the fibrinolytic system: a new target for treatment of depression with psychedelics (pdf)
pdf version

bookmarks

search on psilosophy:  
   

The Fibrinolytic System: a New Target for Treatment of Depression with Psychedelics

by

Idell RD, M.D1 , Florova G PhD2, Komissarov AA PhD2, Shetty S PhD2, Girard R B.S3 and Idell S M.D., PhD2


1 Department of Behavioral Health, Child and Adolescent Psychiatry
2 Department of Cellular and Molecular Biology,
3 Biotechnology Graduate Program, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Tyler TX, 75708

Please address all correspondence to:
Richard Idell, M.D., Assistant Professor
Department of Behavioral Health, Child and Adolescent Psychiatry
The University of Texas Health Science Center at Tyler
11937 US Highway 271, Tyler, TX 75708
Phone (903) 877 7168
Fax (903) 877 8355
Email: richard.idell@uthct.edu

Funding:
1 Department of Behavioral Health Institutional Funding and
2 Texas Workforce Commission.
3 Institutional Funding from The University of Texas Health Science Center at Tyler derived from offset, NHLBI Grants RO-1HL118401-01A3 and UO-1 HL 121841-01A1 (SI, PI).

Table of Contents:
Introduction
The Linkage Between Peripheral or Cerebral Inflammation and Suppression of the Fibrinolysis in the Brain
Synaptic Plasticity, Depression, And The Fibrinolytic System In The Brain
Antidepressants, Ketamine and Psilocybin: Established and Hypothetical Effects on the Brain Fibrinolytic System and Depression
References

Introduction

Major depression is among the most common mental health disorders in the United States and carries the heaviest burden of disability among mental and behavioral disorders [1]. Over one third of patients will not achieve remission after initiation of an antidepressant treatment and the likelihood of achieving remission diminishes with subsequent medication trials [2]. These considerations demand exploration of alternative treatment strategies and identification of novel mechanisms that can be exploited to improve outcomes. The finding that glutamate modulators such as ketamine have rapid acting antidepressant effects has expanded the current model of depression beyond the traditional monoamine theory involving serotonin, dopamine and norepinephrine. Recent research has focused on the role of cytokine-mediated inflammation, neurogenesis, and the role of the glutamate in the pathogenesis of depression [3].

The involvement of inflammation in the development of depression has been extensively studied, while that of the fibrinolytic system, which is down-regulated by inflammation in a range of disorders including lung and pleural injury, cardiovascular disease, glomerulonephritis, and cirrhosis [4- 6] has been comparatively ignored, even though depression is considered to be an independent risk factor for coronary artery disease that predicts increased morbidity and mortality [7]. Brain derived neurotrophic factor (BDNF), a neurotrophic factor regulated by tissue type plasminogen activator (tPA), has been posited as a key link between stress, cardiovascular disease, and depression as well as its treatment, mainly via tPA-mediated cleavage of BDNF by plasmin [8-10]. Animal models with BDNF Val66Met polymorphisms are associated with decreased BDNF activity and demonstrate increased activation of platelets, alterations in coagulation pathways, changes in vessel wall protein composition and increased depressive phenotype [11]. Here, we review these prior hypotheses and extend them in light of more recent understanding of the role of impaired fibrinolysis, aberrant extravascular fibrin deposition and tissue remodeling that has been the longstanding focus of our group. We also provide new supporting evidence, some from our own laboratory, that newly recognized mechanisms underlying impaired fibrinolysis in the lung and pleural space could occur within the brain parenchyma to promote architectural alterations that lead to the development of depressive symptoms. While psychological explanations for depression are certainly important, our focus in this manuscript is on biologic mechanisms that specifically involve the fibrinolytic system, that could likewise contribute to the pathogenesis of depression and that may be amenable to novel pharmacologic approaches including administration of psychedelic agents.

tPA, urokinase (uPA), plasminogen activator inhibitor 1 (PAI-1), neuroserpin, and urokinase receptor (uPAR) are expressed in the brain in neurons, microglia and astrocytes [12,13] while soluble uPAR (suPAR) is a proteolytic cleavage product that can be detected within the systemic circulation. Interestingly, increased suPAR is a biomarker of depression [12] and potentially suicidality [13]. This supports the concept that abnormalities of the fibrinolytic system occur in depression and could potentially contribute to its pathogenesis (Figure 1). We posit that plasminogen activators, uPAR, and the inhibitors, PAI-1 and neuroserpin, are integral to the pathogenesis of depression, in part by regulating the production of mature BDNF (mBDNF) as well as remodeling of brain architecture, neurotransmission and synaptic plasticity. We also propose that psilocybin, a 5-ht2a serotonin receptor agonist and classic psychedelic can exert anti-depressant effects that are mediated by salutary changes in the fibrinolytic system. The classic psychedelic 5-ht2A receptor agonists, which include d-lysergic acid diethylamide (LSD), mescaline, and N,N-dimethyltryptamine (DMT) are capable of inducing robust changes in affect, perception, and cognition. Psilocybin in particular may induce positive psychological experiences of high personal significance leading to enduring beneficial changes in mood, thinking, and behavior [14].

Figure 1. Hypothesis: The contribution of the fibrinolytic system to processing of BDNF as a link to depression. Serpins (PAI-1 and NSP) are elevated in depression and inhibit both tissue (tPA) and urokinase (uPA) plasminogen activators (including uPA bound to its receptor uPAR), suppress activation of plasminogen, and block activation of proBDNF. Inhibition of the fibrinolytic activity promotes transient extravascular fibrin deposition in the brain. An increase in PA activity also results in cleavage of plasminogen producing plasmin, which then activates proBDNF to the activated cleavage product; mature (m)BDNF. However, transient fibrin, due to its high affinity to plasmin and tPA competes with proBDNF for plasmin, and thus affects proBDNF processing.

Our overarching hypothesis is that exploration of fibrinolytic system in the brain will provide an avenue for the development of new treatments for depression including administration of psychedelic agents to patients with refractory depression [15]. We specifically propose that serotonergic classic psychedelics such as psilocybin will demonstrate therapeutic effects on the brain including normalization of changes that occur as a result of chronic stress and disruption of the fibrinolytic system through interactions between neuroserpin, tPA and PAI-1 (Figure 2). We infer that psilocybin may decrease PAI1 activity via reduction of TNF-α levels, leading to disinhibition of tPA, increased mBDNF production, normalized synaptic plasticity, and resolution of depression (Figure 3). This hypothesis relies in part on the established link between peripheral and central inflammation in the pathogenesis of depression, which is described in the next section.

Figure 2. Proposed effects of dysregulated fibrinolysis on the pathogenesis of depression. Derangements of the fibrinolytic system are integral to the pathogenesis of depression: Stress initiates a cascade in the brain wherein proinflammatory cytokines such as TNF-α increase PAI-1 levels. This inhibits PA activity and blocks plasmin-mediated cleavage of proBDNF to mBDNF. Inhibition of PA activity also promotes transient fibrin deposition. A decrease in mBDNF (and increase in the proBDNF/mBDNF ratio) leads to disruption of hippocampal neurogenesis, synaptic plasticity, and increased hippocampal atrophy resulting in depression.

Figure 3. Proposed contribution of the fibrinolytic system to the mitigation of depression by psilocybin and other treatments. Psilocybin, Ketamine, Electroconvulsive therapy and SSRI's may act through antinflammatory, profibrinolytic mechanisms simultaneously decreasing TNF-α and PAI-1 levels thereby increasing PA activity to generate plasmin which cleaves pro BDNF to mature; mBDNF. This may lead to restoration of homeostatic functional neurocircuitry, increased hippocampal neurogenesis, and euthymia. Possible delay in activation of proBDNF could occur due to competition for plasmin and tPA with transient extravascular fibrin deposition within the brain parenchyma (Figure 1).

The Linkage Between Peripheral or Cerebral Inflammation and Suppression of the Fibrinolysis in the Brain

Evidence from human studies suggests that increased peripheral cytokine levels are associated with depression and suicidality [16]. A recent meta-analysis indicates that levels of interleukin-6 (IL-6) and TNF-α are significantly higher in depressed patients [17]. Aberrant cytokine elevation profiles have been shown to be potential biomarkers of treatment responses, as a recent study showed that subjects with non-remitted Major Depressive Disorder (MDD) have high baseline levels of TNF-α, which falls with exercise as opposed to antidepressant medications [18]. This study underscores the potential utility of alternative depression strategies or treatments, such as treatment with psilocybin for resistant depression.

Peripheral proinflammatory cytokines may access or directly affect the central nervous system (CNS) through several mechanisms such as activating the vagus nerve, disrupting the blood brain barrier (BBB), or accessing the brain directly via the circumventricular organs or saturable transport systems [19]. The BBB is regulated by several mechanisms involving tPA, which opens the BBB and PAI-1, which tightens the BBB [20]. Overexpression of proinflammatory cytokines in the CNS or in the circulation with induction of a relatively more open BBB, may contribute to neuroinflammation. These and other proinflammatory mediators activate microglia and astrocytes, leading to an enhanced local inflammation and the potential for glial scarification. These processes may suppress normal hippocampal neurogenesis which is associated with depression [21].

Disruption of hippocampal neurogenesis may occur throughout the life cycle as a result of chronic peripheral inflammation due to medical illness [22] or chronic stress [23]. In humans, numerous medical comorbidities including inflammatory bowel disease, diabetes mellitus, and obesity have all been linked to depression and cognitive impairment [24], likely mediated by disruption of hippocampal neurogenesis. These reports suggest a link between chronic inflammation due to co-morbidities with suppression of the fibrinolytic system in the brain.

Synaptic Plasticity, Depression, And The Fibrinolytic System In The Brain

Inflammation, coagulation, and fibrinolysis are intricately interwoven systems that are interactive [4,25]. While inflammation has been intensely studied as a risk factor for depression, the role of the fibrinolytic system in the pathogenesis of this disorder remains poorly understood. Several key elements of the fibrinolytic system linked to synaptic plasticity appear to be altered during stress. For example, uPA and uPAR have been shown to increase cellular viability in the stressed lung epithelium [26] and in lung fibroblasts [27] and we infer that they may similarly do so in the brain. uPA may also promote synaptic plasticity in the brain when upregulated by proinflammatory cytokines involved in depression. tPA and uPA convert plasminogen to its active form plasmin. In the vasculature, plasmin is known to degrade fibrin clots. In the brain, fibrin has been demonstrated to activate microglia, increasing neuroinflammation and potentially depression [28]. While it is currently unclear whether or not transitional fibrin occurs with low grade inflammation in the brain in depression, fibrin possesses high affinity for both tPA [29] and plasmin [30,31]. Its presence in the brain parenchyma could adversely affect neuroplasticity via inhibition of proBDNF activation, thus promoting depression. Moreover, PAI-1, which is upregulated in alveolar epithelial cells during lung inflammation, has been shown to inhibit neutrophil apoptosis and subsequent phagocytosis thereby leading to prolonged inflammation within the injured lung [32]. PAI-1 is primarily located in astrocytes and has been suggested to be antiapoptotic for neurons in the brain [33]. This suggests that both tPA and PAI-1 may be neurotoxic or neurotrophic depending on their relative concentrations. PAI-1 is a biomarker and mediator of poor outcomes in lung and pleural diseases [4,34] and we infer that elevated PAI-1 could likewise be a biomarker of depression (Figures 1 and 2).

While the fibrinolytic system plays a key role in the pathogenesis of renal [35,36], hepatic [37] and acute and chronic lung [4] injuries, this system may be of particular importance in the pathogenesis of depression in patients with lung disease. A recent study has shown that about one in four patients with chronic obstructive pulmonary disease (COPD) have persistent depressive symptoms which are associated with risk of COPD exacerbation and decreased exercise tolerance [38]. Additionally, patients with cystic fibrosis (CF) have been shown to have increased incidence of depression and anxiety [39]. The link between lung illness and depression is becoming better characterized by new research showing the influence of mood on other organ systems and vice versa. Inflammation induced epithelial-mesenchymal transition (EMT) in the lungs is associated with increased expression of epithelial PAI-1 and suppressed uPA and loss of lung function[40].

A process analogous to that which occurs in pulmonary remodeling may occur in the brain as a result of stress-induced inflammation. While fibrinogen, the precursor to fibrin, is not present at extravascular sites within the healthy brain it is elevated in the brains of individuals with schizophrenia [41], multiple sclerosis [42], Alzheimer's disease [43] and normal aging [44], all of which are disorders characterized by neuroinflammation and transient or long lasting BBB disruption[20]. These finding suggest that increased inflammation, decreased fibrinolysis and fibrosis may be involved in the pathogenesis of depression. Transitional fibrin deposition may perpetuate microglial activation, in addition to stress-induced, cytokine mediated microglial activation associated with decreased fibrinolysis, increased neuroinflammation, and depression. uPAR is involved in the recruitment of immune cells and cellular adhesion [45] and is a very sensitive marker of low grade inflammation typically seen in depression [12,13]. Further studies are necessary to characterize the roles of fibrin, tPA, uPA, uPAR, PAI-1 and neuroserpin in regulating stress, neural inflammation and mood (Figure 1 and 2).

In the CNS, tPA has been shown to exert effects that extend beyond traditional fibrinolysis and bridge to the regulation of neural cell functionality and behavior. For example, tPA has been demonstrated to influence synaptic plasticity though several mechanisms including degradation of the extracellular matrix through activation of matrix metalloproteases and interaction with the N-methyl-Daspartate (NMDA) receptor in addition to activation of proBDNF [46,47]. In the brain, tPA has been shown to have a role in memory, learning, and stress dependent behavioral responses [48]. In addition to its role in learning, tPA through NMDA receptor mediated activity, has been shown to be involved in the development of the fear response to acute stress through regulation of plasticity in the hippocampus [49]. While the administration of tPA itself for treatment of depression carries the risk of intracerebral bleeding and potentially neurotoxicity in the ischemic brain [50], the up-regulation of endogenous tPA activity is in principal an approach that could be pursued for the treatment of depression.

The literature also provides a link between the fibrinolytic system in the brain, BDNF and depression. BDNF is synthesized in cell bodies of neurons and glia and is transported to terminals where it is released [51]. It has been demonstrated to play a pivotal role in neurogenesis and depression. proBDNF and mBDNF have been shown to have opposite effects on neurogenesis and accordingly patients with major depression demonstrate elevated levels of proBDNF and decreased levels of mBDNF [52]. proBDNF induces dendritic retraction and apoptosis and long-term depression, while mBDNF promotes dendritic growth, cell survival, and long term potentiation indicating the importance of appropriate levels of functional tPA or perhaps uPA. A recent study demonstrated that an enriched environment increases tPA-dependent plasmin cleavage of proBDNF in mice [46]. Exercise has also been shown to increase mBDNF and tPA levels in humans which correlates with euthymia [53]. In rats, electro convulsive therapy, a rapid acting neuromodulatory treatment that is the gold standard treatment for resistant depression, has been shown to increase mBDNF and tPA levels [54], unlike imipramine, suggesting a novel tPA-mediated regulatory mechanism of action.

In the normal brain with no infiltrating microglia, PAI-1 is minimally expressed, and biochemical evidence showing strong inhibition of tPA suggests that the primary inhibitor of tPA is likely neuroserpin [55], particularly as overexpression of neuroserpin decreases activity levels of tPA [56]. Neuroserpin and tPA are expressed in neurons throughout the developing and adult nervous system [47]. Both overexpression and knockout of neuroserpin lead to increased anxiety like responses in mice, further supporting the role of the fibrinolytic system in regulating mood [57].

The literature suggests that tPA is a gliotransmitter mediating cross talk between neurons and astrocytes [58]. Astrocytes regulate the effective concentration of extracellular tPA and glutamate,influencing NMDA receptor signaling involved in regulation of mood. During chronic stress, excess hypothalamic-pituitary-adrenal (HPA) activation leads to activation ot microglia and impaired astrocyte reuptake of glutamate leading to excess extracellular NMDA receptor stimulation, neuro-inflammation and subsequent depression [59]. The disruption of the homeostatic balance of available extrasynaptic tPA, which is regulated by neuroserpin and astrocyte reuptake of glutamate, appears to be critical to cell survival and limitation of neuroinflammation.

uPA may be involved in the regulation of mood as well. Both tPA and uPA activate plasminogen to plasmin leading to degradation of extracellular matrix, which is critical to axonal and synaptic plasticity. Mice deficient in uPAR exhibit increased anxiety and reduced social behavior [60] and cognitive impairment [61], a finding that lends strength to our postulate that this receptor, through localization of uPA within brain cells, also contributes to regulation of cleavage of BDNF and alleviation of depressive symptoms. Notably, uPA-/ - mice have been demonstrated to exhibit a clear reduction in exploratory activity, an enhanced fear response to tone [62] and increased neuroinflammation[63].

Antidepressants, Ketamine and Psilocybin: Established and Hypothetical Effects on the Brain Fibrinolytic System and Depression

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, and citalopram inhibit the serotonin transporter (SERT, SCC6A4), a plasma membrane integral glycoprotein found in neurons and platelets that regulates reuptake of serotonin across the plasma membrane. Inhibition of SERT leaves more serotonin available in the synaptic cleft to increase serotonergic neurotransmission, one of the putative mechanisms of SSRIs. SSRIs have been shown to have significant efficacy in severe depression [64]. However, these drugs exert various side effects such as akathisia, sexual dysfunction and weight gain that may lead to discontinuation [65]. Furthermore, SSRIs may take up to 3-4 weeks to take effect, during which time the medication may be discontinued prior to titration to the optimal dose.

Neural circuits involved in emotional processing and reward seeking have been demonstrated to be dysfunctional in major depressive disorder. Individuals with major depressive disorder have demonstrated decreased resting state functional connectivity (RSFC) among specific circuits in the affective network involved in emotional processing and increased RSFC among default mode network neural circuits involved in self referential processing [66]. These imaging studies suggest electrophysiologic circuits that could be interrogated to see if these areas are functionally altered by disruptions of fibrinolysis or transient fibrin deposition in the depressed brain (Figure 1 and 2). Interestingly, psilocybin and mindfulness meditation has been shown to decrease activity in the default mode network [15,67] which could be therapeutic in depression by decreasing rumination or negative self-referencing contributing to the stress response, neuroinflammation and decreased fibrinolysis associated with depression.

Depressive derangements of the hippocampus have also been associated with altered functionality of the fibrinolytic system in the brain (Figure 2). In rats, sertraline (Zoloft), a selective SSRI, has been shown to increase the expression of tPA in the hippocampus and reverse depressive behavioral change in rats exposed to five weeks of chronic unpredictable mild stress [68]. In the same study, sertraline increased BDNF levels in the prefrontal cortex and hippocampus.

There is a growing body of additional clinical evidence supporting the hypothesis that the activity of the fibrinolytic system is decreased in depression. A study of women with MDD on anti-depressant therapy showed elevated plasma PAI-1 associated with increased abdominal fat compared with controls [69]. Variants of the SERPINE1 gene that encodes PAI-1 have been demonstrated to predict response to SSRI's in adults with MDD [70] and in individuals with Alzheimer's disease (AD) and depression [71]. These findings indicate that AD and MDD may show overlapping pathophysiology regulated by derangements in fibrinolysis, potentially alleviated by psilocybin.

Blockade of serotonin uptake in platelets by SSRis could decrease associated PAI-1 release and its subsequent activity in the blood and brain, in effect elevating Plasminogen Activator (PA) activity leading to higher plasmin levels with cleavage of proBDNF to mBDNF (Figures 2 and 3). Increased mBDNF promotes hippocampal neurogenesis and resolution of depressive symptoms associated with chronic stress induced hypersecretion of cortisol and adrenaline. Whether SSRIs regulate PAI-1 in the systemic circulation in patients receiving these drugs and how cardiovascular risk is affected with chronic use of these drugs is currently unclear.

Ketamine, an NMDA receptor antagonist and fast acting antidepressant has been shown to modulate the inflammation mediated kynurenine pathway with treatment response predicted by baseline levels of IL-6 [72]. To our knowledge, the effect of ketamine on PAI-1 expression within the brain has not been evaluated. Because PAI-1 can revert to an irreversibly latent form or can be cleaved with loss of inhibitory activity, the processing of PAI-1 in response to exposure to ketamine and other drugs and how it is processed in depression itself are issues that are germane to the better understanding of the pathogenesis of this condition. It is possible that by decreasing TNF-α and other pro-inflammatory cytokine activity, ketamine may indirectly affect PAI-1 levels, fibrin deposition, and increases of PA activity involved in hippocampal neurogenesis and the pathogenesis of depression.

Psilocybin binds with high affinity to the 5-ht1a, 5-ht2a/c, 5-ht6 and 5-ht7 subtypes of the serotonin receptors [73]. Psilocybin and other serotonergic classic psychedelics have been shown to exert their effects through agonism at the 5-ht2a subtype of the serotonin receptor [74], which is associated not only with psilocybin's psychedelic effects, but also with vascular smooth muscle contraction, platelet aggregation, thrombus formation, and coronary artery spasm [75]. The psychedelic effects of psilocybin include perceptual changes, labile moods vacillating from joy to anxiety, and cognitive changes including sense of meaning, insight or ideas of reference. The mystical experience, as defined by Roland Griffiths at Johns Hopkins, induced by psilocybin, is defined by abstract traits such as transcendence of time/space, unitary being, sense of sacredness, and ineffability. Researchers at Johns Hopkins have demonstrated that these traits of psilocybin experiences can be quantified by questionnaires that assess the occurrence of the mystical experience after psilocybin administration, the presence of which can be correlated with enduring positive attitudes, mood and behavior after psilocybin administration [14].

Recent studies suggest that 5-ht2a receptor modulation may have therapeutic potential in treating depression. Downregulation of 5-ht2A receptors, which may occur in response to 5-ht2a receptor stimulation, mediates antidepressant and antianxiety effects of antidepressants and atypical antipsychotic drugs [76]. Studies have shown that cortical 5-ht2a receptor expression is increased in postmortem samples of depressed and suicidal patients [77,78]. It is possible that the region-specific up regulation of 5-ht2a receptors associated with mood disorders and borderline personality disorder [79] may occur in response to stress related decreases in serotonin transmission, and that these receptors may subsequently be regulated to salutary levels in response to increased 5-ht2a stimulation associated with psychedelic use.

It appears that the 5-ht2a receptor upregulation is linked to the response to inflammation and fibrinolysis as well. C57BL/6J mice have varying degrees of psychological resiliency when exposed to chronic stress, with some mice manifesting behavioral symptoms of depression such as floating in the forced swim test and hyperactivity under stressful lighting conditions. Mice that manifest depressive symptoms demonstrate elevated TNF-α and SERT in the pre-frontal area, while all chronically stressed animals, resilient or susceptible, showed enhanced expression of 5-ht2a and Cox-1 in the pre-frontal area. The study suggests a unique, direct correlation between TNF-α levels, neuroinflammation and expression of 5-ht2a receptors. Previous studies in rabbits demonstrated that 5-ht2a agonists such as LSD can significantly reduce cortical 5-ht2a expression by 33-66% within days [80]. Of note, it has already been established that TNF-α and PAI-1 levels are directly correlated, suggesting that psilocybin could restore the 5-ht2a receptor to pre-stress levels with concomitant and potentially critical salutary downregulation of PAI-1 or perhaps neuroserpin.

R-DOI, a potent psychedelic and 5-ht2a agonist has been demonstrated to have potent antiinflammatory effects. R-DOI is noteworthy for its specificity to the 5-ht2a receptor which differentiates it from psilocybin. Studies show that R-DOI can block progression of a mouse model of asthma [81], possibly via blockade of TNF-α signaling, which could lead to reduction in PAI-1 levels and alleviation of depressive symptoms. There is also evidence that demonstrates that the microglial 5-ht2a receptor may regulate the release of microglial vesicles called exosomes that may contain cytokines involved in neuroinflammation and growth factors involved in neurogenesis [82]. It is plausible that 5-ht2a agonism may regulate the stress response at the level of the microglia via regulation of exosomal cytokines and growth factors necessary for neuronal growth and survival.

Emerging evidence supports the idea that psilocybin may exert effects through the limbic system including the hippocampus and amygdala that are involved in emotional processing. Psilocybin has been shown to normalize limbic hyperactivity in individuals with depressed mood by attenuating amygdala hyperactivity and increasing positive affect [83]. In mice, low dose psilocybin has been demonstrated to rapidly extinguish cued fear conditioning and induce a slight non-significant trend toward increased hippocampal neurogenesis, suggesting a potential role in the treatment of Post-Traumatic Stress Disorder (PTSD) [84] and possibly depression. Psilocybin has also been shown to be well-tolerated in humans in a controlled setting with proper supervision, screening and preparation [14] and may lead to increases in the personality domain of openness in healthy adults [85]. Small pilot studies in humans have shown efficacy of psilocybin in the treatment of anxiety in advanced stage cancer [86], as well as tobacco [87] and alcohol addiction [88]. Analysis of data from the National Survey of Drug Use and Health pooled across 2008-2012 by Hendricks et al. [89] demonstrated that psilocybin may be protective in patients with psychological distress and suicidality. Recently, a clinical study has demonstrated that psilocybin may reduce high sensitivity to social rejection that is characteristic of depression, suggesting that this drug is useful in reducing predisposing factors to depression [90]. Another small recent pilot study suggests that psilocybin administration with psychological support is a safe, efficacious treatment for refractory depression [91].

The role of ketamine and psilocybin in the regulation of the fibrinolytic system in the brain has not yet to our knowledge been studied. However, previous studies of the 5-ht2a receptor suggest a possible therapeutic role for psilocybin in depression involving the fibrinolytic system. Hypertrophic adipocytes have been shown to upregulate expression of the 5-ht2a receptor and PAI-1, while suppression of 5-ht2a gene expression enhances adiponectin expression, which is involved in regulation of glucose levels as well as fatty acid breakdown and is normally downregulated in obesity [92]. This finding demonstrates that downregulation of the 5-ht2a receptor by psilocybin could be associated with reduced PAI-1 expression and potentially help with weight loss and depression simultaneously. PAI-1 is deleteriously up-regulated in both conditions. Whether 5-ht2a receptor modulation and PAI-1 upregulation predispose to depression through interactions with components of the fibrinolytic system remains to be determined.

The role of psilocybin in the treatment of depression remains to be delineated. However, we posit that its administration is beneficial in reducing neuroinflammation, and restoring the fibrinolytic system to baseline, a postulate that can be tested in wild type mice with depressive behavior. If we are correct that effective therapy for depression is unified around a restoration of tPA leading to plasmin mediated activation of BDNF, preservation of neurogenesis and synaptic plasticity and that psilocybin reverses downregulation of tPA activity, the postulate can be confirmed. Additionally, the importance of changes in key components of the fibrinolytic system; tPA, uPA, uPAR or PAI-1 to depressive phenotype can be tested in knockout mice or in animals deficient in plasminogen and exposed to depressive stimuli. Transgenic mice that have upregulation of PAI-1 are also available to determine how its overexpression affects depressive symptoms.

Through in vitro studies with astrocytes involving the assessment of the effect of inflammatory cytokines such as TGF-β and TNF-α on the fibrinolytic system, we can assess the potential of psilocybin to alleviate pro-inflammatory, anti-fibrinolytic changes induced in glial cells. Clincally, we are assessing the role of mindfulness mediation on inflammatory and fibrinolytic biomarkers in depression. These studies may add support to pursuing further clinical trials using psilocybin for treatment resistant depression.

In conclusion, the preponderance of literature suggests that the pathogenesis of depression involves dysregulation of the fibrinolytic system and that antidepressants in common use and treatment candidates could be involved in their regulation. We specifically hypothesize that the fibrinolytic system exerts potentially critical effects in the pathogenesis of depression and that psychedelics such as psilocybin may regulate the fibrinolytic system in a salutary manner. We further posit that the therapeutic effects of psilocybin and perhaps commonly used antidepressants act as anti-inflammatory, profibrinolytic treatments that reduces neuroinflammation engendered by chronic stress. Increased inflammation through TNF-α and likely other proinflammatory mediators expressed in the brain is associated with elevated PAI-1 levels, increased 5-ht2a cortical expression, and decreased tPA activity in the CNS. These alterations disrupt synaptic plasticity in structures that mediate functional brain circuits involved in mood. We hypothesize that psilocybin exerts an antidepressant effect by reducing PAI-1 levels, decreases neuro-inflammation and fibrin deposition in the brain and restores the 5-ht2a receptor to pre-stress levels leading to normalized serotonergic tone associated with euthymic mood. Psychedelics have been historically stigmatized, and are currently schedule 1 substances in the U.S. making initiation of new research into the treatment of resistant depression with psilocybin a challenging endeavor. Despite these challenges, we believe that it is imperative to leave no stone unturned when alleviation of chronic suffering from depression is a potential outcome.

References

  1. Major Depression Among Adults n.d. http://www.nimh.nih.gov/health/statistics/prevalence/majordepression-among-adults.shtml (accessed October 21, 2015).
  2. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163:1905-17. doi:10.1176/appi.ajp.163.11.1905.
  3. Wang N, Yu H-Y, Shen X-F, Gao Z-Q, Yang C, Yang J-J, et al. The rapid antidepressant effect of ketamine in rats is associated with down-regulation of pro-inflammatory cytokines in the hippocampus. Ups J Med Sci 2015;120:241-8. doi:10.3109/03009734.2015.1060281.
  4. Tucker T, Idell S. Plasminogen-Plasmin System in the Pathogenesis and Treatment of Lung and Pleural Injury. Semin Thromb Hemost 2013;39:373-81. doi:10.1055/s-0033-1334486.
  5. ªalaru DL, Mertens PR, Bartsch P. Loss of heparin-binding protein prevents necrotizing glomerulonephritis: first clues hint at plasminogen activator inhibitor-1. Int Urol Nephrol 2013;45:1483-7. doi:10.1007/s11255- 013-0415-1.
  6. Tofler GH, Massaro J, O'Donnell CJ, Wilson PWF, Vasan RS, Sutherland PA, et al. Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study. Thromb Res 2016;140:30-5. doi:10.1016/j.thromres.2016.02.002.
  7. Garfield LD, Scherrer JF, Hauptman PJ, Freedland KE, Chrusciel T, Balasubramanian S, et al. Association of anxiety disorders and depression with incident heart failure. Psychosom Med 2014;76:128-36. doi:10.1097/PSY.0000000000000027.
  8. Tsai S-J. The possible role of tissue-type plasminogen activator and the plasminogen system in the pathogenesis of major depression. Med Hypotheses 2006;66:319-22. doi:10.1016/j.mehy.2005.10.009.
  9. Tsai S-J. The P11, tPA/plasminogen system and brain-derived neurotrophic factor: Implications for the pathogenesis of major depression and the therapeutic mechanism of antidepressants. Med Hypotheses 2007;68:180-3. doi:10.1016/j.mehy.2006.06.005.
  10. Tsai S-J. Statins may enhance the proteolytic cleavage of proBDNF: implications for the treatment of depression. Med Hypotheses 2007;68:1296-9. doi:10.1016/j.mehy.2006.09.043.
  11. Amadio P, Colombo GI, Tarantino E, Gianellini S, Ieraci A, Brioschi M, et al. BDNFVal66met polymorphism: a potential bridge between depression and thrombosis. Eur Heart J 2015. doi:10.1093/eurheartj/ehv655.
  12. Haastrup E, Grau K, Eugen-Olsen J, Thorball C, Kessing LV, Ullum H. Soluble urokinase plasminogen activator receptor as a marker for use of antidepressants. PloS One 2014;9:e110555. doi:10.1371/journal.pone.0110555.
  13. Ventorp F, Gustafsson A, Träskman-Bendz L, Westrin Å, Ljunggren L. Increased Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Levels in Plasma of Suicide Attempters. PLoS ONE 2015;10:e0140052. doi:10.1371/journal.pone.0140052.
  14. Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. Psilocybin occasioned mysticaltype experiences: immediate and persisting dose-related effects. Psychopharmacology (Berl) 2011;218:649-65. doi:10.1007/s00213-011-2358-5.
  15. Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A 2012;109:2138- 43. doi:10.1073/pnas.1119598109.
  16. Oquendo MA, Sullivan GM, Sudol K, Baca-Garcia E, Stanley BH, Sublette ME, et al. Toward a Biosignature for Suicide. Am J Psychiatry 2014;171:1259-77. doi:10.1176/appi.ajp.2014.14020194.
  17. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010;67:446-57. doi:10.1016/j.biopsych.2009.09.033.
  18. Rethorst CD, Toups MS, Greer TL, Nakonezny PA, Carmody TJ, Grannemann BD, et al. Pro-Inflammatory Cytokines as Predictors of Antidepressant Effects of Exercise in Major Depressive Disorder. Mol Psychiatry 2013;18:1119-24. doi:10.1038/mp.2012.125.
  19. Chesnokova V, Pechnick RN, Wawrowsky K. Chronic peripheral inflammation, hippocampal neurogenesis, and behavior. Brain Behav Immun n.d. doi:10.1016/j.bbi.2016.01.017.
  20. Bardehle S, Rafalski VA, Akassoglou K. Breaking boundaries - coagulation and fibrinolysis at the neurovascular interface. Front Cell Neurosci 2015:354. doi:10.3389/fncel.2015.00354.
  21. Beatriz Currier M, B. Nemeroff C. Inflammation and Mood Disorders: Proinflammatory Cytokines and the Pathogenesis of Depression. Anti-Inflamm Anti-Allergy Agents Med Chem Former Cu 2010;9:212-20.
  22. Zonis S, Pechnick RN, Ljubimov VA, Mahgerefteh M, Wawrowsky K, Michelsen KS, et al. Chronic intestinal inflammation alters hippocampal neurogenesis. J Neuroinflammation 2015;12:65. doi:10.1186/s12974- 015-0281-0.
  23. Cameron HA, Glover LR. Adult Neurogenesis: Beyond Learning and Memory. Annu Rev Psychol 2015;66:53-81. doi:10.1146/annurev-psych-010814-015006.
  24. Kiecolt-Glaser JK, Derry HM, Fagundes CP. Inflammation: Depression Fans the Flames and Feasts on the Heat. Am J Psychiatry 2015:appiajp201515020152. doi:10.1176/appi.ajp.2015.15020152.
  25. Idell S. The pathogenesis of pleural space loculation and fibrosis. Curr Opin Pulm Med 2008;14:310-5. doi:10.1097/MCP.0b013e3282fd0d9b.
  26. Bhandary YP, Shetty SK, Marudamuthu AS, Gyetko MR, Idell S, Gharaee-Kermani M, et al. Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system. Am J Physiol - Lung Cell Mol Physiol 2012;302:L463-73. doi:10.1152/ajplung.00099.2011.
  27. Bhandary YP, Shetty SK, Marudamuthu AS, Ji H-L, Neuenschwander PF, Boggaram V, et al. Regulation of lung injury and fibrosis by p53-mediated changes in urokinase and plasminogen activator inhibitor-1. Am J Pathol 2013;183:131-43. doi:10.1016/j.ajpath.2013.03.022.
  28. Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 2012;34:43-62. doi:10.1007/s00281-011-0290-8.
  29. Nieuwenhuizen W, Voskuilen M, Vermond A, Hoegee-de Nobel B, Traas DW. The influence of fibrin(ogen) fragments on the kinetic parameters of the tissue-type plasminogen-activator-mediated activation of different forms of plasminogen. Eur J Biochem FEBS 1988;174:163-9.
  30. Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982;257:2912-9.
  31. Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost 1999;82:259-70.
  32. Park Y-J, Liu G, Lorne EF, Zhao X, Wang J, Tsuruta Y, et al. PAI-1 inhibits neutrophil efferocytosis. Proc Natl Acad Sci U S A 2008;105:11784-9. doi:10.1073/pnas.0801394105.
  33. Soeda S, Koyanagi S, Kuramoto Y, Kimura M, Oda M, Kozako T, et al. Anti-apoptotic roles of plasminogen activator inhibitor-1 as a neurotrophic factor in the central nervous system. Thromb Haemost 2008;100:1014-20.
  34. Prabhakaran P, Ware LB, White KE, Cross MT, Matthay MA, Olman MA. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003;285:L20-28. doi:10.1152/ajplung.00312.2002.
  35. Huang Y, Noble NA. PAI-1 as a target in kidney disease. Curr Drug Targets 2007;8:1007-15.
  36. Pinheiro MB, Gomes KB, Dusse LMS. Fibrinolytic system in preeclampsia. Clin Chim Acta Int J Clin Chem 2013;416:67-71. doi:10.1016/j.cca.2012.10.060.
  37. Leebeek FWG, Rijken DC. The Fibrinolytic Status in Liver Diseases. Semin Thromb Hemost 2015;41:474-80. doi:10.1055/s-0035-1550437.
  38. Yohannes AM, Müllerová H, Hanania NA, Lavoie K, Tal-Singer R, Vestbo J, et al. Long-term Course of Depression Trajectories in Patients With COPD: A 3-Year Follow-up Analysis of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Cohort. Chest 2016;149:916-26. doi:10.1016/j.chest.2015.10.081.
  39. Quittner AL, Goldbeck L, Abbott J, Duff A, Lambrecht P, Solé A, et al. Prevalence of depression and anxiety in patients with cystic fibrosis and parent caregivers: results of The International Depression Epidemiological Study across nine countries. Thorax 2014;69:1090-7. doi:10.1136/thoraxjnl-2014-205983.
  40. [40] Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci 2006;103:13180-5. doi:10.1073/pnas.0605669103.
  41. Körschenhausen DA, Hampel HJ, Ackenheil M, Penning R, Müller N. Fibrin degradation products in post mortem brain tissue of schizophrenics: a possible marker for underlying inflammatory processes. Schizophr Res 1996;19:103-9.
  42. Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ. Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain J Neurol 2007;130:2800-15. doi:10.1093/brain/awm236.
  43. Cortes-Canteli M, Mattei L, Richards AT, Norris EH, Strickland S. Fibrin deposited in the Alzheimer's disease brain promotes neuronal degeneration. Neurobiol Aging 2015;36:608-17. doi:10.1016/j.neurobiolaging.2014.10.030.
  44. Viggars AP, Wharton SB, Simpson JE, Matthews FE, Brayne C, Savva GM, et al. Alterations in the blood brain barrier in ageing cerebral cortex in relationship to Alzheimer-type pathology: a study in the MRC-CFAS population neuropathology cohort. Neurosci Lett 2011;505:25-30. doi:10.1016/j.neulet.2011.09.049.
  45. Rijneveld AW, Levi M, Florquin S, Speelman P, Carmeliet P, Poll T van der. Urokinase Receptor Is Necessary for Adequate Host Defense Against Pneumococcal Pneumonia. J Immunol 2002;168:3507-11. doi:10.4049/jimmunol.168.7.3507.
  46. Obiang P, Maubert E, Bardou I, Nicole O, Launay S, Bezin L, et al. Enriched housing reverses age-associated impairment of cognitive functions and tPA-dependent maturation of BDNF. Neurobiol Learn Mem 2011;96:121-9. doi:10.1016/j.nlm.2011.03.004.
  47. Lee TW, Tsang VWK, Birch NP. Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system. Front Cell Neurosci 2015:396. doi:10.3389/fncel.2015.00396.
  48. Revest J-M, Le Roux A, Roullot-Lacarrière V, Kaouane N, Vallée M, Kasanetz F, et al. BDNF-TrkB signaling through Erk1/2 MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids. Mol Psychiatry 2014;19:1001-9. doi:10.1038/mp.2013.134.
  49. Norris EH, Strickland S. Modulation of NR2B-regulated contextual fear in the hippocampus by the tissue plasminogen activator system. Proc Natl Acad Sci U S A 2007;104:13473-8. doi:10.1073/pnas.0705848104.
  50. Fan M, Xu H, Wang L, Luo H, Zhu X, Cai P, et al. Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13. Sci Rep 2016;6:25971. doi:10.1038/srep25971.
  51. Leßmann V, Brigadski T. Mechanisms, locations, and kinetics of synaptic BDNF secretion: An update. Neurosci Res 2009;65:11-22. doi:10.1016/j.neures.2009.06.004.
  52. Zhou L, Xiong J, Lim Y, Ruan Y, Huang C, Zhu Y, et al. Upregulation of blood proBDNF and its receptors in major depression. J Affect Disord 2013;150:776-84. doi:10.1016/j.jad.2013.03.002.
  53. Sartori CR, Vieira AS, Ferrari EM, Langone F, Tongiorgi E, Parada CA. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavagerelated genes, p11 and tPA. Neuroscience 2011;180:9-18. doi:10.1016/j.neuroscience.2011.02.055.
  54. Segawa M, Morinobu S, Matsumoto T, Fuchikami M, Yamawaki S. Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus. Int J Neuropsychopharmacol 2013;16:339-50. doi:10.1017/S1461145712000053.
  55. Osterwalder T, Cinelli P, Baici A, Pennella A, Krueger SR, Schrimpf SP, et al. The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin. J Biol Chem 1998;273:2312-21.
  56. Cinelli P, Madani R, Tsuzuki N, Vallet P, Arras M, Zhao CN, et al. Neuroserpin, a neuroprotective factor in focal ischemic stroke. Mol Cell Neurosci 2001;18:443-57. doi:10.1006/mcne.2001.1028.
  57. Madani R, Kozlov S, Akhmedov A, Cinelli P, Kinter J, Lipp H-P, et al. Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin. Mol Cell Neurosci 2003;23:473-94.
  58. Cassé F, Bardou I, Danglot L, Briens A, Montagne A, Parcq J, et al. Glutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals. J Neurosci 2012;32:5186-99. doi:10.1523/JNEUROSCI.5296-11.2012.
  59. Kim Y-K, Na K-S. Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry 2016. doi:10.1016/j.pnpbp.2016.03.009.
  60. Powell EM, Campbell DB, Stanwood GD, Davis C, Noebels JL, Levitt P. Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction. J Neurosci Off J Soc Neurosci 2003;23:622-31.
  61. Bissonette GB, Bae MH, Suresh T, Jaffe DE, Powell EM. Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons. Behav Brain Res 2014;259:143-51. doi:10.1016/j.bbr.2013.10.051.
  62. Rantala J, Kemppainen S, Ndode-Ekane XE, Lahtinen L, Bolkvadze T, Gurevicius K, et al. Urokinase-type plasminogen activator deficiency has little effect on seizure susceptibility and acquired epilepsy phenotype but reduces spontaneous exploration in mice. Epilepsy Behav EB 2015;42:117-28. doi:10.1016/j.yebeh.2014.11.001.
  63. Gur-Wahnon D, Mizrachi T, Maaravi-Pinto F-Y, Lourbopoulos A, Grigoriadis N, Higazi A-AR, et al. The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention. J Neuroinflammation 2013;10:124. doi:10.1186/1742-2094-10-124.
  64. Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010;303:47-53. doi:10.1001/jama.2009.1943.
  65. Murphy TK, Segarra A, Storch EA, Goodman WK. SSRI adverse events: how to monitor and manage. Int Rev Psychiatry Abingdon Engl 2008;20:203-8. doi:10.1080/09540260801889211.
  66. Kim SM, Park SY, Kim YI, Son YD, Chung U-S, Min KJ, et al. Affective network and default mode network in depressive adolescents with disruptive behaviors. Neuropsychiatr Dis Treat 2015;12:49-56. doi:10.2147/NDT.S95541.
  67. Berkovich-Ohana A, Glicksohn J, Goldstein A. Studying the default mode and its mindfulness-induced changes using EEG functional connectivity. Soc Cogn Affect Neurosci 2014;9:1616-24. doi:10.1093/scan/nst153.
  68. Tang M, Jiang P, Li H, Cai H, Liu Y, Gong H, et al. Antidepressant-like effect of n-3 PUFAs in CUMS rats: role of tPA/PAI-1 system. Physiol Behav 2015;139:210-5. doi:10.1016/j.physbeh.2014.11.054.
  69. Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk: The POWER Study. Metabolism 2005;54:918-24. doi:10.1016/j.metabol.2005.02.006.
  70. Tsai S-J, Hong C-J, Liou Y-J, Yu YW-Y, Chen T-J. Plasminogen activator inhibitor-1 gene is associated with major depression and antidepressant treatment response. Pharmacogenet Genomics 2008;18:869-75. doi:10.1097/FPC.0b013e328308bbc0.
  71. Fang Y, Zhang L, Zeng Z, Lian Y, Jia Y, Zhu H, et al. Promoter polymorphisms of SERPINE1 are associated with the antidepressant response to depression in Alzheimer's disease. Neurosci Lett 2012;516:217-20. doi:10.1016/j.neulet.2012.03.090.
  72. Yang J-J, Wang N, Yang C, Shi J-Y, Yu H-Y, Hashimoto K. Serum interleukin-6 is a predictive biomarker for ketamine's antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry 2015;77:e19-20. doi:10.1016/j.biopsych.2014.06.021.
  73. Nichols DE. Psychedelics. Pharmacol Rev 2016;68:264-355. doi:10.1124/pr.115.011478.
  74. Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 2010;11:642-51. doi:10.1038/nrn2884.
  75. Nagatomo T, Rashid M, Abul Muntasir H, Komiyama T. Functions of 5-HT2A receptor and its antagonists in the cardiovascular system. Pharmacol Ther 2004;104:59-81. doi:10.1016/j.pharmthera.2004.08.005.
  76. Van Oekelen D, Luyten WHML, Leysen JE. 5-HT2A and 5-HT2C receptors and their atypical regulation properties. Life Sci 2003;72:2429-49.
  77. Shelton RC, Sanders-Bush E, Manier DH, Lewis DA. Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A. Neuroscience 2009;158:1406-15. doi:10.1016/j.neuroscience.2008.11.036.
  78. Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Pandey SC, Pesold C, et al. Higher Expression of Serotonin 5-HT2A Receptors in the Postmortem Brains of Teenage Suicide Victims. Am J Psychiatry 2002;159:419-29. doi:10.1176/appi.ajp.159.3.419.
  79. Soloff PH, Price JC, Meltzer CC, Fabio A, Frank GK, Kaye WH. 5-HT2A Receptor Binding is Increased in Borderline Personality Disorder. Biol Psychiatry 2007;62:580-7. doi:10.1016/j.biopsych.2006.10.022.
  80. Harvey JA, Quinn JL, Liu R, Aloyo VJ, Romano AG. Selective remodeling of rabbit frontal cortex: relationship between 5-HT2A receptor density and associative learning. Psychopharmacology (Berl) 2004;172:435-42. doi:10.1007/s00213-003-1687-4.
  81. Nau F, Miller J, Saravia J, Ahlert T, Yu B, Happel KI, et al. Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model. Am J Physiol - Lung Cell Mol Physiol 2015;308:L191-8. doi:10.1152/ajplung.00138.2013.
  82. Glebov K, Löchner M, Jabs R, Lau T, Merkel O, Schloss P, et al. Serotonin stimulates secretion of exosomes from microglia cells. Glia 2015;63:626-34. doi:10.1002/glia.22772.
  83. Kraehenmann R, Preller KH, Scheidegger M, Pokorny T, Bosch OG, Seifritz E, et al. Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biol Psychiatry n.d. doi:10.1016/j.biopsych.2014.04.010.
  84. Catlow BJ, Song S, Paredes DA, Kirstein CL, Sanchez-Ramos J. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Exp Brain Res 2013;228:481-91. doi:10.1007/s00221-013-3579-0.
  85. MacLean KA, Johnson MW, Griffiths RR. Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol Oxf Engl 2011;25:1453-61. doi:10.1177/0269881111420188.
  86. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry 2011;68:71-8. doi:10.1001/archgenpsychiatry.2010.116.
  87. Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol (Oxf) 2014:269881114548296. doi:10.1177/0269881114548296.
  88. Bogenschutz MP. Studying the effects of classic hallucinogens in the treatment of alcoholism: rationale, methodology, and current research with psilocybin. Curr Drug Abuse Rev 2013;6:17-29.
  89. Hendricks PS, Johnson MW, Griffiths RR. Psilocybin, psychological distress, and suicidality. J Psychopharmacol (Oxf) 2015;29:1041-3. doi:10.1177/0269881115598338.
  90. Preller KH, Pokorny T, Hock A, Kraehenmann R, Stämpfli P, Seifritz E, et al. Effects of serotonin 2A/1A receptor stimulation on social exclusion processing. Proc Natl Acad Sci U S A 2016. doi:10.1073/pnas.1524187113.
  91. Carhart-Harris RL, Bolstridge M, Rucker J, Day CMJ, Erritzoe D, Kaelen M, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry 2016. doi:10.1016/S2215-0366(16)30065-7.
  92. Uchida-Kitajima S, Yamauchi T, Takashina Y, Okada-Iwabu M, Iwabu M, Ueki K, et al. 5-Hydroxytryptamine 2A receptor signaling cascade modulates adiponectin and plasminogen activator inhibitor 1 expression in adipose tissue. FEBS Lett 2008;582:3037-44. doi:10.1016/j.febslet.2008.07.044.



search on psilosophy:  
 

TutorialS ]   [ ForuM ]   [ SpecieS ]   [ GalerY (pl) ]   [ TripograM ]   [ PsilosOpediuM ]  

© psilosophy 2001-2022