T (54.8 vs. 70.1)
SHAPS (2.8 vs. 7.5)
|2.||Carhart RL et al., 2017 ||Psilocybin,
1. dose: 10 mg,
2. dose: 25 mg
|19||MDD (treatment-resistant)||A significant reduction in depressive symptoms lasting up to 5 weeks, measured by QIDS-SR16, were observed in 18 patients (95%) (mean change: −9.2); 9 patients (47%) met criteria for response (≤50% reductions).
Reduced depressive symptoms were correlated with decreased amygdala CBF in fMRI.
|3.||Carhart RL et al., 2018 ||Psilocybin,
1. dose: 10 mg,
2. dose: 25 mg
|19||MDD (severe, treatment-resistant)||A significant reduction in depressive symptoms lasting up to 6 months, relative to the baseline, measured by:
QIDS-SR16 (p = 0.0035)
BDI (19.5 vs. 34.5)
STAI (53.8 vs. 68.6)
|4.||Roseman L et al., 2018 ||Psilocybin,
1. dose: 10 mg,
2. dose: 25 mg
|20||MDD (moderate to severe, treatment-resistant)||Post-treatment increased amygdala responses to emotional stimuli in fMRI suggest that psilocybin allows to confront and work through negative emotions (induced by showing fearful and happy faces).|
|5.||Mertens LJ et al., 2020 ||Psilocybin,
1. dose: 10 mg,
2. dose: 25 mg
|19||MDD (moderate to severe, treatment-resistant)||Post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices in fMRI during face processing.|
|6.||Uthaug MV et al., 2020 ||DMT, 17–61 mg||10||-(Healthy volunteers)||Significant reduction of depressive symptoms, sustained at 7-day follow-up, measured in DASS-21.|
2.5. Adverse Events after Hallucinogen Use
Five out of fourteen studies did not include any information about adverse effects . The reported adverse events were divided into five categories: psychological, neurological, cardiovascular, gastroenterological, and general. The most common psychological adverse events were transient anxiety  and psychological discomfort , while the most common neurological events were headache  and, for MDMA administration, dizziness and jaw clenching . In the psilocybin studies, there were also gastroenterological adverse events noted, most commonly nausea and/or vomiting . Most researchers measured blood pressure and heart rate during psilocybin studies and observed an elevation in blood pressure  and heart rate ; however, these increases were often not considered adverse events . There were also some general adverse events noted, mostly in MDMA studies, including fatigue  and a lack of appetite .
Some hallucinogens are effective at reducing depressive symptoms and indicate that these agents may be used in the future as a novel treatment for depression. The administration of hallucinogens, especially psilocybin, results in a sustained reduction in depressive symptoms with an absence of serious adverse effects. It is worth mentioning the importance of the psychedelic experience itself and realizing that it can often be intense and overwhelming for a patient. Thus, the presence of a properly qualified monitor-therapist throughout the experience is necessary to ensure a positive result from each session. Compared to currently available methods, psychedelic therapy seems to be safer than the chronic use of antidepressant drugs but requires more time than regular therapy, as the effects of psychedelics can last up to 12 h. However, antidepressants and psychotherapy should remain first-line treatments, as their efficacy and safety are validated in clinical practice and available literature.
There are a few limitations of the existing studies on psychedelics. First, the sample size used was small and often consisted of healthy volunteers rather than patients suffering from actual conditions. Due to the characteristic and inimitable effects of these drugs, it has also been difficult to construct a study with adequate double blinding. To overcome this problem, some researchers have used a low, “placebo-like” dose of a substance for the control group, which can produce some effects that may not be obvious to the participants.
The entry is from 10.3390/life11080765
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