Shroom Therapy. Use of Psilocybin in End of Life Anxiety Treatment

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1 Shroom Therapy Use of Psilocybin in End of Life Anxiety Treatment Karolina Grzesiak, PharmD PGY1 Pharmacy PracCce Resident Central Texas Veterans Health Care System Pharmacotherapy Rounds November 17 th 2017

2 Objec;ves 2 Review end of life anxiety and American Society of Clinical Oncology treatment guidelines Outline the history and pharmacology of psilocybin Explore the physiological and psychological effects of psilocybin on healthy individuals Evaluate literature describing use of psilocybin for end of life anxiety Discuss future direc;on for treatment with hallucinogens

3 Pa;ent Case 3 I am so anxious that it is hard to think about anything else. I had lost my faith because of anxiety and it is terrifying. AL is a 53 year old woman with a diagnosis of metasta;c ovarian cancer. Pa;ent is currently receiving pallia;ve treatment for pain and nausea. She has been suffering from anxiety and depression since her diagnosis 3 months ago. Current medica;ons: Morphine ER 60mg daily Morphine IR 10mg three ;mes daily PRN Ondansetron 4mg ODT every 8 hours PRN Sertraline 150mg daily Buspirone 20mg three ;me daily Trazodone 150mg at bed;me Alprazolam 0.5mg three ;mes daily PRN Gabapen;n 800mg three ;mes daily Is this pa;ent a good candidate for Psilocybin therapy?

4 End of Life Anxiety

5 End of Life 5 End of life care care for terminally ill patents focused on improving quality of life and making them more comfortable End of life emo;ons Fear Anger Guilt and regret Grief Anxiety Depression Feeling alone Seeking meaning hwps://

6 Epidemiology 6 In pallia;ve care, anxiety disorders affect approximately 10% of pa;ents More common in women, physically impaired, younger pa;ents Symptoms are reported by 25-48% of advanced cancer pa;ents Mul;factorial causes of anxiety Treatment process Disease progression Uncontrolled pain Dying Uncertainty J Pain Symptom Manage. 2011;42(5):

American Society of Clinical Oncology Guidelines 7 All pa;ents with cancer are

care 7 item GAD-7 None/mild symptoms 0-4, 5-9 Moderate symptoms 10-14 Severe symptoms

interven;ons, ± Pharmacologic Suppor;ve Care CBT, Pharmacologic, combined

7 American Society of Clinical Oncology Guidelines 7 All pa;ents with cancer are evaluated for symptoms of depression and anxiety periodically across the trajectory of care 7 item GAD-7 None/mild symptoms 0-4, 5-9 Moderate symptoms Severe symptoms Offer referral to suppor;ve care services Psychosocial, Psychological interven;ons, ± Pharmacologic Suppor;ve Care CBT, Pharmacologic, combined Psychological (individual) Pharmacological (SSRI, anxioly;cs) Psychosocial (group) J Oncol Pract. 2015;11(2):133-4.

8 Psilocybin Overview

Psilocybin History 9 Isolated from Central American mushroom (Psilocybe mexicana) by a Swiss chemist Albert Hofmann in 1957 Found in many species of mushrooms worldwide n Psilocybe, Conocybe,

9 Psilocybin History 9 Isolated from Central American mushroom (Psilocybe mexicana) by a Swiss chemist Albert Hofmann in 1957 Found in many species of mushrooms worldwide n Psilocybe, Conocybe, Gymnopilus, Panaeolus, and Stropharia n Along with peyote and dimethyltryptamine, psilocybin has a long history of ceremonial use Produced synthe;cally in 1958 Indocybin Sandoz n Pure synthe;c psilocybin n Marketed for experimental use Addict Biol. 2002;7(4):

Detectable in plasma in 20-40 min aher oral administra;on T ½ = 163 ± 64 min with PO administra;on Considered 30x stronger than

10 Psilocybin Pharmacology 10 Hallucinogenic alkaloid 4-phosphoryloxy-N,N-dimethyltryptamine Similar chemical structure to serotonin Metabolized to 4 metabolites (psilocin, 4H1A, 41-IIAA, 41-IT) Highly potent agonist at serotonin 5-HT 2A 50% oral absorp;on Detectable in plasma in min aher oral administra;on T ½ = 163 ± 64 min with PO administra;on Considered 30x stronger than mescaline, 1/ as potent as LSD Strongly visual, less emo;onally intense, less likely to result in paranoia Addict Biol. 2002;7(4):

11 Physiological and Psychological Effects 11 Eight healthy volunteers par;cipated in a doubleblind, placebo-controlled, dose-effect study Doses: Very low dose (VLD) 45 mcg/kg Low dose (LD) 115 mcg/kg Medium dose (MD) 215 mcg/kg High dose (HD) 315 mcg/kg BP, EKG, temperature, neuroendocrine data, blood chemistry Global Altered State of Consciousness Score Addict Biol. 2002;7(4): Psychopharmacology (Berl). 2004;172(2):

12 Physiological Effects 12 EKG No evidence of Psilocybin induced change of cardiac electrophysiology Blood pressure Increased blood pressure is apparent at 60-90min Temperature No significant changes Addict Biol. 2002;7(4): Psychopharmacology (Berl). 2004;172(2):

Physiological Effects 13 Neuroendocrine data TSH, prolac;n, ACTH, and cor;sol levels were increased at t+105min, returned back to baseline at t+300min Blood chemistry At high

13 Physiological Effects 13 Neuroendocrine data TSH, prolac;n, ACTH, and cor;sol levels were increased at t+105min, returned back to baseline at t+300min Blood chemistry At high doses, liver func;on tests (GGT and AST) were elevated at t+105 min and returned to normal at t+300 Addict Biol. 2002;7(4): Psychopharmacology (Berl). 2004;172(2):

14 Psychological Effects 14 Serotonin receptors (5-HT) play an important role in percep;on, affect regula;on, and awen;on Doses between mcg/kg are clearly rated as psychoac;ve Dose dependent changes in mood, sensory percep;on, as well as ;me, space, and self percep;on Effects last about 3 to 6 hours Addict Biol. 2002;7(4): Psychopharmacology (Berl). 2004;172(2):

15 Literature Review

16 Arch Gen Psychiatry. 2011;68(1):71-8. J Psychopharmacol (Oxford). 2016;30(12): J Psychopharmacol (Oxford). 2016;30(12): Symptom Scales 16 Beck Depression Inventory (BDI) Series of ques;ons developed to measure the intensity, severity, and depth of depression Hospital Anxiety and Depression Scale (HADS) Commonly used by doctors to determine levels of anxiety and depression that a pa;ent is experiencing State-Trait Anxiety Inventory (STAI) Self-reported assessment of anxiety, differen;ates between the temporary condi;on of state anxiety and the more general and long-standing quality of trait anxiety Hamilton Anxiety/Depression RaCng Scale (HAM-A, HAM-D) Clinician rated scales to assess severity of anxiety/depression Profile of Mood States Brief Psychiatric Ra;ng Scale 5-Dimension Altered States of Consciousness Profile

17 Pilot Study of Psilocybin Treatment for Anxiety in Pa;ents with Advanced Stage Cancer Grob CS, Danforth AL, Chopra GS, et al (2011)

18 Grob, et al (2011) 18 Objec;ve To explore the safety and efficacy of psilocybin in pa;ents with advancedstage cancer and reac;ve anxiety Design Double-blind, placebo-controlled study Crossover design Interven;on Psilocybin 0.2 mg/kg Placebo (niacin 250mg) Arch Gen Psychiatry. 2011;68(1):71-8.

Grob, et al (2011) 19 Inclusion Advanced stagecancer DSM-IV diagnosis of acute stress disorder due to cancer or

hepa;c and renal func;on Diabetes Life;me history of schizophrenia, bipolar disease, other psychiatric illness Anxiety

19 Grob, et al (2011) 19 Inclusion Advanced stagecancer DSM-IV diagnosis of acute stress disorder due to cancer or adjustment disorder with anxiety Exclusion Central nervous system involvement of the cancer Severe CV illness Abnormal hepa;c and renal func;on Diabetes Life;me history of schizophrenia, bipolar disease, other psychiatric illness Anxiety of affec;ve disorder within 1 year prior to cancer diagnosis Contraindicated medica;ons Endpoints Primary: Safety and subject experience Beck Depression Inventory (BDI) Profile of Mood States (POMS) State-Trait Anxiety Inventory (STAI) AddiConal: 5-Dimension Altered States of Consciousness profile (5D-ASC) Brief Psychiatric Ra;ng Scale Arch Gen Psychiatry. 2011;68(1):71-8.

20 Grob, et al (2011) subjects (11 women, 36 to 58 years old) 4 breast cancer 3 colon cancer 2 ovarian cancer 1 salivary gland cancer 1 peritoneal cancer 1 mul;ple myeloma 3 mo 12 par;cipants 4 mo 11 par;cipants 6 mo 8 par;cipants Arch Gen Psychiatry. 2011;68(1):71-8.

21 Grob, et al (2011) 21 BDI, POMS, STAI BDI, POMS, STAI BDI, POMS, STAI Day -1 Day 0 Day +1 Day +14 Monthly POMS, STAI, 5D- ASC, Brief Psychiatric RaCng Scale BDI, POMS, STAI BDI Beck Depression Inventory POMS Profile of Mood States STAI State- Trait Anxiety Inventory 5D-ASC 5-Dimension Altered State Of Consciousness Profile Arch Gen Psychiatry. 2011;68(1):71-8.

22 Grob, et al (2011) 22 5-Dimension Altered State of Consciousness Profile Oceanic Boundlessness Visionary Restructuraliza;on Anxious Ego Dissolu;on Arch Gen Psychiatry. 2011;68(1):71-8.

23 Grob, et al (2011) 23 Arch Gen Psychiatry. 2011;68(1):71-8.

24 Grob, et al (2011) 24 Arch Gen Psychiatry. 2011;68(1):71-8.

25 Grob, et al (2011) 25 Summary Safe physiologically and psychologically Profile of Mood States Improvement during 2 weeks post treatment Beck Depression Inventory Significant improvement at 6mo State- Trait Anxiety Inventory Downward trend in trait anxiety LimitaCons Small sample size Not generalizable popula;on Treatment order apparent to par;cipants Arch Gen Psychiatry. 2011;68(1):71-8.

26 Rapid and Sustained Symptom Reduc;on Following Psilocybin Treatment for Anxiety and Depression in Pa;ents with Life- Threatening Cancer: A Randomized Controlled Trial Ross S, Bossis A, Guss J, et al (2016)

27 Ross, et al (2016) 27 Objec;ve To determine if psilocybin in conjunc;on with targeted psychotherapy would significantly decrease anxiety and depression symptoms in pa;ents with lifethreatening cancer diagnosis. Design Double-blind, randomized, controlled study Crossover design Interven;on Psilocybin 0.3 mg/kg Placebo (Niacin 250 mg) J Psychopharmacol (Oxford). 2016;30(12):

Ross, et al (2016) 28 Inclusion 18 to 76 years old Projected life expectancy of at least 1 year Terminal cancer diagnosis

Depression Exclusion HADS <8 Epilepsy, renal disease, diabetes, abnormal liver func;on, severe CV disease Personal or

disorder Current substance use disorder Endpoints Primary: Hospital Anxiety and Depression Scale (HADS) Beck Depression

28 Ross, et al (2016) 28 Inclusion 18 to 76 years old Projected life expectancy of at least 1 year Terminal cancer diagnosis Primary diagnosis of Acute Stress Disorder, GAD, Anxiety Disorder due to cancer, Adjustment Disorder with Anxiety +/- Depression Exclusion HADS <8 Epilepsy, renal disease, diabetes, abnormal liver func;on, severe CV disease Personal or immediate family history of schizophrenia, bipolar disorder, delusional disorder, paranoid disorder, or schizoaffec;ve disorder Current substance use disorder Endpoints Primary: Hospital Anxiety and Depression Scale (HADS) Beck Depression Inventory (BDI) State- Trait Anxiety Inventory (STAI) AddiConal: Cardiovascular measures (HR, BP) Adverse events J Psychopharmacol (Oxford). 2016;30(12):

Ross, et al (2016) 29 31 subjects (90% Caucasian, 62% women) 31% breast

other Dose 1 29 subjects 6 wk 28 subjects Dose 2 26 subjects 6 wk 24

29 Ross, et al (2016) subjects (90% Caucasian, 62% women) 31% breast cancer 28% reproduc;ve cancer 17% GI cancer 14% hematologic cancer 10% other Dose 1 29 subjects 6 wk 28 subjects Dose 2 26 subjects 6 wk 24 subjects 6 mo 23 subjects J Psychopharmacol (Oxford). 2016;30(12):

Dose 2 6 weeks, Day -1 Day 1, 6 weeks, 26 weeks AE, Depression/ Anxiety AE,

30 Ross, et al (2016) 30 Psychotherapy Psychotherapy Psychotherapy AE, BP/HR, Depression/ Anxiety AE, BP/HR AE, BP/HR Day 1, 2 weeks, Baseline Day -1 Dose 1 Dose 2 6 weeks, Day -1 Day 1, 6 weeks, 26 weeks AE, Depression/ Anxiety AE, Depression/ Anxiety AE, Depression/ Anxiety J Psychopharmacol (Oxford). 2016;30(12):

31 Ross, et al (2016) 31 J Psychopharmacol (Oxford). 2016;30(12):

32 Ross, et al (2016) 32 J Psychopharmacol (Oxford). 2016;30(12):

33 Ross, et al (2016) 33 J Psychopharmacol (Oxford). 2016;30(12):

34 Ross, et al (2016) 34 Summary Robust, rapid, and long-las;ng anxioly;c and an;- depressant effects in pa;ents At 7 weeks sustained reduc;on in BDI, HADS, STAI LimitaCons Crossover design Psilocybin or psychotherapy Sample size, lack of generalizability J Psychopharmacol (Oxford). 2016;30(12):

35 Psilocybin Produces Substan;al and Sustained Decreases in Depression and Anxiety in Pa;ent with Life-Threatening Cancer: A Randomized Double-Blind Trial Griffiths RR, Johnson MW, Carducci MA, et al (2016)

36 Griffiths, et al (2016) 36 Objec;ve To determine the efficacy of a classic hallucinogen for treatment of depressed mood and anxiety in psychologically distressed cancer pa;ents. Design Double-blind, randomized, controlled study Crossover design Interven;on Psilocybin high dose (22 or 30mg/70kg) Psilocybin low dose (1 or 3mg/70kg) J Psychopharmacol (Oxford). 2016;30(12):

Griffiths, et al (2016) 37 Inclusion 21 to 80 years old Life-threatening cancer diagnosis

Adjustment Disorder with anxiety Exclusion Cancer with known CNS involvement Hepa;c dysfunc;on

diabetes Current psychoac;ve medica;ons Potent metabolic inducers or inhibitors Psychiatric

Anxiety and Depression Scale (HADS) Beck Depression Inventory (BDI) State- Trait Anxiety

37 Griffiths, et al (2016) 37 Inclusion 21 to 80 years old Life-threatening cancer diagnosis DSM-IV diagnosis that included: GAD, Acute Stress Disorder, PTSD, MDD, Dysthymic Disorder, Adjustment Disorder with anxiety Exclusion Cancer with known CNS involvement Hepa;c dysfunc;on CV condi;ons (HTN, angina Afib, TIA, stroke) Epilepsy, Renal insufficiency, Insulin-dependent diabetes Current psychoac;ve medica;ons Potent metabolic inducers or inhibitors Psychiatric exclusions Endpoints Primary: Hamilton Depression/Anxiety Ra;ng Scale (HAM- D and -A) Hospital Anxiety and Depression Scale (HADS) Beck Depression Inventory (BDI) State- Trait Anxiety Inventory (STAI) AddiConal: Cardiovascular measures Adverse effects J Psychopharmacol (Oxford). 2016;30(12):

38 Griffiths, et al (2016) subjects (94% Caucasian, 49 % women) 13 breast cancer 7 aerodiges;ve cancer 4 GI cancer 18 genitourinary cancer 8 hematologic malignancies 1 other cancer Dose 1 51 subjects Dose 2 49 subjects 6 mo 46 subjects J Psychopharmacol (Oxford). 2016;30(12):

39 Griffiths, et al (2016) 39 Anxiety Depression Anxiety Depression Anxiety Depression Baseline Dose 1 5 weeks Dose 2 5 weeks 6 months BP/HR, AE BP/HR, AE Anxiety Depression J Psychopharmacol (Oxford). 2016;30(12):

40 Griffiths, et al (2016) 40 Star symbol indicates a significant difference between the two groups at the Post-session 1 ;me-point (p<0.05, planned comparison). Cross symbol indicates a significant difference between the Post-session 1 and Post-session 2 ;me-points in the Low-Dose-1st (High-Dose-2nd) Group (p<0.05, planned comparison). J Psychopharmacol (Oxford). 2016;30(12):

41 Griffiths, et al (2016) 41 Star symbol indicates a significant difference between the two groups at the Post-session 1 ;me-point (p<0.05, planned comparison). Cross symbol indicates a significant difference between the Post-session 1 and Post-session 2 ;me-points in the Low-Dose-1st (High-Dose-2nd) Group (p<0.05, planned comparison). J Psychopharmacol (Oxford). 2016;30(12):

42 Griffiths, et al (2016) 42 J Psychopharmacol (Oxford). 2016;30(12):

43 Griffiths, et al (2016) 43 83% 57% J Psychopharmacol (Oxford). 2016;30(12):

44 Griffiths, et al (2016) 44 Summary Long term clinical response to treatment (83%) at 6 months Pa;ents expected psilocybin both ;mes, less expectancy effects Higher incidence of adverse effects LimitaCons Not diverse popula;on >90% Caucasian, college or post-graduate educa;on Crossover design J Psychopharmacol (Oxford). 2016;30(12):

45 Summary and Conclusion

46 Summary 46 Grob et al (2011) Ross et al (2016) Griffiths et al (2016) Psilocybin 0.2 mg/kg Niacin 250 mg Psilocybin 0.3 mg/kg Niacin 250 mg Psilocybin 0.3 or 0.4mg/kg Psilocybin 0.01 or 0.04mg/kg 12 cancer pa;ents 31 cancer pa;ents 51 cancer pa;ents 6 month follow-up 6 month follow-up 6 month follow-up Brief contact to check-in during session STAI trend BDI 6 months significant improvement Professional psychotherapy pre and post session 7 weeks sustained reduc;on in BDI, HADS, STAI Session monitors, introduced pre session 6 month clinical significant response (83% HAM-A)

47 Presenter s Conclusion 47 Psilocybin is safe to use in a very narrow pa;ent popula;on with end of life anxiety End organ damage Serotonergic drugs Chronic diseases Not enough safety and efficacy data to use as standard of care Inconsistent study design creates biased results

AL is a 53 year old woman with a diagnosis of metasta;c ovarian cancer.

48 Pa;ent Case 48 I am so anxious that it is hard to think about anything else. I had lost my faith because of anxiety and it is terrifying. AL is a 53 year old woman with a diagnosis of metasta;c ovarian cancer. Pa;ent is currently receiving pallia;ve treatment for pain and nausea. She has been suffering from anxiety and depression since her diagnosis 3 months ago. Is this pa;ent a good candidate for Psilocybin therapy?

49 Future Direc;on 49 Promising results warrant a need for further inves;ga;on Larger, more diverse popula;on Study design Exploring other hallucinogenic drugs and their poten;al medical use MDMA for PTSD Psilocybin for treatment-resistant depression and anxiety Gran;ng access to Schedule I drugs for research and medical use

50 Acknowledgment 50 Evaluator: Troy Moore, PharmD, MS Pharm, BCPP Stephen Saklad, PharmD, BCPP Katerine Getchell, PharmD, BCACP CTVHCS Co-Residents and Preceptors

51 References 51 American Cancer Society. Emo;ons as you near the end. Available at: hwps:// nearing-the-end-of-life/emo;ons.html. Accessed October 12th Andersen BL, Rowland JH, Somerfield MR. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American society of clinical oncology guideline adapta;on. J Oncol Pract. 2015;11(2): Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substan;al and sustained decreases in depression and anxiety in pa;ents with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol (Oxford). 2016;30(12): Grob C.S., Bossis A.P., Griffiths R.R. (2013) Use of the Classic Hallucinogen Psilocybin for Treatment of Existen;al Distress Associated with Cancer. In: Carr B., STEEL J. (eds) Psychological Aspects of Cancer. Springer, Boston, MA Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in pa;ents with advanced-stage cancer. Arch Gen Psychiatry. 2011;68(1):71-8. Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology (Berl). 2004;172(2): Kolva E, Rosenfeld B, Pessin H, Breitbart W, Brescia R. Anxiety in terminally ill cancer pa;ents. J Pain Symptom Manage. 2011;42(5): Na;onal Cancer Ins;tute. Pallia;ve Care in Cancer. Available at hwps:// care-choices/pallia;ve-care-fact-sheet#q1. Accessed October 12th Na;onal Cancer Ins;tute. Hospice Care. Available at hwps:// Accessed October 12th Passie T, Seifert J, Schneider U, Emrich HM. The pharmacology of psilocybin. Addict Biol. 2002;7(4): Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduc;on following psilocybin treatment for anxiety and depression in pa;ents with life-threatening cancer: a randomized controlled trial. J Psychopharmacol (Oxford). 2016;30(12):

52 Shroom Therapy Use of Psilocybin in End of Life Anxiety Treatment Karolina Grzesiak, PharmD PGY1 Pharmacy PracCce Resident Central Texas Veterans Health Care System Pharmacotherapy Rounds November 17 th 2017

The Benefits of Psychedelic Drug Application for Clinical Treatment of Mental Illness. Timothy Shumate. The University of Kansas School of Nursing

The Benefits of Psychedelic Drug Application for Clinical Treatment of Mental Illness Timothy Shumate The University of Kansas School of Nursing About the author: Tim Shumate is from Wichita, Kansas. He