`
`Asian J Psychiatr. 2016 Dec;24:51-52. doi: 10.1016/j.ajp.2016.08.010. Epub 2016 Aug 23.
`
`Return of the psychedelics: Psilocybin for treatment
`resistant depression.
`Patra S1.
`Author information
`1
`
`Department of Psychiatry, AIIMS Bhubaneswar, India. Electronic address:
`patrasuravi@gmail.com.
`Abstract
`
`Psilocybin, the clinically most researched classic psychedelic has recently been tested for its safety
`
`and efficacy in a clinical population of treatment resistant depression. The efficacy of psilocybin in
`
`clinical depression previously demonstrated in the elecrophysiologic and neuroimaging findings as
`
`also in neuropsychological assessments is further validated by the findings of this rigorously
`
`conducted randomized trial. Mechanism of action of psilocybin and efficacy in treatment resistant
`
`depression are discussed in this paper. Ethical issues of conducting clinical trials with psychedelics
`
`are also discussed with particular emphasis on their relative safety and absence of addiction
`
`potential. Implications of these issues for conduct of larger trials for establishing risk benefit ratio
`
`in treatment resistant depression are further suggested.
`
`
`
`Ther Adv Psychopharmacol. 2016 Jun;6(3):193-213. doi: 10.1177/2045125316638008. Epub 2016 Mar
`
`18.
`
`Antidepressive, anxiolytic, and antiaddictive effects of
`ayahuasca, psilocybin and lysergic acid diethylamide
`(LSD): a systematic review of clinical trials published in
`the last 25 years.
`Dos Santos RG1, Osório FL2, Crippa JA2, Riba J3, Zuardi AW2, Hallak JE2.
`Author information
`1
`
`Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de
`Ribeirão Preto, Universidade de São Paulo, Hospital das Clínicas, Terceiro Andar, Av.
`Bandeirantes, 3900, Ribeirão Preto, São Paulo, Brazil.
`
`2
`
`Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São
`Paulo, SP, Brazil National Institute for Translational Medicine (INCT-TM), CNPq, Brazil.
`3
`Centre d'Investigació de Medicaments, Servei de Farmacologia Clínica, Hospital de la Santa
`Creu i Sant Pau, Barcelona, Spain.
`Abstract
`
`EXHIBIT P
`
`

`

`To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show
`
`limited efficacy, leaving a large number of patients suffering severe and persistent symptoms.
`
`Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid
`
`diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we
`
`conducted a systematic review of clinical trials published from 1990 until 2015, assessing these
`
`therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO
`
`databases. Only clinical trials published in peer-reviewed journals were included. Of these, 151
`
`studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial
`
`effects for treatment-resistant depression, anxiety and depression associated with life-threatening
`
`diseases, and tobacco and alcohol dependence. All drugs were well tolerated. In conclusion,
`
`ayahuasca, psilocybin and LSD may be useful pharmacological tools for the treatment of drug
`
`dependence, and anxiety and mood disorders, especially in treatment-resistant patients. These
`
`drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop
`
`new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them
`
`were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies
`
`with more patients are needed to replicate these preliminary findings.
`
`
`
`Neurotherapeutics. 2017 Jul;14(3):734-740. doi: 10.1007/s13311-017-0542-y.
`
`Potential Therapeutic Effects of Psilocybin.
`Johnson MW1, Griffiths RR2,3.
`Author information
`1
`
`Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
`Medicine, Baltimore, MD, USA. mwj@jhu.edu.
`
`2
`
`Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
`Medicine, Baltimore, MD, USA.
`3
`Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
`Abstract
`
`Psilocybin and other 5-hydroxytryptamine2A agonist classic psychedelics have been used for
`
`centuries as sacraments within indigenous cultures. In the mid-twentieth century they were a focus
`
`within psychiatry as both probes of brain function and experimental therapeutics. By the late 1960s
`
`and early 1970s these scientific inquires fell out of favor because classic psychedelics were being
`
`used outside of medical research and in association with the emerging counter culture. However, in
`
`the twenty-first century, scientific interest in classic psychedelics has returned and grown as a result
`
`of several promising studies, validating earlier research. Here, we review therapeutic research on
`
`

`

`psilocybin, the classic psychedelic that has been the focus of most recent research. For mood and
`
`anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of
`
`depression and anxiety in the context of cancer-related psychiatric distress for at least 6 months
`
`following a single acute administration. A small, open-label study in patients with treatment-resistant
`
`depression showed reductions in depression and anxiety symptoms 3 months after two acute doses.
`
`For addiction, small, open-label pilot studies have shown promising success rates for both tobacco
`
`and alcohol addiction. Safety data from these various trials, which involve careful screening,
`
`preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse
`
`reactions. Modest drug-related adverse effects at the time of medication administration are readily
`
`managed. US federal funding has yet to support therapeutic psilocybin research, although such
`
`support will be important to thoroughly investigate efficacy, safety, and therapeutic mechanisms.
`
`
`
`Nurs Stand. 2016 Jun 8;30(41):15. doi: 10.7748/ns.30.41.15.s18.
`
`Magic mushroom compound is a potential treatment for
`patients with major depression.
`[No authors listed]
`Abstract
`
`A hallucinogenic compound derived from magic mushrooms could provide a new route for
`
`antidepressant research.
`
` J
`
` Psychopharmacol. 2016 Dec;30(12):1220-1229. Epub 2016 Nov 17.
`
`Psychedelics in the treatment of unipolar mood
`disorders: a systematic review.
`Rucker JJ1,2, Jelen LA3,4, Flynn S5, Frowde KD5, Young AH3,4.
`Author information
`1
`
`The Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
`james.rucker@kcl.ac.uk.
`
`2
`
`South West London and St George's Mental Health NHS Trust, London, UK.
`3
`The Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
`4
`South London and Maudsley NHS Foundation Trust, London, UK.
`5
`King's College London School of Medicine, London, UK.
`Abstract
`
`

`

`Unipolar mood disorders, including major depressive disorder and persistent depressive disorder
`
`(dysthymia), confer high rates of disability and mortality and a very high socioeconomic burden.
`
`Current treatment is suboptimal in most cases and there is little of note in the pharmaceutical
`
`development pipeline. The psychedelic drugs, including lysergic acid diethylamide and psilocybin,
`
`were used extensively in the treatment of mood disorders, and other psychiatric conditions, before
`
`their prohibition in the late 1960s. They are relatively safe when used in medically controlled
`
`environments, with no reported risk of dependence. Here, we present a systematic review of
`
`published clinical treatment studies using psychedelics in patients with broadly defined UMD, and
`
`consider their place in psychiatry. Whilst all of the included studies have methodological
`
`shortcomings, of 423 individuals in 19 studies, 335 (79.2%) showed clinician-judged improvement
`
`after treatment with psychedelics. A recently completed pilot study in the UK favours the use
`
`of psilocybin with psychological support in treatment resistant depressive disorder. The evidence
`
`Commented [CR1]: Studies from 1950s and 60’s
`reviewed suggest psychedelics worked as antidepressants
`
`overall strongly suggests that psychedelics should be re-examined in modern clinical trials for their
`
`use in unipolar mood disorders and other non-psychotic mental health conditions.
`
`
`
`Med Hypotheses. 2017 Mar;100:46-53. doi: 10.1016/j.mehy.2017.01.013. Epub 2017 Jan 23.
`
`The fibrinolytic system: A new target for treatment of
`depression with psychedelics.
`Idell RD1, Florova G2, Komissarov AA2, Shetty S2, Girard RB3, Idell S2.
`Author information
`1
`
`Department of Behavioral Health, Child and Adolescent Psychiatry, The University of Texas
`Health Science Center at Tyler, 11937 US HWY 271, Tyler, TX 75708, United States. Electronic
`address: richard.idell@uthct.edu.
`
`2
`
`Department of Cellular and Molecular Biology, The University of Texas Health Science Center at
`Tyler, 11937 US HWY 271, Tyler, TX 75708, United States.
`3
`Biotechnology Graduate Program, The University of Texas Health Science Center at Tyler, 11937
`US HWY 271, Tyler, TX 75708, United States.
`Abstract
`
`Current understanding of the neurobiology of depression has grown over the past few years beyond
`
`the traditional monoamine theory of depression to include chronic stress, inflammation and disrupted
`
`synaptic plasticity. Tissue plasminogen activator (tPA) is a key factor that not only promotes
`
`fibrinolysis via the activation of plasminogen, but also contributes to regulation of synaptic plasticity
`
`and neurogenesis through plasmin-mediated activation of a probrain derived neurotrophic factor
`
`(BDNF) to mature BDNF. ProBDNF activation could potentially be supressed by competition with
`
`fibrin for plasmin and tPA. High affinity binding of plasmin and tPA to fibrin could result in a decrease
`
`

`

`of proBDNF activation during brain inflammation leading to fibrosis further perpetuating depressed
`
`mood. There is a paucity of data explaining the possible role of the fibrinolytic system or aberrant
`
`extravascular fibrin deposition in depression. We propose that within the brain, an imbalance
`
`between tPA and urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-
`
`1) and neuroserpin favors the inhibitors, resulting in changes in neurogenesis, synaptic plasticity,
`
`and neuroinflammation that result in depressive behavior. Our hypothesis is that peripheral
`
`inflammation mediates neuroinflammation, and that cytokines such as tumor necrosis factor alpha
`
`(TNF-α) can inhibit the fibrinolytic system by up- regulating PAI-1 and potentially neuroserpin. We
`
`propose that the decrement of the activity of tPA and uPA occurs with downregulation of uPA in part
`
`involving the binding and clearance from the surface of neural cells of uPA/PAI-1 complexes by the
`
`urokinase receptor uPAR. We infer that current antidepressants and ketamine mitigate depressive
`
`symptoms by restoring the balance of the fibrinolytic system with increased activity of tPA and uPA
`
`with down-regulated intracerebral expression of their inhibitors. We lastly hypothesize that
`
`psychedelic 5-ht2a receptor agonists, such as psilocybin, can improve mood through anti-
`
`inflammatory and pro-fibrinolytic effects that include blockade of TNF-α activity leading to decreased
`
`PAI-1 activity and increased clearance. The process involves disinhibition of tPA and uPA with
`
`subsequent increased cleavage of proBDNF which promotes neurogenesis, decreased
`
`neuroinflammation, decreased fibrin deposition, normalized glial-neuronal cross-talk, and optimally
`
`functioning neuro-circuits involved in mood. We propose that psilocybin can alleviate deleterious
`
`changes in the brain caused by chronic stress leading to restoration of homeostatic brain fibrinolytic
`
`capacity leading to euthymia.
`
`
`
`Arch Gen Psychiatry. 2011 Jan;68(1):71-8. doi: 10.1001/archgenpsychiatry.2010.116. Epub 2010 Sep 6.
`
`Pilot study of psilocybin treatment for anxiety in patients
`with advanced-stage cancer.
`Grob CS1, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, Greer GR.
`Author information
`1
`
`Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, CA 90509, USA.
`cgrob@labiomed.org
`Abstract
`
`CONTEXT:
`
`Researchers conducted extensive investigations of hallucinogens in the 1950s and 1960s. By the
`
`early 1970s, however, political and cultural pressures forced the cessation of all projects. This
`
`

`

`investigation reexamines a potentially promising clinical application of hallucinogens in the treatment
`
`of anxiety reactive to advanced-stage cancer.
`
`OBJECTIVE:
`
`To explore the safety and efficacy of psilocybin in patients with advanced-stage cancer and reactive
`
`anxiety.
`
`DESIGN:
`
`A double-blind, placebo-controlled study of patients with advanced-stage cancer and anxiety, with
`
`subjects acting as their own control, using a moderate dose (0.2 mg/kg) of psilocybin.
`
`SETTING:
`
`A clinical research unit within a large public sector academic medical center.
`
`PARTICIPANTS:
`
`Twelve adults with advanced-stage cancer and anxiety.
`
`MAIN OUTCOME MEASURES:
`
`In addition to monitoring safety and subjective experience before and during experimental treatment
`
`sessions, follow-up data including results from the Beck Depression Inventory, Profile of Mood
`
`States, and State-Trait Anxiety Inventory were collected unblinded for 6 months after treatment.
`
`RESULTS:
`
`Safe physiological and psychological responses were documented during treatment sessions. There
`
`were no clinically significant adverse events with psilocybin. The State-Trait Anxiety Inventory trait
`
`anxiety subscale demonstrated a significant reduction in anxiety at 1 and 3 months after treatment.
`
`The Beck Depression Inventory revealed an improvement of mood that reached significance at 6
`
`months; the Profile of Mood States identified mood improvement after treatment with psilocybin that
`
`approached but did not reach significance.
`
`CONCLUSIONS:
`
`This study established the feasibility and safety of administering moderate doses of psilocybin to
`
`patients with advanced-stage cancer and anxiety. Some of the data revealed a positive trend toward
`
`improved mood and anxiety. These results support the need for more research in this long-neglected
`
`field.
`
`
`
`Ther Adv Psychopharmacol. 2017 Jan;7(1):54-56. doi: 10.1177/2045125316676092. Epub 2016 Oct 27.
`
`Role of psilocybin in the treatment of depression.
`
`

`

`Mahapatra A1, Gupta R2.
`Author information
`1
`
`Department of Psychiatry, 4th floor Academic Block, All India Institute of Medical Sciences,
`Ansari Nagar, New Delhi 110029, India.
`
`2
`
`Junior Resident, Department of Psychiatry and National Drug-Dependence Treatment Centre
`(NDDTC), All India Institute of Medical Sciences (AIIMS), New Delhi, India.
`Abstract
`
`Psilocybin is a naturally occurring alkaloid, pharmacologically similar to the classic hallucinogen
`
`lysergic acid diethylamide (LSD). Although primarily used as a recreational drug or an entheogen in
`
`particular cultural settings, recent population based studies have shown that it does not lead to
`
`serious physical or mental health problems or dependent use. In view of recent work
`
`demonstrating psilocybin's potential to increase subjective sense of wellbeing and because of its
`
`novel mechanism of 5-HT2A serotonin receptor agonism, it is being explored for possible therapeutic
`
`utility in mood and anxiety disorders.
`
`
`
`Clin Pharmacol Ther. 2017 Feb;101(2):209-219. doi: 10.1002/cpt.557. Epub 2016 Dec 26.
`
`Psychedelics as Medicines: An Emerging New Paradigm.
`Nichols DE1, Johnson MW2, Nichols CD3.
`Author information
`1
`
`Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
`
`2
`
`Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
`Medicine, Baltimore, Maryland, USA.
`3
`Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
`Abstract
`
`Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists)
`
`has dramatically increased within the last decade. Clinical studies administering psychedelics with
`
`psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety
`
`and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has
`
`suggested that these compounds have potential efficacy against inflammatory diseases through
`
`novel mechanisms, with potential advantages over existing antiinflammatory agents. We propose
`
`that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local
`
`brain network hubs and global network connectivity via amplification of neuronal avalanches,
`
`providing the occasion for brain network "resetting" after the acute effects have resolved.
`
`Antiinflammatory effects may hold promise for efficacy in treatment of inflammation-related
`
`nonpsychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate
`
`

`

`through unique mechanisms that show promising effects for a variety of intractable, debilitating, and
`
`lethal disorders, and should be rigorously researched.
`
`
`
`