PH 46A

• Originator Trino Therapeutics
• Class Anti-inflammatories; Benzoates; Indans; Muscle relaxants; Small molecules
• Mechanism of Action Mast cell stabilisers

• Orphan Drug Status No
• New Molecular Entity Yes

Highest Development Phases

• Phase I Ulcerative colitis

Most Recent Events

• 31 Aug 2014 Trino Therapeutics completes a phase I trial in Ulcerative colitis (In volunteers) in United Kingdom (ISRCTN90725219)
• 07 Feb 2014 Phase-I clinical trials in Ulcerative colitis (in volunteers) in United Kingdom (PO)
• 04 Jun 2012 Pharmacodynamics data from a preclinical trial in Ulcerative colitis released by Trino Therapeutics

Cytokines can be produced by various cell populations and have been shown to augment or limit immune responses to pathogens and influence the autoimmune response. One family of cytokines, which uses the common receptor gamma chain (cc), a component of receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21, has been classically defined as growth and survival factors.

IL-2 production can induce an immune response by promoting the proliferation and generation of CD4+ Thl, CD4+ Th2 and CD8+ CTL effector cells. Many of the immunosuppressive drugs used in the treatment of autoimmune diseases and organ transplant rejection, such as corticosteroids and immune suppressive drugs (ciclosporin, tacrolimus) work by inhibiting the production of IL-2 by antigen -activated T cells. Others (sirolimus) block IL-2R signalling, thereby preventing the clonal expansion and function of antigen-selected T cells [ref: Opposing functions of IL-2 and IL-7 in the regulation of immune responses Shoshana D. Katzman, Katrina . Hoyer, Hans Dooms, Iris K. Gratz, Michael D. Rosenblum, Jonathan S. Paw, Sara H. Isakson, Abul K. Abbas. Cytokine 56 (201 1) 1 16-121]

In contrast IL-2 can inhibit the immune response by promoting the survival and functionality of natural (thymic) regulatory T-cells (Tregs), promoting the generation of induced (peripheral) Tregs and inhibiting the generation of CD4+ Thl 7 effector cells [ref: IL-2 and autoimmune disease. Anneliese Schimpl , A., Berberich, I, Kneitz, B., Kramer, S., Santner-Nanan, B., Wagner, S., Wolf, M., Hunig, T. Cytokine & Growth Factor Reviews 13 (2002) 369-378]. Interleukin-2/IL-2R deficiency with time leads to multiorgan inflammation and the formation of autoantibodies of various specificities. Depending on the genetic background, death occurs within a few weeks to a few months, mostly from autoimmune hemolytic anemia or inflammatory bowel disease (IBD) [ref. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993;75:253-61]. IL-2 signalling has been shown to be important in both the initiation and regulation of immune responses. In these dual and opposing roles, IL-2 acts to balance immune response, both driving immune cell activation and subsequent reduction. The potential clinical applicability of either augmenting or inhibiting signals mediated by IL-2 is significant and includes cancer, autoimmune inflammatory diseases, organ transplantation and HIV.

Inflammatory bowel disease (IBD) is an autoimmune inflammatory disease that consists of two idiopathic inflammatory diseases, ulcerative colitis (UC) and Crohn’s disease (CD). The greatest distinction between UC and CD is the range of inflamed bowel tissue. Inflammation in CD is discontinuously segmented, known as regional enteritis, while UC is superficial inflammation extending proximally and continuously from the rectum. At present, the exact cause of IBD is unknown. The disease seems to be related to an exaggerated mucosal immune response to infection of the intestinal epithelium because of an imbalance of pro- inflammatory and immune- regulatory molecules. The inheritance patterns of IBD suggest a complex genetic component of pathogenesis that may consist of several combined genetic mutations. Currently no specific diagnostic test exists for IBD, but as an understanding of pathogenesis is improved so will the corresponding testing methods. Treatment of IBD consists of inducing and maintaining remission. IBD patients may be maintained on remission by use of a 5-aminosalycilate. However, while the use of aminosalycilates in UC provides considerable benefit, both in inducing remission in mild to moderate disease and in preventing relapse, the usefulness of these drugs to maintain remission in CD is questionable and is no longer recommended. The mainstay of treatment of active disease is a corticosteroid, commonly used for limited periods to return both UC and CD patients to remission, though budesonide, designed for topical administration with limited systemic absorption, has no benefit in maintaining remission. Alternatives, such as the immunosuppressive drugs azathioprine and mercaptopurine, together with methotrexate and cyclosporine have limited efficacy and the capability of inducing grave adverse effects. Anti- TNFa antibodies, such as infliximab and adalimubab, may be used in those patients unresponsive to standard immunosuppressive therapy. However, many patients fail to respond to anti-TNFa therapy, either due to their particular phenotype or by the production of autoantibodies.

PATENTS

WO 2013014660

https://encrypted.google.com/patents/WO2013014660A1?cl=en

Compound 6: The N-Methyl-(D)-Glucamine salt (NMDG) of compound 2.

Compound 6 physiochemical properties:

Appearance: Off-white solid

Molecular Weight: 577 (free acid: 382)

Molecular Formula: C33H39O8N (free acid: C₂₆H₂₂0₃)

Melting Point: 165-167 °C

Compound 6: [a]_D:-76.5 (sample concentration: 200 mg/10 ml in Water)

Mass (Da): ES+ only [NMDG+Na] was visible

Elemental analysis: Calc: C (68.61), H (6.80), N (2.42), O (22.16). Found: C (68.44), H

(6.80), N (2.50), 0 (21.98) δ_Η(400 MHz, DMSO-d6): 2.48 (3H, apparent s, NCH₃), 2.65 (1H, d, J=13.56 Hz, HCH), 2.84-

3.02 (4H, m), 3.16 (1H, d, J= 13.60 Hz, HCH), 3.40-3.70 (7H, m), 3.85-3.92 (l H, m), 5.06 (1H, s, CH-OH), 5.93 (1H, broad s, CH- OH), 6.41 (1H, f, .CH=C), 6.80 (2H, d, J=7.92 Hz, Ar-H), 7.06-7.41 (8H, m, Ar-H), 7.64 (2H, d, J=7.80 Hz, Ar-H).

6c(100 MHz, DMSO): 33.8 (CH₃), 37.9 (CH₂), 38.2 (CH₂), 39.5 (CH₂), 51.6 (CH₂-N), 55.8

(quat. C), 63.5 (CH₂-0), 69.0 (CH-O), 70.3 (CH-O), 70.6 (CH-O), 71.3 (CH-O), 81.1 (CH-OH), 120.1 (tert. C), 123.4 (tert. C), 123.7 (tert. C), 124.3 (tert. C), 124.4 (tert. C), 126.1 (tert. C), 126.3 (tert. C), 127.0 (tert. C), 127.5 (tert. C), 2 x 128.5 (2 x tert. C), 2 x 129.1 (2 x tert. C), 140,4 (quat. C), 141.1 (quat. C), 142.9 (quat. C), 144.5 (quat. C), 145.2 (quat. C), 154.3 (quat. C), 170.4 (C=0).

Synthesis of methyl 4- (lS,2S)-l-hvdroxy-2,3-dihvdro-lHJ’H-f2,2′-biinden1-2-yl)methyl) benzoate (17):

To a solution of 4-(((15,25)-l-hydroxy-2,3-dihydro-lH, l’H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K₂C0₃ (72 mg, 0.52 mmol) in DMF (2.5 mL), was added Mel (148 mg, 1.04 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCI (50 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with 10 % aq. NaHC0₃ (25 mL), brine (25 mL), dried over anhydrous Na₂S04 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20 % ethyl acetate in chloroform as an eluent to yield 62 mg (59 %) of the title compound as an off white solid.

LCMS (-OH): observed 379.2, calculated 396.17, molecular formula C₂₇H₂₄0₃

Purity (HPLC): 97 %.

Ή NMR (400 MHz, CDC1₃): 6 2.84 (1H, d, J = 13.28 Hz, ¾), 3.00 (1H, d, J = 15.64 Hz, CH₂), 3.05 (1H, d, J = 15.56 Hz, CPb), 3.27 (lH, d, J = 13.32 Hz, CH ), 3.45 (1H, d, J = 22.52 Hz, CH₂), 3.57 (1H, d, J = 22.60 Hz, CH₂), 3.89 (3H, s, OCH₃), 5.25 (1H, s, CHQH), 6.47 (1H, s, CH=C), 6.96 (2H, d, J = 8.24 Hz, Ar-H), 7.17 (1H, dt, J = 2.04, 9.88 Hz, Ar-H), 7.24-7.33 (5H, m, Ar-H), 7.43 (2H, d, J = 7.60 Hz, Ar-H), 7.83 (2H, dd, J = 1.76, 6.60 Hz, Ar-H).

PATENT

WO 2013174916

PATENT

US 9260376

US 20150141506

PH 46A (S,S & R,R) racemic

Melting point 141–143 °C. 1H NMR (400 MHz, CDCl3) δH (ppm) 6.99 (d, J = 7.72 Hz, 2H), 7.46 (d, J = 7.04 Hz, 2H), 7.20–7.31 (m, 6H), 6.97 (d, J = 7.80 Hz, 2H), 6.50 (s, 1H), 5.29 (d, J = 24.16 Hz, 1H), 3.91 (s, 3H), 3.60 (d, J = 22.68 Hz, 1H), 3.48 (d, J = 22.88 Hz, 1H), 3.28 (d, J = 13.24 Hz, 1H), 3.06 (d, J = 15.64 Hz, 1H), 3.51 (d, J = 16.00 Hz, 1H), 2.86 (d, J = 13.28 Hz, 1H). 13C NMR (100 MHz, CDCl3) δC (ppm) 166.9, 152.3, 144.1, 143.9, 143.4, 142.4, 140.0, 2 × 129.8, 2 × 128.6, 128.1, 128.0, 127.5, 126.6, 126.0, 124.4, 123.9, 123.6, 123.2, 120.2, 82.4, 55.5, 51.6, 39.6, 38.2, 38.0. HRMS (ESI) m/z calculated for C27H24O3 (M + Na)+ , 419.1606; found, 419.1618. Achiral HPLC: Zorbax C18 XDB (150 x 4.6 mm), 20:80:0.1 (v:v:v) water:MeOH:TFA, 1.0 mL/min, 254 nm, RT: 4.31 min. Chiral HPLC: Chiralpak IC, 90:10:0.1 (v:v:v) heptane:IPA:TFA, 1.0 mL/min, 210 nm, RT: 7.98 min & 9.38 min.

PH 46A

¹H NMR (400 MHz, dmso-d₆) δH (ppm): 7.70 (d, J = 8.4 Hz, 2H, Ar–H), 7.34–7.40 (m, 2H, Ar–H), 7.14–7.25 (m, 5H, Ar–H), 7.07 (t, J = 14.4 Hz, 1H, Ar–H), 6.97 (d, J = 8.4 Hz, 2H, Ar–H), 6.39 (s, 1H, CH = C), 5.85 (d, J = 7.2 Hz, 1H, CHOH), 5.06 (d, J = 6.8 Hz, 1H, CHOH), 3.77 (s, 3H, CH₃), 3.56 (d, J = 23.2 Hz, 1H, CH₂), 3.42 (d, J = 23.2 Hz, 1H, CH₂), 3.20 (d, J = 13.6 Hz, 1H, CH₂), 2.96 (s, 2H, CH₂), 2.73 (d, J = 13.6 Hz, 1H, CH₂).

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https://www.sciencedirect.com/science/article/pii/S0040403916301332

Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent

Graham R. Cumming^†∥, Tao Zhang^‡∥ , Gaia Scalabrino^‡∥, Neil Frankish^‡§, and Helen Sheridan^*‡§

^†Celtic Catalysts Ltd, NovaUCD, Belfield, Dublin 4, Ireland

^‡Trino Therapeutics Ltd, The Tower, Trinity Technology & Enterprise Campus, Dublin 2, Ireland

^§ Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute (TBSI), Trinity College, Dublin 2, Ireland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00258

Publication Date (Web): November 27, 2017

Copyright © 2017 American Chemical Society

*E-mail: hsheridn@tcd.ie.

PH46A, belonging to a class of 1,2-Indane dimers, has been developed by our research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in large part to the generation of undesired diastereoisomer 5 and the unwanted enantiomer (R,R)-8 during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A. Significant progress was made on the ketone reduction step, where the use of triisobutylaluminum [TiBA, Al(iBu)₃] afforded high selectivity for the target diastereoisomer (rac)-6, compared to the unfavorable ratio obtained using a previous process. This enabled a multikilo scale synthesis of PH46A in a GMP environment. Further, a brief proof-of-principle investigation was carried out using an achiral phase transfer catalyst (PTC) for alkylation at the methine carbon of the parent indanone.

Patent ID	Patent Title	Submitted Date	Granted Date
US2015141506	INDANE DIMERS FOR USE IN THE TREATMENT OF AUTOIMMUNE INFLAMMATORY DISEASE	2013-05-23	2015-05-21
US9260376	COMPOUNDS FOR USE IN THE TREATMENT OF IMMUNE RELATED INFLAMMATORY DISEASE	2012-07-20	2014-04-17

from PubChem

///////////////////////PH46A, PH 46A, phase 1, trino

O=C(OC)c1ccc(cc1)C[C@]3(Cc2ccccc2[C@H]3O)C4=Cc5ccccc5C4

FDA approves Admelog, the first short-acting “follow-on” insulin product to treat diabetes

The U.S. Food and Drug Administration today approved Admelog (insulin lispro injection), a short-acting insulin indicated to improve control in blood sugar levels in adults and pediatric patients aged 3 years and older with type 1 diabetes mellitus and adults with type 2 diabetes mellitus. Admelog is the first short-acting insulin approved as a “follow-on” product (submitted through the agency’s 505(b)(2) pathway). Continue reading.

///////////////FDA2017,  Admelog, insulin,  diabetes, insulin lispro, Sanofi-Aventis

FEVIPIPRANT

UNII-2PEX5N7DQ4; 2PEX5N7DQ4; NVP-QAW039; QAW039;

CAS 872365-14-5

Product patent WO2005123731A2, NOVARTIS

2-[2-methyl-1-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-b]pyridin-3-yl]acetic acid

• 2-Methyl-1-[[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]methyl]-1H-pyrrolo[2,3-b]pyridine-3-acetic acid
• [1-(4-((Methane)sulfonyl)-2-trifluoromethylbenzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]acetic acid

Fevipiprant (INN; code name QAW039) is a drug being developed by Novartis which acts as a selective, orally available antagonistof the prostaglandin D₂ receptor 2 (DP₂ or CRTh2).^[1][2][3]

As of 2016, it is in Phase III^[4] clinical trials for the treatment of asthma.^[5]

Novartis is developing fevipiprant, a prostaglandin D2 receptor (PD2/CRTh2) antagonist, as an oral capsule formulation for treating asthma and moderate to severe atopic dermatitis.

PATENT

WO2005123731

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005123731

PATENT

CN 106188040

The invention discloses a Fevipiprant and Fevipiprant intermediate preparation method. The method is characterized in that 2-amino-3-bromopyridine and 4-mesyl-2-trifluoromethylbenzaldehyde to condensation reaction to obtain a Schiff base intermediate, then performing reduction reaction to obtain 3-bormo-N-(4-(mesyl)-2-(trifluoromethyl)phenyl)-pyridine-2-amine, subjecting the 3-bormo-N-(4-(mesyl)-2-(trifluoromethyl)phenyl)-pyridine-2-amine to ullmann ring closing reaction with methyl levulinate or ethyl levulinate, and performing saponification reaction or decarboxylic reaction to obtain Fevipiprant namely N[1-(4-((methane)sulfonyl)-2-trifluoromethylphenyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl] acetic acid. The Fevipiprant and Fevipiprant intermediate preparation method which is a brand new method is short in step, technically convenient in operation, easy in product purification and large-scale production, high yield can be achieved, and Fevipiprant industrial production can be realized easily.

Example 5: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0056] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40 · 9g, 0 · lmo 1) and levulinic acid A ester (13.0g, 0. lmo 1) was added 300 mL N, N- dimethylformamide, was added copper iodide (1 · 9g, 0 · 0lmo 1) and N, N- dimethylglycine (1.0g , 0.01 mol), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, water was added 200mL of saturated sodium chloride solution was cooled and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water , was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give the crude product after recrystallization from ethanol in pure 34.5g, yield 81%.

[0057] · ΜΚ (300ΜΗζ, (16-0Μ50) δ: 12 · 3 (ΐ3Γ, 1Η, α) 2Η), 8.24 (s, lH, PhH), 8.11 ~ 8.12 (d, lH, PhH), 8.00 ~ 8.02 (d, lH, PyH), 7.91 ~ 7.93 (d, lH, PyH), 7.09 ~ 7.10 (d, lH, PhH), 6.46 ~ 6.48 (d, lH, PhH), 5.73 (s, 2H, NCH2) , 3.70 (s, 2H, q ^ C〇2H), 3.30 (s, 3H, CH 3).

[0058] HPLC: 99.9%.

[0059] Example 6: N [l- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0060] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – (. 40.9g, 0 lmo 1) pyridin-2-amine and acetyl malonate methyl ester (18.8g, 0. lmol) was added 300 mL N, N- dimethylformamide, was added copper iodide (1.9g, O.Olmol) and N, N- dimethylglycine (1. (^ , 0.01111〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 1211, 200mL saturated brine was added after cooling, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL of water, was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol, a crude product was obtained from ethanol crystallized to give pure 34. lg, 80% yield.

[0061] HPLC: 99.8%.

[0062] Example 7: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0063] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40 · 9g, 0 · lmo 1) and levulinic acid A ester (13. (^, 0.1111〇1) was added ^ 3,001,111, 1-dimethyl formamide, was added copper iodide (3.88,0.02111〇1) and N, N- dimethylglycine (2. (^, 0.02111〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 1211, 200mL saturated brine was added after cooling, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water , was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure 34. lg, 80% yield billion

[0064] HPLC: 99.9%.

[0065] Example 8: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0066] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 300mL N, N- two after dimethylformamide, was added copper iodide (1.9g, 0.01mol) and 2,2,6,6-tetramethyl-heptane-3,5-dione (3.6g, 0.02mo 1), purged with nitrogen , the reaction temperature was raised to 120 degrees 12h, water was added 200mL of saturated sodium chloride solution was cooled and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water was added sodium hydroxide (8g , 0.2 mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 30.2 g, yield 71%.

[0067] HPLC: 99.6%.

[0068] Example 9: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0069] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 1’1 ^ 3,001,111, 1 ‘| – dimethylformamide, was added copper iodide (1.98,0.011] 1〇1) and proline (1.28,0.011] 1〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, after cooling, 200mL saturated brine, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water was added sodium hydroxide (8g, 0.2mol) was heated to 60 degrees reaction 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 33.2 g, 78% yield.

[0070] HPLC: 99.8%.

[0071] Example 10: N [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] pyridin – preparation of 3- yl] acetic acid (1).

[0072] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 300mL N, N- two after dimethylformamide, was added copper iodide (1.9g, 0. Olmol) and N, N- dimethylglycine (1.0g, 0.01 mo 1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, cooled was added 200mL saturated brine, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL of acetic acid and 100mL of concentrated hydrochloric acid was heated to reflux for 6h, cooled to 0 ° C, was added 100mL water analysis crystal was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 33.2 g, 78% yield.

[0073] HPLC: 99.1%.

PATENT

WO 2017056001

Example 3b: Preparation of Compound A

Production of C8: Compound C6, (3-[2-({[4-Methanesulfonyl-2-(trifluoromethyl)-phenyl]methyl}amino)pyridin-3-yl]prop-2-yn-l-ol) (20 g, 52 mmol) was dissolved in a mixture of methyl isobutyl ketone (MIBK, 125 g), 25.3 g (156 mmol) of 1 , 1 , 1 -triethoxy ethane, and acetic acid (0.625 g, 10 mmol). The mixture was heated within 40 minutes to 140 °C under a N₂ over-pressure of 1 – 4 bar. During the reaction ethanol was formed and removed from the vessel by a pressure-regulated valve. After 3.5 h a second portion of acetic acid (0.625g) was added and the mixture was heated for 3.5 h at 140 °C under a N₂ over-pressure of 1 – 4 bar. The resultant product was a solution of Ethyl 2-(l- {[4-methanesulfonyl-2-(trifluoromethyl)phenyl]methyl}-2-methyl-lH-pyrrolo[2,3-¾]pyridin-3-yl)acetate and the conversion rate was measured at 98% and the yield 90%. The solution was filtered and 40 g MIBK was added. The solution was heated to IT=80 °C and cooled down within 3 h to

IT=20 °C. At an IT of 65 °C seed crystals were added. At IT 20 °C intermediate C8 was isolated and washed with 40 g MIBK and dried in the oven at IT=60°C/20mbar.

Conversion to Compound A: The intermediate C8 was concentrated under vacuum at

100 °C/200 mbar and water (6000ml). A sodium hydroxide solution (1734 g, 30%, 13 mol) was added to the mixture and heated for 4 h at 50 °C. The solution was distilled again at 100 °C/100 mbar. The phases were separated at 50 °C and the water phase was extracted with methyl isobutyl ketone (2000 ml). Again the phases were separated and the water phase was filtered at 50 °C. To the filtrate methyl isobutyl ketone (5000 ml) was added and the aqueous solution neutralized in 2 portions with hydrochloric acid (963 g, 37%, 9.8 mol) to pH 4 – 4.5. The phases were heated to 80 °C and the organic phases separated. Water (1000 ml) was added to wash the organic phase and after phase separation the organic phase was cooled down to 70 °C. Seed crystals of Compound A were added along with heptane (1000 ml). The resulting suspension was stirred for 30 minutes before cooling further down to 0 °C within 3 h. The suspension was stirred for 3 h at 0 °C and then filtered through a nutsche. The filter cake was washed first with pre-cooled HPTF/methyl isobutyl ketone (1000 g, 5: 1), then with acetone/water (1000 g, 1 :2) and finally with water (1000 g). Wet Compound A was dried in the oven at 60 °C for 8 h under vacuum to isolate 804 g of compound A. The conversion was calculated to be 99%; the yield was 79%.

Example 3 c: Alternative Preparation of Compound A

Molecular Weight: 426 41

Exact Mass: 384.08 Molecular Weight: 453.48

5 g of (3-[2-({[4-Methanesulfonyl-2-(trifluoromethyl)-phenyl]methyl}amino)pyridin-3-yl]prop-2-yn-l-ol), methyl isobutyl ketone (MIBK, 50 ml), and 1 , 1 -dimethoxy-N,N-dimethylethanamine were put together in a 200 ml reactor and stirred for 15 h at 100 °C. The mixture was acidified by addition of hydrochloric acid (15 ml) and kept stirring for 15 h at 100 °C. Then water (25 ml) was added, and the temperature was decreased to 50 °C. Caustic soda (about 15 ml) was added to set the pH around 12. Then, after phase split and a second extraction with water (10 ml), the combined aqueous phases were diluted with methyl isobutyl ketone (25 ml) and acidified at 80 °C to pH 4 with hydrochloric acid. The mixture was cooled to 70 °C, seeded and cooled to 0 °C within 2 h. After 2 h aging at 0 °C, the crystalline solid was collected by filtration, washed with methyl isobutyl ketone (10 ml) and water (10 ml), and dried under vacuum at 60 °C until constant weight. Yield 2.93 g.

PATENT

WO-2017210261

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017210261&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Novel deuterated analogs of pyrrolo[2,3-b]pyridine compounds, particularly fevipiprant and their salts and compositions and combination comprising them are claimed. Also claims is their use for treating asthma, allergic rhinitis and atopic dermatitis. Compounds are claimed to be a prostaglandin D2 receptor 2 antagonist. Represents first PCT filing from CoNCERT Pharmaceuticals and the inventor on this API.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(5), 582-586

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP₂Receptor Antagonist for Treatment of Asthma

David A. Sandham^*† , Lucy Barker, Lyndon Brown, Zarin Brown, David Budd, Steven J. Charlton, Devnandan Chatterjee, Brian Cox, Gerald Dubois, Nicholas Duggan, Edward Hall, Julia Hatto, Janet Maas, Jodie Manini, Rachael Profit, Darren Riddy, Catherine Ritchie, Bindi Sohal, Duncan Shaw, Rowan Stringer, David A. Sykes, Matthew Thomas, Katharine L. Turner, Simon J. Watson, Ryan West, Elisabeth Willard, Gareth Williams, and Jennifer Willis

Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom

ACS Med. Chem. Lett., 2017, 8 (5), pp 582–586

DOI: 10.1021/acsmedchemlett.7b00157

*E-mail: david.sandham@novartis.com. Tel: + 1 (617)-871-8000.

Abstract

Further optimization of an initial DP₂ receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.

RM  sodium methanesulfinate and 4-fluoro-2-(trifluoromethyl)benzaldehyde

Step 1:

4-(methylsulfonyl)-2-(trifluoromethyl)benzaldehyde

A suspension of sodium methanesulfinate (29.6 g, 290 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (50 g, 260 mmol) in DMSO (200 ml) was heated at 90˚C overnight. The thick yellow suspension was poured onto crushed ice (ca 800 g), diluted with water and the solid reside collected by filtration, washed with water and dried in vacuo to afford 4- (methylsulfonyl)-2-(trifluoromethyl)benzaldehyde as an off-white solid (50.7 g, 77%). LRMS mass ion not detected. 1H NMR (CDCl3) 3.14 (3H s), 8.30 (1H d J=7.5), 8.36 (1H d J=7.5), 8.40 (1H s), 10.49 (1H s).

Step 2:

(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol

(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol as an off-white solid (50.7 g, 99%). LRMS mass ion not detected. 1H NMR (CDCl3) 3.11 (3H s), 5.02 (2H s), 8.09 (1H d J=7.5), 8.19 (1H d J=7.5), 8.25 (1H s).

STEP 3

1-(bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl)benzene

1-(bromomethyl)-4-(methylsulfonyl)-2- (trifluoromethyl)benzene (47.1 g, 74%) as a white solid. LRMS mass ion not detected. 1H NMR (CDCl3) 3.11 (3H s), 4.67 (2H s), 7.86 (1H d J=7.5), 8.14 (1H d J=7.5), 8.25 (1H s).

STEP 4

methyl 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate

(83:17) of methyl 2-(2-methyl-1-(4-(methylsulfonyl)-2- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (N-1 product) and methyl 2-(2-methyl-7-(4- (methylsulfonyl)-2-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-b]pyridin-3-yl)acetate (N-7 product) as a white solid (22.5 g 42%). LRMS C20H19F3N2O4S requires M+ 440.4 found [MH]+ m/z 441. 1H NMR (CDCl3) 2.27 (3H s), 3.06 (3H s N-1 product), 3.11 (3H s N-7 product), 3.72 (3H s), 3.77 (2H s), 5.03 (2H s N-7 product), 5.82 (2H s N-1 product), 6.66 (1H d J=8.2), 7.16 (1H dd J=7.8, 4.8), 7.91 (1H d, J=8.3), 7.95 (1H d J=7.7), 8.12 (1H d J=7.8 N-7), 8.19 (1H d J=8.1 N-7), 8.17 (1H s N-7), 8.27 (1H d J=3.6), 8.30 (1H s).

FINAL

2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid 11 as needles, m.p. 208˚C (16.3 g, 44%). HRMS C19H18F3N2O4S requires [MH]+ 427.0939 found [MH]+ 427.093. 1H NMR (500 MHz, DMSO-d6) 2.28 (3H s), 3.28 (3H s), 3.73 (2H s), 5.76 (2H s), 6.49 (1H d J=8.3), 7.12 (1H dd J=7.7, 4.8), 7.95 (1H d J=7.8), 8.04 (1H d, J=8.3), 8.14 (1H d J=4.7), 8.26 (1H s), 12.28 (1H br s ). Elemental analysis calcd. for C19H17F3N2O4S: C, 53.52; H, 4.02; N, 6.57; S, 7.52%. Found C, 53.90 ± 0.04; H, 4.28 ± 0.06; N, 6.43 ± 0.02; S, 7.76 ± 0.09%.

PAPER

Drug Metabolism & Disposition (2017), 45(7), 817-825

References

Fevipiprant

Clinical data
Routes of administration	Oral
ATC code	none
Legal status
Legal status	Investigational
Pharmacokinetic data
Bioavailability	Unaffected by food[1]
Metabolism	Hepatic glucuronidation
Biological half-life	~20 hours
Excretion	Renal (≤30%)
Identifiers
IUPAC name[show]
CAS Number	872365-14-5
PubChem CID	23582412
ChemSpider	23582412
UNII	2PEX5N7DQ4
KEGG	D10631
Chemical and physical data
Formula	C19H17F3N2O4S
Molar mass	426.41 g/mol
3D model (JSmol)	Interactive image

////////////////FEVIPIPRANT, QAW039, PHASE 3, asthma, UNII-2PEX5N7DQ4,2PEX5N7DQ4, NVP-QAW039, QAW039, 872365-14-5,

CC1=C(C2=C(N1CC3=C(C=C(C=C3)S(=O)(=O)C)C(F)(F)F)N=CC=C2)CC(=O)O

FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA. Continue reading.

//////////////Nucala, mepolizumab, fda 2017, gsk,  Eosinophilic Granulomatosis, Polyangiitis, Churg-Strauss Syndrome, Priority Review, Orphan Drug

Gedatolisib

Pfizer

PF-05212384; PF-5212384; PKI-587

CAS 1197160-78-3
Chemical Formula: C32H41N9O4
Molecular Weight: 615.72

• Phase III Acute myeloid leukaemia
• Phase II Colorectal cancer; Non-small cell lung cancer
• Phase I Breast cancer; Solid tumours
• Discontinued Endometrial cancer

Most Recent Events

• 22 Nov 2017Pfizer suspends patient enrolment in a phase I/II trial due to drug supply delay in Non-small cell lung cancer (Combination therapy, Inoperable/Unresectable, Metastatic disease, Late-stage disease) in USA (IV) (NCT02920450)
• 04 Nov 2017No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease, Second-line therapy or greater) in Canada (IV, Infusion)
• 04 Nov 2017No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease, Second-line therapy or greater) in Italy (IV, Infusion)

Gedatolisib, also known as PKI-587 and PF-05212384, is an agent targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. Upon intravenous administration, PI3K/mTOR kinase inhibitor PKI-587 inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated independent of PI3K.

PKI-587 is a PI3K/mTOR inhibitor, currently being developed by Pfizer. The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. PKI-587  has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously.

PATENT

WO 2009143317

WO 2010096619

WO 2012148540

WO 2014151147

PATENT

US 20170119778

PAPER

Journal of Medicinal Chemistry (2010), 53(6), 2636-2645

http://pubs.acs.org/doi/abs/10.1021/jm901830p

Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5′-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound 26 (PKI-587), a Highly Efficacious Dual Inhibitor

Abstract

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure−activity relationships and the in vitro and in vivo activity of analogues in this series are described.

Preparation of 1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4- yl-1,3,5-triazin-2-yl)phenyl]urea (26)

MS (ESI) m/z = 616.7. HRMS: calcd for C₃₂H₄₁N₉O₄ + H⁺, 616.335 43; found (ESI-FTMS, [M + H]⁺), 616.334 24. Purity by analytical HPLC 99.3%. (Prodigy ODS3, 0.46 cm × 15 cm, 20 min gradient acetonitrile in water, trifluoroacetic acid, detector wavelengths, 215 and 254 nm.) ¹H NMR (DMSO-d₆) δ 1.29−1.36 (m, 6H), 2.6 (m, 4H), 2.9 (m,1H), 3.3 (m, 4H), 3.6 (m, 8H), 3.7 (m, 8H), 7.3 (d, J = 8.3 Hz, 2H), 7.51−7.57 (m, 4H), 8.3 (d, J = 8.3 Hz 2H), 8.9 (s, 1H), 9.0 (s, 1H) ppm. Anal. Calcd for C₃₂H₄₁N₉O₄: C 62.42%, H 6.71%, N 20.47%. Found: C 62.34%, H 6.67%, N 20.39%.

PAPER

Bioorganic & Medicinal Chemistry Letters (2011), 21(16), 4773-4778.

http://www.sciencedirect.com/science/article/pii/S0960894X11008468

PAPER

New and Practical Synthesis of Gedatolisib

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00298

Xiangyu Liu^†, Guoqing Zhu^†, Lingai Li^†, Yaowei Liu^†, Feng Wang^†, Xiaoping Song^‡, and Yongjun Mao^*† 

^† College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, China

^‡ Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan Normal University, 99 South Longkun Road, Haina 571158, China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00298

*Fax: +86 21 67791214. E-mail: yongjun.mao@hotmail.com.

Abstract

A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.

off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 1.46 (brs, 2H), 1.89 (brs, 2H), 2.29 (s, 6H), 2.94 (brs, 2H), 3.76 (m, 8H), 3.89 (m, 8H), 7.09 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 8.28 (s, 1H), 8.31 (d, J = 8.6 Hz, 2H), 8.48 (s, 1H). ESI-MS (m/z) 615.9 (M + H). HPLC conditions: Column: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5 μm); Detection: 254 nm; Flow rate: 0.8 mL/min; Temperature: 30 °C; Injection load: 1 μL; Solvent: MeOH; Concentration: 0.5 mg/mL; Run time: 20 min; Mobile phase A: water; Mobile phase B: MeOH/TEA = 100:0.1; Gradient program: time (min): 20; % of mobile phase A: 10; % of mobile phase B: 90; t_R = 2.598 min, purity: 99.34%

• Zhao, X.; Tan, Q.; Zhang, Z.; Zhao, Y. Med. Chem. Res. 2014, 23, 5188– 5196 DOI: 10.1007/s00044-014-1084-z
• Khafizova, G.; Potoski, J. R. PCT Int. Appl. WO 2010096619, 2010.
• Venkatesan, A. M.; Chen, Z.; Dehnhardt, C. M.; Dos Santos, O.; Delos Santos, E. G.; Zask, A.; Verheijen, J. C.; Kaplan, J. A.; Richard, D. J.; Ayral-Kaloustian, S.; Mansour, T. S.; Gopalsamy, A.; Curran, K. J.; Shi, M. PCT Int. Appl. WO 2009143317, 2009.

REFERENCES

1: Gedaly R, Galuppo R, Musgrave Y, Angulo P, Hundley J, Shah M, Daily MF, Chen C, Cohen DA, Spear BT, Evers BM. PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation. J Surg Res. 2013 Nov;185(1):225-30. doi: 10.1016/j.jss.2013.05.016. Epub 2013 May 25. PubMed PMID: 23769634.

2: Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Evers BM. PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation. J Surg Res. 2012 Aug;176(2):542-8. doi: 10.1016/j.jss.2011.10.045. Epub 2011 Nov 21. PubMed PMID: 22261591.

3: Dehnhardt CM, Venkatesan AM, Chen Z, Delos-Santos E, Ayral-Kaloustian S, Brooijmans N, Yu K, Hollander I, Feldberg L, Lucas J, Mallon R. Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8. doi: 10.1016/j.bmcl.2011.06.063. Epub 2011 Jun 21. PubMed PMID: 21763134.

4: Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15. PubMed PMID: 21325073.

5: Venkatesan AM, Chen Z, dos Santos O, Dehnhardt C, Santos ED, Ayral-Kaloustian S, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Chaudhary I, Mansour TS. PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73. doi: 10.1016/j.bmcl.2010.07.104. Epub 2010 Jul 30. PubMed PMID: 20797855.

6: Venkatesan AM, Dehnhardt CM, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, Khafizova G, Brooijmans N, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Gibbons J, Abraham RT, Chaudhary I, Mansour TS. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010 Mar 25;53(6):2636-45. doi: 10.1021/jm901830p. PubMed PMID: 20166697.

????????????PF 05212384, PF 5212384, PKI-587, PF-05212384; PF-5212384; PKI 587, gedatolisib, antitumor agent, PHASE 3, PFIZER, гедатолисиб , غيداتوليسيب , 吉达利塞 , 

O=C(NC1=CC=C(C2=NC(N3CCOCC3)=NC(N4CCOCC4)=N2)C=C1)NC5=CC=C(C(N6CCC(N(C)C)CC6)=O)C=C5

 Journal of Medicinal Chemistry (2017), 60(17), 7524-7538 PQR 309

Tis the season for snowball fights, Christmas decorations, and food – SO MUCH FOOD. If you celebrate Christmas (or Hanukkah), chances are you’ll be indulging this holiday season. While I fully support everyone’s right to treat themselves, a lot of kids (and parents) don’t realize that various types of food can actually be fatal for dogs due to a common, all natural sweetener called xylitol (yikes). Because I’m a dog lady, I compiled a list of products that contain xylitol for dog owners to refer to!

https://simplewag.com/xylitol-dogs-a/

Xylitol is a sugar alcohol commonly used in candy and chewing gum (and some other products, such as peanut butter.) It is also found in some pharmaceuticals and oral health products such as chewable vitamins and throat lozenges. While Xylitol is safe for humans, xylitol and dogs do not mix. The compound doesn’t affect glucose levels in people, but when ingested by dogs it can cause a dangerous surge of insulin. (In as little as 15 minutes, the blood sugar of a dog that has eaten gum containing Xylitol may register a marked drop in blood sugar.) At higher doses, Xylitol is believed toxic to the canine liver.

Contents [

• 1 Xylitol and Dogs: Statistics
• 2 Xylitol & Dogs: Symptoms
• 3 Xylitol & Dogs: Diagnosis
• 4 Xylitol & Dogs: Treatment
• 5 Xylitol & Dogs: Prognosis
• 6 Xylitol In Products: Peanut Butter
• 7 Xylitol In Products: Chocolate
• 8  Xylitol In Products: Cookies, Desserts, Mixes, Ice Cream & Yogurt
• 9 Xylitol In Products: Jams & Syrups
• 10  Xylitol in Products- Condiments & Sauces
• 11 Xylitol In Products: Water & Drink Powders
• 12 Xylitol In Products: Power & Protein Bars, and Powders
• 13 Xylitol In Products: Candies, Gum & Mints
• 14 Xylitol In Products: Honey, Raw Xylitol & Sweeteners
• 15  Xylitol in Products: Dental & Nasal: Toothpaste, Floss, Mouthwash & Rinses
• 16 Xylitol In Products: Cosmetics & Hair Care
• 17  Xylitol In Products: Final Thoughts

Xylitol and Dogs: Statistics

In the past 5 years, Pet Poison Helpline, an animal poison control based out of Minneapolis, MN, has had over 1500 calls for xylitol poisoning, due to the growing awareness of this common kitchen toxin. In both humans and dogs, the level of blood sugar is controlled by the release of insulin from the pancreas. Xylitol does not stimulate the release of insulin from the pancreas in humans.

However, when non-primate species (e.g.,  a dog) eat something containing xylitol, the xylitol is quickly absorbed into the bloodstream, resulting in a potent release of insulin from the pancreas.  This rapid release of insulin results in a rapid and profound decrease in the level of blood sugar (hypoglycemia), an effect that occurs within 10-60 minutes of eating the xylitol. Untreated, this hypoglycemia can be life-threatening.It can also be used in home baking.

Just three grams of Xylitol can kill a 65-pound dog. Because the amount of sweetener used in sugar-free chewing gums varies by manufacturer and product, the number of sticks of gum that would prove fatal to a pooch of that size can’t be stated with precision. As a general rule of thumb, between eight and ten pieces of gum might be deadly to a 65-pound canine, but a smaller dog could easily die after ingesting far less (perhaps as few as two sticks of gum).

If you suspect that your pet has eaten a xylitol-containing product, please contact your veterinarian or Pet Poison Helpline (800-213-6680) immediately. Do not induce vomiting or give anything orally to your dog unless specifically directed to do so by your veterinarian. It is important to get treatment for your dog as quickly as possible.  As some dogs may already be hypoglycemic, inducing vomiting can make them worse!

Xylitol & Dogs: Symptoms

Symptoms of xylitol toxicity develop rapidly, usually within 15-30 minutes of consumption. Signs of hypoglycemia may include any or all of the following:

• Vomiting
• Weakness
• Incoordination or difficulty walking or standing (walking like drunk)
• Depression or lethargy
• Tremors
• Seizures
• Coma

In severe cases, the dog may develop seizures or liver failure. Dogs that develop liver failure from xylitol poisoning often show signs of hypoglycemia.

Xylitol & Dogs: Diagnosis

A presumptive diagnosis of xylitol poisoning is made if there is a known or possible history that the dog ate something containing xylitol, coupled with symptoms of hypoglycemia. Since toxicity develops rapidly, your veterinarian will not wait for a confirmed diagnosis before beginning treatment. There is no antidote for xylitol toxicity, although treatment with sugar supplementation, IV fluids, and liver protective drugs are beneficial.

Xylitol & Dogs: Treatment

Fast and aggressive treatment by your veterinarian is essential to effectively reverse any toxic effects and prevent the development of severe problems. If your dog has just eaten xylitol but has not yet developed any clinical signs, your veterinarian may induce vomiting to prevent further absorption, depending on what your dog’s blood glucose level is. If clinical signs have developed, treatment will be based on the symptoms that are being shown.

Since xylitol toxicity can cause both low blood glucose and low potassium levels, your veterinarian will perform blood work to determine whether these problems need to be treated. In all cases, your dog will require hospitalization for blood sugar monitoring, dextrose administration, intravenous fluids, liver protectants, and any other supportive care that may be needed. Blood work should be monitored frequently to make sure that blood sugar and liver function remain normal.

Xylitol & Dogs: Prognosis

The prognosis is good for dogs that are treated before symptoms develop, or for dogs that develop uncomplicated hypoglycemia that is reversed rapidly. If liver failure or a bleeding disorder develops, the prognosis is generally poor. If the dog lapses into a coma, the prognosis is very poor. If you personally use products containing xylitol, make sure they are stored safely, out of reach of your pets. Do not share any food that may contain xylitol with your pets. Only use pet toothpaste for pets, never human toothpaste. Keep in mind that there are some veterinary products that contain small amounts of xylitol (e.g., gabapentin medication, mouthwashes). At prescribed doses, these should not result in xylitol poisoning; however, if ingested in large amounts, can potentially result in poisoning.

Many people start a new year with a plan to live a healthier life. But, unbeknownst to some dog owners, a common sugar additive that is used in reduced sugar and diet products has the ability to be lethal to their pup. That sugar additive is called xylitol.

Xylitol is a sugar alcohol commonly used in candy and chewing gum (and some other products, such as peanut butter.) It is also found in some pharmaceuticals and oral health products such as chewable vitamins and throat lozenges.

While Xylitol is safe for humans, it can be harmful to dogs!!

Here is a list of the known products that contain xylitol.

Xylitol In Products: Peanut Butter

Xylitol product list sorted alphabetically by company or distributor

Go Nuts, Co.
Almond Butter
Almond Butter – Chocolate Almond Butter
Peanut Butter – Dark Chocolate Mint
Peanut Butter – Natural Chocolate Flavor
Peanut Butter – Natural Flavor
Peanut Butter – Organic Maple Flavor

Krush Nutrition
Nutty By Nature Peanut Butter Brownie Batter
Nutty By Nature Peanut Butter Cookie Dough
Nutty By Nature Peanut Butter Snickerdoodle Cookie
Nutty By Nature Peanut Butter Thick & Creamy

Nuts ‘N More®
Almond Spread – Almond Butter
High Protein + Almond Spread – Almond Butter
High Protein + Almond Spread – Chocolate Almond
High Protein + Almond Spread – Cinnamon Raisin
High Protein + Peanut Spread – Chocolate Peanut
High Protein + Peanut Spread – Peanut Butter Flavor
High Protein + Peanut Spread – Pumpkin Spice
High Protein + Peanut Spread – Toffee Crunch
Peanut & Protein Spread – Sesame Cranbutter
Peanut Spread – Peanut Butter Flavor
Peanut Spread – Toffee Crunch

P28 Foods
High Protein Spread – Almond Butter
High Protein Spread – Banana Raisin
High Protein Spread – Peanut Spread
High Protein Spread – Signature Blend

Protein Plus PB
Hank’s Protein Plus – Almond Butter
Hank’s Protein Plus – Banana
Hank’s Protein Plus – Caramel Pretzel
Hank’s Protein Plus – Chocolate Chip
Hank’s Protein Plus – Coconut
Hank’s Protein Plus – Honey Maple
Hank’s Protein Plus – Plain
Hank’s Protein Plus – Snickerdoodle

Xylitol In Products: Chocolate

Xylitol product list sorted alphabetically by company or distributor

 Avalon Select
Tru Chocolate – Assorted Flavors

Bulletproof 
Chocolate Fuel Bars – Assorted Flavors
Truffled Chocolate Coffee Beans

Dr. John’s
Gourmet Chocolates: Cool Mint, Creamy Peanut Butter, Exotic Coconut, Pecan Caramel Perfection Bars, Pecan Caramel Perfection Clusters, Raspberry Rapture, Sea Salt Caramel, Signature Sampler Collection, Toasted Toffee with Almonds

Healthy Chocolate Co, Inc
Health 4Living Xylitol COQ10 Chocolate
Healthy Chocolate – Dark Assorted, Dark Coffee, Dark Coconut, Dark Mint, Dark Orange, Dark Plain, Dark Raspberry

The Raw Chocolate Co
Mint Raw Chocolate
Orange Raw Chocolate

 Xylitol In Products: Cookies, Desserts, Mixes, Ice Cream & Yogurt

Xylitol product list sorted alphabetically by company or distributor

Barry Farm
Sugar Free Pie Filling – Assorted Flavors

Clemmy’s Ice Cream
Clemmy’s Rich and Creamy Ice Cream – Chocolate, Chocolate Chip, Orange Creme, Toasted Almond, Vanilla Bean, Coffee
Clemmy’s Rich and Creamy Bars – Cherry Vanilla, Chocolate Fudge, Orange Creme, Strawberries ‘N Creme

Health Garden
Kosher Choc-Oh-Chip Cookies

Jell-O
Jell-O – Boston Cream Pie Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Dulce de leche Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Chocolate Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Chocolate Vanilla Swirls Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Dark Chocolate Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Double Chocolate Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Chocolate Indulgence Mousse Sugar Free
Jell-O – Dark Chocolate Decadence Mousse Sugar Free
Jell-O – Creme Brûlée Rice Pudding Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Rice Pudding Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Vanilla Sugar Free / Reduced Calorie Pudding Snacks

Sophie Yogurt
Non-Fat Greek Yogurt – Assorted Flavors

SweetDeliverance
B-Sugarless – Diabetic Cake Mixes – Assorted Flavors

Wegmans
Sugar Free Pudding: Chocolate, Chocolate Vanilla Swirl
Sugar Free Pudding with Calcium : Dark Chocolate

Wheyhey 
Protein Ice Cream – Assorted Flavors

Xylitol In Products: Jams & Syrups

Xylitol product list sorted alphabetically by company or distributor

Focus Nutrition
XyloBurst Sugar-Free Jam: Apricot, Blueberry, Mountain Berry, Peach, Raspberry, Strawberry

Nature’s Hollow
Apricot Sugar-Free Jam Preserves
Blueberry Sugar-Free Jam Preserves
Mountain Berry Sugar-Free Jam Preserves
Peach Sugar-Free Jam Preserves
Raspberry Sugar-Free Jam Preserves
Strawberry Sugar-Free Jam Preserves
Wild Blueberry Sugar-Free Jam Preserves
Maple Sugar-Free Syrup
Raspberry Sugar-Free Syrup

Xylabrands
Xyla Jam – Apricot, Blueberry, Mountain Berry, Peach, Raspberry, Strawberry

 Xylitol in Products- Condiments & Sauces

Xylitol product list sorted alphabetically by company or distributor

Health Garden
Sugar-Free Tomato Ketchup

Nature’s Hollow
Sugar Free Hickory Maple BBQ Sauce
Sugar Free Honey Mustard BBQ Sauce
Sugar-Free Ketchup

Xylabrands
Xyla BBQ Sauce – Original
Xyla Buffalo Wing Sauce
Xyla Chipotle BBQ Sauce
Xyla Ketchup
Xyla Sesame Teriyaki Sauce

Xylitol In Products: Water & Drink Powders

Xylitol product list sorted alphabetically by company or distributor

Designs For Health 
Electrolyte Synergy Grape Flavor

Natural Factors®
SlimStyles® Weight Loss Drink with PGX® – Assorted Flavors

NOW® Foods
Berry Lemonade Slender Sticks
Berry Energy Tea Slender Sticks
Effer-C Acai Berry Sticks
Effer-C Cranberry Pomegranate Packets
Effer-C Elderberry Packets
Grape Slender Sticks
Pomegranate Berry Slender Sticks

Natural Max (no website found)
Skinny Fast Hunger Rescue Chocolate Fix

xyWater
xyWater Nutritional Drink – Assorted Flavors

ZipFizz®
Energy Drink Mix – Assorted Flavors
Immune Fizz – Fruit Punch

Xylitol In Products: Power & Protein Bars, and Powders

Xylitol product list sorted alphabetically by company or distributor

Betty Lou’s
Low Glycemic Protein Shake: Chocolate, Orange Cream, Vanilla

Designs For Health
PaleoBar Chocolate Coated

Life Extension® 
Pure Plant Protein

NOW® Foods
Berry Lemonade Slender Sticks
Berry Energy Tea Slender Sticks
Effer-C Acai Berry Sticks
Effer-C Cranberry Pomegranate Packets
Effer-C Elderberry Packets
Grape Slender Sticks
Pomegranate Berry Slender Sticks

Natural Max (no website found)
Skinny Fast Hunger Rescue Chocolate Fix

Protocol For Life Balance® 
Plant Protein Complete

Renew Life 
FitSMART Shake – Assorted Flavors
FitSMART Vegan Shake – Assorted Flavors

Xylitol In Products: Candies, Gum & Mints

Xylitol product list sorted alphabetically by company or distributor

Bach Flower
Rescue® Chewing Gum – Orange & Elderflower
Rescue® Pastilles – Assorted Flavors

B Fresh®
B Fresh Energy Mints – Assorted Flavors
B Fresh® Gum – Assorted Flavors

Branam
Branam Xylitol Gum – Hot Cha Cha Cinnamon, Snappy Apple

Designs For Health
Brain Power Sours

Camellix
MighTeaFlow® Dry Mouth Chewing Gum
MighTeaFlow® Dry Mouth Gel
MighTeaFlow® Dry Mouth Moisturizing Lozenges
MighTeaFlow® Dry Mouth Moisturizing Oral Rinse
MighTeaFlow® Dry Mouth Moisturizing Oral Spray
MighTeaFlow® Green Tea Lozenges

Carifree®
CTx1 Lollies
CTx2 Xylitol Gum

Cleure
Cleure Fresh Fruit Gum
Cleure Lemon Drops

Cracked Candy
Cracked Candy – Assorted Flavors

CVS Pharmacy®
CVS Sugar Free Breath Strips Blue Mint

Dentyne®
Dentyne Pure Mint With Citrus Accents
Dentyne Pure Mint With Herbal Accents
Dentyne Pure Mint With Melon Accents

Dr. John’s
Hard Candy: Butterscotch Bliss, Cafe Caramel, Cherry Blossom, Classic Fruits Collection, Cream Soda, Creamsicle Swirl Collection, Fresh Fruits Collection, Luscious Licorice, Mighty Mango, Peppermint Pop, Perfect Pear, Pink Grapefruit, Radiant Rainbow, Signature Sours Collection, Sour Cherry, Sour Lemon, Strawberry Cheesecake, Sunkissed Fruits Collection, Ultimate Hard Candy Collection, Ultimate Sweets Collection

Lollipops: Blue Raspberry Blast, Butterscotch Bliss, Cheeky Cherry, Classic Fruits Collection, Classic Fruits Collection, Creamsicle Swirl Collection, Fresh Fruits Collection, Juicy Grape, Peppermint Pop, Pomegranate Punch, Proudly Patriotic, Radiant Rainbow, Signature Sours Collection, Sunkissed Fruits Collection, Ultimate Lollipop Collection, Ultimate Sweets Collection, Whimsical Watermelon

Soft Candies: Butter Crunch Caramels, Butterscotch Bliss Caramels, Cafe Caramel Caramels, Caramel Lovers Collection, Chocolate Caramel Swirls, Luscious Licorice Taffy, Peppermint Pop Taffy, Ultimate Sweets Collection, Vanilla Caramel Swirls

Sweet Advantage Gum – Fruit Punch
Sweet Advantage Gum – Peppermint Pop
Sweet Advantage Tablet: Peppermint Pop
Sweet Advantage Tablet: Tangy Melon

Eco-Dent®
Between! Dental Gum – Assorted Flavors

Epic Dental
Xylitol Gum: Cinnamon, Fresh Fruit, Peppermint, Spearmint
Xylitol Mints: Peppermint, Fresh Fruit, Cinnamon

Extra Ice (Wrigley’s)
Extra® Ice – Spearmint
Extra® Ice – Peppermint

Focus Nutrition
XyloBurst Gum: Cinnamon, Fruit, Green Tea, Peppermint, Spearmint,
XyloBurst Xylitol Mints: Berry, Cinnamon, Ginger, Lemon, Licorice, Peppermint, Wintermint
XyloBurst Xylitol Fruit Sours: Cherry, Grape, Orange Citrus, Lemon Lime, Peach Sour, Watermelon
XyloBurst Sugar Free Lollipops with Xylitol: Apple, Orange, Raspberry, Strawberry

Glee Gum
Sugar-Free Glee Gum: Lemon-Lime, Refresh-Mint, Wild Watermelon

Hager Pharma
Hager Pharma Miradent Chewing Gum: Cinnamon, Cranberry, Fresh Fruit, Green Tea, Peppermint, Spearmint

Healthy Grid
Tooth Friendly Xylitol Candies – Assorted Flavors

Hersheys®
Ice Breakers® – Cool Blasts Gum – Assorted Flavors
Ice Breakers® – Ice Cubes Gum – Assorted Flavors

Ice Chips Candy
Ice Chips – Assorted Flavors

Juicy Fruit (Wrigley’s)
Juicy Fruit Fruity Chews – Original

Lotte Confectionery
Lotte Xylitol Gum – Assorted Flavors
Lotte Xylitol Alpha Project Gum – Assorted Flavors
Anytime Candy – Assorted Flavors

Melaleuca
Exceed Gum – Assorted Flavors
Exceed Mints – Assorted Flavors

Mentos®
Mentos® Pure Gum – Assorted Flavors
Mentos® SugarFree Gum – Assorted Flavors
Mentos® Gum UP2U – Assorted Flavors

Nature’s Stance (XyliChew)
XyliChew Gum: Black Licorice, Cinnamon, Fruit, Peppermint, Spearmint

Nicorette®
Nicorette Stop Smoking Aid – Coated Gum: Cinnamon Surge, Fruit Chill, Mint

Nutraceutical
Zylicious Xylitol gum
XyliVita Gum

Orbit®
Orbit Gum – Assorted Flavors

Peelu
Cinnamon Sass Chewing Gum with Xylitol
Citrus Breeze Chewing Gum with Xylitol
Peppermint Blast Chewing Gum with Xylitol
Spearmint Chewing Gum with Xylitol

Peppersmith
Chewing Gum – Assorted Flavors
Fresh Mints – Assorted Flavors

Pür
Pür Gum – Assorted Flavors
Pür Mints – Assorted Flavors

Rainbow Light®
MintAsure

Rite Aid
Rite Aid Pharmacy Stop Smoking Aid – Sugar Free, Coated Gum: Cinnamon, Mint

Scandinavian Formulas
Salivasure Lozenges

Seroyal
Homeofresh Chewing Gum

Starbucks®
Gum
Mints

Stevita
SteviaDent Gum: Cinnamon, Peppermint

Stride Gum – Mondalez International
Stride Gum – NonStop Mint, Spark Kinetic Fruit, Spark Kinetic Mint, Spearmint

Supersmile®
Professional Whitening Gum

TheraBreath®
Professional Formula Sugar Free Chewing Gum
TheraBreath® Mouth-Wetting Lozenges
Zox Breath Mints

TheraMints
100% Xylitol Lozenges

Trident® – Mondalez International
Trident Gum: Blueberry Twist®, Bubblegum, Cinnamon, Minty Sweet Twist, Original Flavor, Passionberry Twist®, Spearmint, Splashing Fruit, Splashing Mint, Strawberry Twist, Tropical Twist®, Watermelon Twist®, Wintergreen

Walgreens
Walgreens Breath Strips Mint

Xlear®
SparX Candy: Berry, Citrus, Fruit
Spry Dental Defense Gum: Cinnamon, Fresh Fruit, Green Tea, Peppermint, Spearmint, Strawberry
Spry Gem Mints: Berry, Cinnamon, Lemon Creme, Peppermint, Spearmint
Spry Mints: BerryBlast, Cinnamon, Green Tea, Power Peppermint, Spearmint

Xylabrands
Xyla Ballpop Lollipops
Xyla Brand Xylitol Candy: Cherry, Citrus, Grape, Key Lime, Raspberry, Watermelon
Xyla Gum: Cinnamon, Fruit Punch, Peppermint, Spearmint,
Xyla Mints: Cocoa Mint, Fruit Punch, Lemon Lime, Licorice, Peppermint, Wintermint
Xyla Taffy: Assorted Flavors
Xyla Assorted 100% Natural Hard Candies

XyliChew
See Nature’s Stance above for product details

Zellie’s
Zellie’s Naturally Sugar Free Gum: Cinnamon, Fresh Fruit, Peppermint, Spearmint
Zellie’s Naturally Sugar Free Mints: Cool Fruit, Cool Mint, Cinnamon, Spearmint
Zellie’s Polar Bears: Cherry, Tropical Fruit

Zollipops®
Zollipops® Lollipops

Xylitol In Products: Honey, Raw Xylitol & Sweeteners

Xylitol product list sorted alphabetically by company or distributor

Designs For Health
Xylitol Powder 500 gms

Dr. John’s
Simply Xylitol Sweetener

Epic Dental
Xylitol Sweetener

Focus Nutrition
XyloBurst All-Natural Xylitol Sweetener Granuals
XyloBurst All-Natural Xylitol Sweetener Packets

Global Sweet
Smart Sweet Xylitol Granules
Smart Sweet Xylitol Honey

Hager Pharma
Hager Pharma Xylitol Sweetener

Health Garden
Real Birch Xylitol
Real Birch Xylitol Vanilla Sweetener

Jarrow Formulas Inc.
XyliPure Powder
Lo Han Sweet Powder

Life Enhancement
Sugar XE Sweetener

Nature’s Hollow
Sugar-Free Honey

NOW® Foods
Now Real Food – Xylitol
Now Real Food – Pure Xylitol Packets

NuNaturals
Sweet X Crystals

Nutraceutical
Kal® Xylitol Sweetener

Piping Rock
100%Pure Xylitol Natural Sweetener

Puritan’s Pride
Xylitol Powder

Source Naturals
XyliSmart® Sweetener

Swanson Health Products
Swanson Premium – 100% Pure Non-GMO Xylitol Granules
Swanson Premium – Xylitol Packets

Xlear®
Lite & Sweet
Xylo-Sweet

Xylabrands
Xyla Xylitol Packets
Xyla Xylitol Bulk
Xyla Powdered Xylitol

Zellie’s
Zellie’s Granular Xylitol
Zellie’s Pure Xylitol Packets

 Xylitol in Products: Dental & Nasal: Toothpaste, Floss, Mouthwash & Rinses

Xylitol product list sorted alphabetically by company or distributor

ACT®
Act Advanced Care Plaque Guard Mouthwash
Act Braces Care Mouthwash
Act Dry Mouth Lozenges
Act Dry Mouth Mouthwash
Act Dry Mouth Toothpaste
Act Total Care Sensitive Formula Mouthwash

American Biotech Labs
SilverSol Tooth Gel

Aquafresh® – GSK
Aquafresh Training Fluoride-Free Toothpaste

Auromere®
Ayurvedic Mouthwash

Babyganics®
Fluoride Free Toothpaste – Assorted Flavors

Biotene®
Dry Mouth Oral Rinse
Moisturizing Mouth Spray
Oral Balance Gel
PBF Oral Rinse

Branam
All Natural Xylitol Tooth Gel – Assorted Flavors

Carifree®
CTx2 Spray
CTx3 Gel
CTx3 Rinse
CTx4 Gel 1100
CTx4 Treatment Rinse

Cleure
Cleure Toothpaste – Assorted Flavors
Cleur Mouthwash – Assorted Flavors

Coral LLC
Coral Kids Toothpaste

Davids
Davids Premium Natural Toothpaste

Dentiste’
Dentiste’ Plus White Nighttime Toothpaste

doTERRA®
On Guard Toothpaste

Dr. Brown’s
Nose & Face Wipes
Tooth & Gum Wipes

Dr. Collins
All White Toothpaste
Natural Toothpaste

Eco-Dent®
Res-Q-Dent Gel Toothpaste

Epic Dental
Fluoride & Xylitol Toothpaste
Spearmint Xylitol Mouthwash

Grants of Australia
Natural Toothpaste – Assorted Flavors
Natural Toothpaste Single Use Sachets
Xylitol Mint Natural Toothpaste
Xylitol Natural Mouthwash

H2Ocean®
H2Ocean Mouthwash – Assorted Flavors
Nasalzyme Maximum Strength Nasal Spray

Hager Pharma
Hager Pharma Dry Mouth Drops
Hager Pharma Happy Morning Xylitol Disposable Toothbrushes
Hager Pharma Xyli-Spray Sugar Free Fresh Breath Spray

Halo
Halo Oral Antiseptic, Berry, Citrus

Healing Scents 
Tooth Gel – Assorted Flavors

Hello® 
Breath Spray – Assorted Flavors
Fluoride Toothpaste – Assorted Flavors
Kids Fluoride Toothpaste – Assorted Flavors
Mouthwash – Assorted Flavors

Heritage Store
Hydrogen Peroxide Tooth Powder
Hydrogen Peroxide Mouthwash + White
Hydrogen Peroxide Mouthwash Wintermint
Ipsab Tooth Powder, Cinnamon
Ipsab Whitening Toothpaste

IntelliWHiTE
IntelliFRESH Breath Gel
IntelliFRESH Oral Rinse Fusion
IntelliWHiTE® CoolBlue Amplifier Gel Pen
IntelliWHiTE® Power Booster & Toothpaste Duo
PM Restore Night Serum
Power Boost Whitening Gel
PRO WhiTE Professional Toothpaste

Jack n’ Jill 
Natural Calendula Toothpaste – Assorted Flavors

Jason®
Healthy Mouth® Tartar Control Anti-Cavity Toothpaste
Healthy Mouth® Tartar Control Cinnamon Clove Mouthwash
Kids Only! Toothpaste – Assorted Flavors
Nutrismile® Enamel Defense Mouthwash
Nutrismile® Enamel Defense Anti-Cavity Toothpaste
Oral Comfort® Soothing Toothpaste
Powersmile® Moutwash: Brightening Peppermint, Strengthening Sea Spearmint, Super Refreshing Cinnamon Powermint
Powersmile® Whitening Anti-Cavity Toothpaste
Sea Fresh® Strengthening Anti-Cavity CoQ10 Gel Toothpaste

Kiss My Face
Obsessively Natural Kids Toothpaste – Berry Smart
Obsessively Natural Kids Fluoride Free Toothpaste – Berry Smart
Sensitive Fluoride Free Gel
Triple Action Fluoride Free Gel
Triple Action Fluoride Free Toothpaste
Triple Action Anticavity Fluoride Toothpaste
Whitening Gel – Anticavity Fluoride
Whitening Gel – Fluoride Free

Life Extension®
Florassist® Throat Health
Florassist® Oral Hygiene
Life Extension Toothpaste

Logona Naturkosmetik
Kids Dental Gel- Assorted Flavors

Melaleuca
Cool Shot® Breath Spray – Fresh Mint
Koala Pals® Tooth Gel – Assorted Flavors
Mouth Rinse – Assorted Flavors
Sensitive Tooth Polish
Whitening Tooth Polish – Assorted Flavors

MedActive®
Oral Relief Spray
Oral Relief Lozenges

Nature’s Answer 
PerioBrite® Natural Mouthwash – Assorted Flavors

Nature’s Gate
Toothpaste Gel – Cherry, Cool Mint, Wintergreen

NaturallyTaylored
Organic Toothpaste Remineralizing Toothpaste

NOW® Foods
Now Solutions – Activated Nasal Mist
Now Solutions – Xyliwhite Mouthwash: Cinnafresh, Neem & Tea Tree, Refreshmint
Now Solutions – Xyliwhite Toothpaste Gel: Bubblegum Splash, Cinnafresh, Orange Splash, Neem & Tea Tree, Refreshmint, Strawberry Splash
Now Solutions – Xyliwhite Plantinum Mint Toothpaste Gel w/ Baking Soda

Nuk – Gerber®
Grins & Giggles® Gum & Tooth Wipes

Nutraceutical
XyliVita Mouthwash
XyliVita Toothpaste – Assorted Flavors
XyliVita Sensitive Whitening Toothpaste – Cool Mint Chia

Oasis Dry Mouth
Oral Demulcent Moisturizing Spray

OraCoat / OraHealth
Avamin Melts – Healthy Mouth Lining
XyliMelts for Dry Mouth, Regular or Mint-Free
XyliGel with H-B12 for Dry Mouth and Mucositis

Organix South
TheraNeem Naturals – Neem Tooth & gum Powder
TheraNeem Naturals – Tea Tree Toothpaste

Parnell Pharmaceuticals
Mouth Kote Dry Mouth Spray

Peelu
Cinnamon Fluoride
Mint Free Fluoride
Peppermint Fluoride
Spearmint Fluoride

Radius
Cranberry Floss with Natural Xylitol
Vegan Xylitol Mint Floss

Redmond Trading Company
Earthpaste – Assorted Flavors

Seroyal
Homeofresh TP Anisum
Homeofresh TP Chlorophyllum
Homeofresh TP Citrus

Solay Wellness
Solay Smile Natural Tooth Powder – Assorted Flavors

Spiffies®
Lusterbrush Xylitol and Fluoride Tooth Gel
Spiffies Tooth Wipes – Assorted Flavors
Spiffies Tooth Gel – Assorted Flavors
Xyliclean Xylitol Oral Cleansing Solution

Squigle
Squigle Toothpaste
Tooth Builder Toothpaste

Starbrite
Whitening Toothpaste

Swanson Health Products
Swanson Ultra – Tea Tree Mouthwash Peppermint
Swanson Ultra – Whitening Toothpaste with Xylitol, Peelu and Tea Tree Oil
Swanson Ultra – Dry Mouth Relief

Tanner’s Tasty Paste®
Tasty Paste Toothpaste – Assorted Flavors

The Natural Dentist
All in One Fluoride Toothpaste
Cavity Zapper Fluoride Rinse – Assorted Flavors
Fluoride-Free Toothpaste
Healthy Balance All-Purpose Rinse
Healthy Breath Antiseptic Rinse
Healthy Teeth Fluoride Rinse
Healthy White Pre-Brush Whitening Rinse
Whitening Fluoride Toothpaste

TheraBreath® 
Periotherapy Oral Rinse
Periotherapy Toothpaste
TheraBreath® Plus Oral Rinse
TheraBreath® Icy Mint Oral Rinse
TheraBreath® Soothing Oral Rinse
TheraBrite Plus® Toothpaste

Tom’s of Maine®
Antiplaque & Whitening Toothpaste – Fluoride-Free – Fennel, Peppermint, Spearmint
Antiplaque & Whitening Toothpaste Gel – Fluoride-Free – Spearmint
Cavity Protection Toothpaste – Peppermint Baking Soda, Spearmint
Children’s Anticavity Fluoride Rinse – Juicy Mint
Clean & Gentle Toothpaste – Peppermint
Enamel Strength® Toothpaste – Peppermint
Fluoride-Free Botanically Bright Toothpaste – Peppermint, Spearmint
Fluoride-Free Propolis Myrrh Toothpaste – Cinnamint, Fennel, Gingermint Baking Soda, Peppermint Baking Soda, Spearmint
Fluoride-Free Sensitive Toothpaste – Wintermint
Fluoride-Free Travel Natural Toothpaste – Fresh Mint
Maximum Strength Sensitive Toothpaste – Soothing Mint
Simply White Toothpaste – Clean Mint
Simply White Toothpaste Gel – Sweet Mint
Toddler Training Toothpaste – Mild Fruit
Travel Natural Toothpaste – Fresh Mint
Whole Care Toothpaste – Cinnamon Clove, Peppermint, Spearmint, Wintermint
Whole Care Toothpaste Gel – Peppermint
Wicked Fresh Mouthwash – Cool Mountain Mint, Peppermint Wave
Wicked Fresh Toothpaste – Spearmint Ice, Cool Peppermint

Walgreens®
Walgreens Dry Mouth Mouthwash

Vita-Myr
Children’s Toothpaste with Xylitol & Natural Orange Flavor
Zinc-Plus XTRA Toothpaste with Xylitol & Co Q 10

VMV Hypoallergenics
Essence Skin-Saving Toothpaste

Xlear®
Kid’s Xlear Saline Nasal Spray
Spry Bubble Gum Tooth Gel
Spry Floss with Xylitol
Spry Toothpaste- Cinnamon
Spry Toothpaste- Cinnamon Fluoride
Spry Coolmint Oral Rinse
Spry Spearmint Oral Rinse
Spry Whitening Kit
Spry Wintergreen Oral Rinse
Xlear Saline Nasal Spray with Xylitol
Xlear Sinus Care Rinse

Young Living 

Thieves® AromaBright Toothpaste
Thieves® Dentarome® Ultra Toothpaste
Thieves® KidScents® Slique Toothpaste

Xylitol In Products: Cosmetics & Hair Care

Xylitol product list sorted alphabetically by company or distributor

ApothecaryMuse
Chocolate Lavender Fields Forever Lip Balm

Aroma Naturals®
Therapeutic Lip Care – Assorted Flavors

Bain de Terre
Purité Healthy Color Protect Shampoo
Purité Healthy Moisture Repair Shampoo

Bioderma
Nodé Fluide Shampoo

Etude House
Dear My Jelly Lips-Talk
Sweet Recipe Candy Stick Lip Gloss – Assorted Colors

GlyMed Plus®
Cell Science Lip Science

Holistic Momma Organics
Mauve Melody Shimmer Lip Balm

Laura Mercier
Tinted Moisturizer – Illuminating Broad Spectrum SPF 20 Sunscreen

Lorac
Natural Performance Foundation

Missha
The Style Beautiful Lip Tint – Assorted Colors

NaturallyTaylored
Love Story Wedding Favor Lip Balm
Mason Jar Wedding Favor Lip Balm

True Natural
Natural Liquid Foundation – Assorted Colors

 Xylitol In Products: Final Thoughts

In the past 5 years, Pet Poison Helpline, an animal poison control based out of Minneapolis, MN, has had over 1500 calls for xylitol poisoning, due to the growing awareness of this common kitchen toxin.

If you suspect that your pet has eaten a xylitol-containing product, please contact your veterinarian or Pet Poison Helpline (800-213-6680) immediately.

Do not induce vomiting or give anything orally to your dog unless specifically directed to do so by your veterinarian. It is important to get treatment for your dog as quickly as possible.

Chelsea Rivera
VP, Content & Media Relations
SimpleWag

OUR MISSION

To promote all-natural methods to raise your pet in a healthy manner.

CONTACT US

Message

Phone: +844-335-4383
Email: ask@simplewag.com
Facebook: Facebook Messenger

Website

SimpleWag.com

• 844-335-4383
• ask@simplewag.com

Chelsea Rivera founded SimpleWag with one goal in mind: to help pet owners ensure their pets live the healthiest lives possible! SimpleWag offers its audience access to loads of great content, including expert information provided by staffed vets, trainers, and behavioral specialists. Additionally, SimpleWag offers a pet food alert that notifies you if your pet’s food has been recalled.There is so information out there that it can be overwhelming for well-intentioned pet owners but SimpleWag’s goal is to do the research so you don’t have to! In addition to working for SimpleWag, Chelsea spends her days getting bossed around by her 5 lb. Maltipoo, Baby Rose, in Los Angeles, CA.

Follow SimpleWag on Facebook or Instagram @simplewag.

(WO2017211293) CRYSTALLINE FORM OF SUCCINATE USED AS DIPEPTIDYL PEPTIDASE-4 INHIBITOR 

WO-2017211293, 

XUANZHU PHARMA CO., LTD. [CN/CN]; 2518, Tianchen Street, National High-Tech Development Zone Jinan, Shandong 250101 (CN)

SHU, Chutian; (CN)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017211293&recNum=1&tab=PCTDocuments&maxRec=&office=&prevFilter=&sortOption=&queryString=

Alcaftadine

NEW PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017211246&redirectedID=true

WO-2017211246, SHENZHEN TARGETRX, INC.

SUBSTITUTED FUSED IMIDAZOLE CYCLIC COMPOUND AND PHARMACEUTICAL COMPOSITION THEREOF

WANG, Yihan; (CN).
XING, Qingfeng; (CN)

Novel deuterated analogs of substituted fused imidazole cyclic compounds, particularly alcaftadine are histamine H1-receptor antagonists and mast cell stabilizers, useful for treating allergy and nasal congestion.

The present invention relates to a substituted fused imidazole cyclic compound and a composition containing said compound and application thereof. Specifically disclosed is the fused imidazole cyclic compound represented by formula (I), or a pharmaceutical composition of its crystalline form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate. The compound of the present invention may be used as a histamine H1-receptor antagonist and mast-cell stabilizer, and is capable of inhibiting mast-cell release of histamine and preventing histamine function, thereby reducing allergic reaction

Example 1 Preparation of 6,11-dihydro -11- (1- (d3- methyl) piperidin-4-ylidene) -5H- imidazo [2,1-b] [3] benzazepine – 3- aldehyde (compound 8)

N-benzyloxycarbonylpiperidine-4-carboxylic acid (2.63 g, 10 mmol) was dissolved in 20 mL of dichloromethane, 6 mL of oxalyl chloride and 1 drop of DMF were added and the mixture was reacted at room temperature for 2 hours under nitrogen. The reaction mixture was concentrated to dryness under reduced pressure, dissolved in 20 mL of acetonitrile, and added with triethylamine (4.1 mL, 30 mmol) in an ice bath and stirred for 3 minutes. A solution of 1-phenethyl-1H-imidazole (2.06 g, 12 mmol) in 5 mL of acetonitrile was slowly added dropwise and the reaction was allowed to warm to room temperature overnight after the addition was completed. The reaction was completed, concentrated to dryness, 30 mL of ethyl acetate and 20 mL of water were added and the mixture was stirred for 5 minutes. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give 3.34 g of a colorless oil, benzyl-4- (1-phenethyl-1H-imidazole-2-formyl) piperidine-1-carboxylate (Compound 3) was obtained in a yield of 80%. ESI-MS: 418 [M ⁺⁺ 1].

//////////////

//////////////nanomaterials, vaccine

FDA approves drug to treat dangerously low blood pressure

The U.S. Food and Drug Administration today approved Giapreza (angiotensin II) injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock. Continue reading.

///////////Giapreza ,  La Jolla Pharmaceutical Company, fda 2017,  low blood pressure, angiotensin II

Psilocybin 

• Molecular FormulaC₁₂H₁₇N₂O₄P
• Average mass284.248 Da

NM 3150000

O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine

P-7825

PDSP1_001391

UNII-2RV7212BP0

MP 220-228 deg C, O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1419

UV max (methanol): 220, 267, 290 nm (log epsilon 4.6, 3.8, 3.6), O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1419

Psilocybin^{[nb 1]} (/ˌsaɪləˈsaɪbɪn/ sy-lə-SY-bin) is a naturally occurring psychedelic prodrug compound produced by more than 200 speciesof mushrooms, collectively known as psilocybin mushrooms. Psilocybin evolved in mushrooms from its ancestor, muscarine, some 20 million years ago.^[4]

The most potent are members of the genus Psilocybe, such as P. azurescens, P. semilanceata, and P. cyanescens, but psilocybin has also been isolated from about a dozen other genera. As a prodrug, psilocybin is quickly converted by the body to psilocin, which has mind-altering effects similar, in some aspects, to those of LSD, mescaline, and DMT. In general, the effects include euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and spiritual experiences, and can include possible adverse reactions such as nausea and panic attacks.

Imagery found on prehistoric murals and rock paintings of modern-day Spain and Algeria suggests that human usage of psilocybin mushrooms predates recorded history. In Mesoamerica, the mushrooms had long been consumed in spiritual and divinatoryceremonies before Spanish chroniclers first documented their use in the 16th century. In a 1957 Life magazine article, American banker and ethnomycologist R. Gordon Wasson described his experiences ingesting psilocybin-containing mushrooms during a traditional ceremony in Mexico, introducing the substance to popular culture. In 1959, the Swiss chemist Albert Hofmann isolated the active principle psilocybin from the mushroom Psilocybe mexicana. Hofmann’s employer Sandoz marketed and sold pure psilocybin to physicians and clinicians worldwide for use in psychedelic psychotherapy. Although the increasingly restrictive drug laws of the late 1960s curbed scientific research into the effects of psilocybin and other hallucinogens, its popularity as an entheogen (spirituality-enhancing agent) grew in the next decade, owing largely to the increased availability of information on how to cultivate psilocybin mushrooms.

Some users of the drug consider it an entheogen and a tool to supplement practices for transcendence, including meditation and psychonautics. The intensity and duration of the effects of psilocybin are variable, depending on species or cultivar of mushrooms, dosage, individual physiology, and set and setting, as was shown in experiments led by Timothy Leary at Harvard University in the early 1960s. Once ingested, psilocybin is rapidly metabolized to psilocin, which then acts on serotonin receptors in the brain. The mind-altering effects of psilocybin typically last from two to six hours, although to individuals under the influence of psilocybin, the effects may seem to last much longer, since the drug can distort the perception of time. Psilocybin has a low toxicity and a relatively low harm potential, and reports of lethal doses of the drug are rare. Several modern bioanalytical methods have been adapted to rapidly and accurately screen the levels of psilocybin in mushroom samples and body fluids. Since the 1990s, there has been a renewal of scientific research into the potential medical and psychological therapeutic benefits of psilocybin for treating conditions including obsessive-compulsive disorder (OCD), post-traumatic stress disorder, social anxiety, treatment-resistant depression, cluster headaches, and anxiety related to terminal cancer.^[5] Possession of psilocybin-containing mushrooms has been outlawed in most countries, and it has been classified as a scheduled drug by many national drug laws.

Effects

The effects of psilocybin are highly variable and depend on the mindset and environment in which the user has the experience, factors commonly referred to as set and setting. In the early 1960s, Timothy Leary and colleagues at Harvard University investigated the role of set and setting on the effects of psilocybin. They administered the drug to 175 volunteers from various backgrounds in an environment intended to be similar to a comfortable living room. Ninety-eight of the subjects were given questionnaires to assess their experiences and the contribution of background and situational factors. Individuals who had experience with psilocybin prior to the study reported more pleasant experiences than those for whom the drug was novel. Group size, dosage, preparation, and expectancy were important determinants of the drug response. In general, those placed in groups of more than eight individuals felt that the groups were less supportive, and their experiences were less pleasant. Conversely, smaller groups (fewer than six individuals) were seen as more supportive. Participants also reported having more positive reactions to the drug in those groups. Leary and colleagues proposed that psilocybin heightens suggestibility, making an individual more receptive to interpersonal interactions and environmental stimuli.^[6] These findings were affirmed in a later review by Jos ten Berge (1999), who concluded that dosage, set, and setting were fundamental factors in determining the outcome of experiments that tested the effects of psychedelic drugs on artists’ creativity.^[7]

After ingesting psilocybin, a wide range of subjective effects may be experienced: feelings of disorientation, lethargy, giddiness, euphoria, joy, and depression. About a third of users report feelings of anxiety or paranoia.^[8] Low doses of the drug can induce hallucinatory effects. Closed-eye hallucinations may occur, in which the affected individual sees multicolored geometric shapes and vivid imaginative sequences.^[9] Some individuals report experiencing synesthesia, such as tactile sensations when viewing colors.^[10] At higher doses, psilocybin can lead to “Intensification of affective responses, enhanced ability for introspection, regression to primitive and childlike thinking, and activation of vivid memory traces with pronounced emotional undertones”.^[11] Open-eye visual hallucinations are common, and may be very detailed although rarely confused with reality.^[9]

A 2011 prospective study by Roland R. Griffiths and colleagues suggests that a single high dosage of psilocybin can cause long-term changes in the personality of its users. About half of the study participants—described as healthy, “spiritually active”, and many possessing postgraduate degrees—showed an increase in the personality dimension of openness (assessed using the Revised NEO Personality Inventory), and this positive effect was apparent more than a year after the psilocybin session. According to the study authors, the finding is significant because “no study has prospectively demonstrated personality change in healthy adults after an experimentally manipulated discrete event.”^[12] Although other researchers have described instances of psychedelic drug usage leading to new psychological understandings and personal insights,^[13] it is not known whether these experimental results can be generalized to larger populations.^[12]

Physical effects

Common responses include: pupil dilation (93%); changes in heart rate (100%), including increases (56%), decreases (13%), and variable responses (31%); changes in blood pressure (84%), including hypotension (34%), hypertension (28%), and general instability (22%); changes in stretch reflex (86%), including increases (80%) and decreases (6%); nausea (44%); tremor (25%); and dysmetria (16%) (inability to properly direct or limit motions).^{[nb 2]} The temporary increases in blood pressure caused by the drug can be a risk factor for users with pre-existing hypertension.^[9] These qualitative somatic effects caused by psilocybin have been corroborated by several early clinical studies.^[15] A 2005 magazine survey of club goers in the UK found that nausea or vomiting was experienced by over a quarter of those who had used psilocybin mushrooms in the last year, although this effect is caused by the mushroom rather than psilocybin itself.^[8] In one study, administration of gradually increasing dosages of psilocybin daily for 21 days had no measurable effect on electrolyte levels, blood sugar levels, or liver toxicity tests.^[1]

Perceptual distortions

Psilocybin is known to strongly influence the subjective experience of the passage of time.^[16] Users often feel as if time is slowed down, resulting in the perception that “minutes appear to be hours” or “time is standing still”.^[17] Studies have demonstrated that psilocybin significantly impairs subjects’ ability to gauge time intervals longer than 2.5 seconds, impairs their ability to synchronize to inter-beat intervals longer than 2 seconds, and reduces their preferred tapping rate.^[17][18] These results are consistent with the drug’s role in affecting prefrontal cortex activity,^[19] and the role that the prefrontal cortex is known to play in time perception.^[20] However, the neurochemical basis of psilocybin’s effects on the perception of time are not known with certainty.^[21]

Users having a pleasant experience can feel a sense of connection to others, nature, and the universe; other perceptions and emotions are also often intensified. Users having an unpleasant experience (a “bad trip“) describe a reaction accompanied by fear, other unpleasant feelings, and occasionally by dangerous behavior. In general, the phrase “bad trip” is used to describe a reaction that is characterized primarily by fear or other unpleasant emotions, not just transitory experience of such feelings. A variety of factors may contribute to a psilocybin user experiencing a bad trip, including “tripping” during an emotional or physical low or in a non-supportive environment (see: set and setting). Ingesting psilocybin in combination with other drugs, including alcohol, can also increase the likelihood of a bad trip.^[8][22] Other than the duration of the experience, the effects of psilocybin are similar to comparable dosages of LSD or mescaline. However, in the Psychedelics Encyclopedia, author Peter Stafford noted, “The psilocybin experience seems to be warmer, not as forceful and less isolating. It tends to build connections between people, who are generally much more in communication than when they use LSD.”^[23]

Uses

Spiritual

Psilocybin mushrooms have been and continue to be used in indigenous New World cultures in religious, divinatory, or spiritual contexts. Reflecting the meaning of the word entheogen (“the god within”), the mushrooms are revered as powerful spiritual sacraments that provide access to sacred worlds. Typically used in small group community settings, they enhance group cohesion and reaffirm traditional values.^[24] Terence McKenna documented the worldwide practices of psilocybin mushroom usage as part of a cultural ethosrelating to the Earth and mysteries of nature, and suggested that mushrooms enhanced self-awareness and a sense of contact with a “Transcendent Other”—reflecting a deeper understanding of our connectedness with nature.^[25]

Psychedelic drugs can induce states of consciousness that have lasting personal meaning and spiritual significance in individuals who are religious or spiritually inclined; these states are called mystical experiences. Some scholars have proposed that many of the qualities of a drug-induced mystical experience are indistinguishable from mystical experiences achieved through non-drug techniques, such as meditation or holotropic breathwork.^[26][27] In the 1960s, Walter Pahnke and colleagues systematically evaluated mystical experiences (which they called “mystical consciousness”) by categorizing their common features. These categories, according to Pahnke, “describe the core of a universal psychological experience, free from culturally determined philosophical or theological interpretations”, and allow researchers to assess mystical experiences on a qualitative, numerical scale.^[28]

In the 1962 Marsh Chapel Experiment, which was run by Pahnke at the Harvard Divinity School under the supervision of Timothy Leary,^[29] almost all of the graduate degree divinitystudent volunteers who received psilocybin reported profound religious experiences.^[30] One of the participants was religious scholar Huston Smith, author of several textbooks on comparative religion; he later described his experience as “the most powerful cosmic homecoming I have ever experienced.”^[31] In a 25-year followup to the experiment, all of the subjects given psilocybin described their experience as having elements of “a genuine mystical nature and characterized it as one of the high points of their spiritual life”.^[32]Psychedelic researcher Rick Doblin considered the study partially flawed due to incorrect implementation of the double-blind procedure, and several imprecise questions in the mystical experience questionnaire. Nevertheless, he said that the study cast “a considerable doubt on the assertion that mystical experiences catalyzed by drugs are in any way inferior to non-drug mystical experiences in both their immediate content and long-term effects”.^[33] This sentiment was echoed by psychiatrist William A. Richards, who in a 2007 review stated “[psychedelic] mushroom use may constitute one technology for evoking revelatory experiences that are similar, if not identical, to those that occur through so-called spontaneous alterations of brain chemistry.”^[34]

A group of researchers from Johns Hopkins School of Medicine led by Griffiths conducted a study to assess the immediate and long-term psychological effects of the psilocybin experience, using a modified version of the mystical experience questionnaire and a rigorous double-blind procedure.^[35] When asked in an interview about the similarity of his work with Leary’s, Griffiths explained the difference: “We are conducting rigorous, systematic research with psilocybin under carefully monitored conditions, a route which Dr. Leary abandoned in the early 1960s.”^[36] The National Institute of Drug Abuse-funded study, published in 2006, has been praised by experts for the soundness of its experimental design.^{[nb 3]} In the experiment, 36 volunteers without prior experience with hallucinogens were given psilocybin and methylphenidate (Ritalin) in separate sessions; the methylphenidate sessions served as a control and psychoactive placebo. The degree of mystical experience was measured using a questionnaire developed by Ralph W. Hood;^[37] 61% of subjects reported a “complete mystical experience” after their psilocybin session, while only 13% reported such an outcome after their experience with methylphenidate. Two months after taking psilocybin, 79% of the participants reported moderately to greatly increased life satisfaction and sense of well-being. About 36% of participants also had a strong to extreme “experience of fear” or dysphoria (i.e., a “bad trip”) at some point during the psilocybin session (which was not reported by any subject during the methylphenidate session); about one-third of these (13% of the total) reported that this dysphoria dominated the entire session. These negative effects were reported to be easily managed by the researchers and did not have a lasting negative effect on the subject’s sense of well-being.^[38]

A follow-up study conducted 14 months after the original psilocybin session confirmed that participants continued to attribute deep personal meaning to the experience. Almost one-third of the subjects reported that the experience was the single most meaningful or spiritually significant event of their lives, and over two-thirds reported it among their five most spiritually significant events. About two-thirds indicated that the experience increased their sense of well-being or life satisfaction.^[30] Even after 14 months, those who reported mystical experiences scored on average 4 percentage points higher on the personality trait of Openness/Intellect; personality traits are normally stable across the lifespan for adults. Likewise, in a recent (2010) web-based questionnaire study designed to investigate user perceptions of the benefits and harms of hallucinogenic drug use, 60% of the 503 psilocybin users reported that their use of psilocybin had a long-term positive impact on their sense of well-being.^[8][39]

In 2011, Griffiths and colleagues published the results of further studies designed to learn more about the optimum psilocybin doses needed for positive life-changing experiences, while minimizing the chance of negative reactions. In a 14-month followup, the researchers found that 94% of the volunteers rated their experiences with the drug as one of the top five most spiritually significant of their lives (44% said it was the single most significant). None of the 90 sessions that took place throughout the study were rated as decreasing well-being or life satisfaction. Moreover, 89% reported positive changes in their behaviors as a result of the experiences. The conditions of the experimental design included a single drug experience a month, on a couch, in a living-room-like setting, with eye shades and carefully chosen music (classical and world music). As an additional precaution to guide the experience, as with the 2006 study, the 2011 study included a “monitor” or “guide” whom the volunteers supposedly trusted. The monitors provided gentle reassurance when the volunteers experienced anxiety. The volunteers and monitors all remained blind to the exact dosages for the purpose of the experiment.^[40]

Available forms

Although psilocybin may be prepared synthetically, outside of the research setting, it is not typically used in this form. The psilocybin present in certain species of mushrooms can be ingested in several ways: by consuming fresh or dried fruit bodies, by preparing a herbal tea, or by combining with other foods to mask the bitter taste.^[41] In rare cases people have injected mushroom extracts intravenously.^[8]

Adverse effects

Most of the comparatively few fatal incidents reported in the literature that are associated with psychedelic mushroom usage involve the simultaneous use of other drugs, especially alcohol. Probably the most common cause of hospital admissions resulting from psychedelic mushroom usage involve “bad trips” or panic reactions, in which affected individuals become extremely anxious, confused, agitated, or disoriented. Accidents, self-injury, or suicide attempts can result from serious cases of acute psychotic episodes.^[8] Although no studies have linked psilocybin with birth defects,^[42] it is recommended that pregnant women avoid its usage.^[43]

Toxicity

The toxicity of psilocybin is low. In rats, the median lethal dose (LD₅₀) when administered orally is 280 milligrams per kilogram (mg/kg), approximately one and a half times that of caffeine. When administered intravenously in rabbits, psilocybin’s LD₅₀ is approximately 12.5 mg/kg.^[45] Psilocybin comprises approximately 1% of the weight of Psilocybe cubensismushrooms, and so nearly 1.7 kilograms (3.7 lb) of dried mushrooms, or 17 kilograms (37 lb) of fresh mushrooms, would be required for a 60-kilogram (130 lb) person to reach the 280 mg/kg LD₅₀ value of rats.^[8] Based on the results of animal studies, the lethal dose of psilocybin has been extrapolated to be 6 grams, 1000 times greater than the effective doseof 6 milligrams.^[46] The Registry of Toxic Effects of Chemical Substances assigns psilocybin a relatively high therapeutic index of 641 (higher values correspond to a better safety profile); for comparison, the therapeutic indices of aspirin and nicotine are 199 and 21, respectively.^[47] The lethal dose from psilocybin toxicity alone is unknown at recreational or medicinal levels, and has rarely been documented—as of 2011, only two cases attributed to overdosing on hallucinogenic mushrooms (without concurrent use of other drugs) have been reported in the scientific literature and may involve other factors aside from psilocybin.^{[8][nb 4]}

Psychiatric

Panic reactions can occur after consumption of psilocybin-containing mushrooms, especially if the ingestion is accidental or otherwise unexpected. Reactions characterized by violent behavior, suicidal thoughts,^[50] schizophrenia-like psychosis,^[51][52] and convulsions^[53] have been reported in the literature. A 2005 survey conducted in the United Kingdom found that almost a quarter of those who had used psilocybin mushrooms in the past year had experienced a panic attack.^[8] Other adverse effects less frequently reported include paranoia, confusion, prolonged derealization (disconnection from reality), and mania.^[39] Psilocybin usage can temporarily induce a state of depersonalization disorder.^[54] Usage by those with schizophrenia can induce acute psychotic states requiring hospitalization.^[8]

Recent evidence, however, has suggested against the contention that the use of psilocybin puts one at risk for developing long lasting mental disorders. An analysis of information from the National Survey on Drug Use and Health showed that the use of psychedelic drugs such as psilocybin is associated with significantly reduced odds of past month psychological distress, past year suicidal thinking, past year suicidal planning, and past year suicide attempt.^[55]

The similarity of psilocybin-induced symptoms to those of schizophrenia has made the drug a useful research tool in behavioral and neuroimaging studies of this psychotic disorder.^[56][57][58] In both cases, psychotic symptoms are thought to arise from a “deficient gating of sensory and cognitive information” in the brain that ultimately lead to “cognitive fragmentation and psychosis”.^[57] Flashbacks (spontaneous recurrences of a previous psilocybin experience) can occur long after having used psilocybin mushrooms. Hallucinogen persisting perception disorder (HPPD) is characterized by a continual presence of visual disturbances similar to those generated by psychedelic substances. Neither flashbacks nor HPPD are commonly associated with psilocybin usage,^[8] and correlations between HPPD and psychedelics are further obscured by polydrug use and other variables.^[59]

Tolerance and dependence

Tolerance to psilocybin builds and dissipates quickly; ingesting psilocybin more than about once a week can lead to diminished effects. Tolerance dissipates after a few days, so doses can be spaced several days apart to avoid the effect.^[60] A cross-tolerance can develop between psilocybin and the pharmacologically similar LSD,^[61] and between psilocybin and phenethylamines such as mescaline and DOM.^[62]

Repeated use of psilocybin does not lead to physical dependence.^[1] A 2008 study concluded that, based on US data from the period 2000–2002, adolescent-onset (defined here as ages 11–17) usage of hallucinogenic drugs (including psilocybin) did not increase the risk of drug dependence in adulthood; this was in contrast to adolescent usage of cannabis, cocaine, inhalants, anxiolytic medicines, and stimulants, all of which were associated with “an excess risk of developing clinical features associated with drug dependence”.^[63]Likewise, a 2010 Dutch study ranked the relative harm of psilocybin mushrooms compared to a selection of 19 recreational drugs, including alcohol, cannabis, cocaine, ecstasy, heroin, and tobacco. Psilocybin mushrooms were ranked as the illicit drug with the lowest harm,^[64] corroborating conclusions reached earlier by expert groups in the United Kingdom.^[65]

Interactions

Monoamine oxidase inhibitors (MAOI) have been known to prolong and enhance the effects of psilocybin.^[66] Alcohol consumption may enhance the effects of psilocybin, because acetaldehyde, one of the primary breakdown metabolites of consumed alcohol, reacts with biogenic amines present in the body to produce MAOIs related to tetrahydroisoquinolineand β-carboline. Tobacco smokers may also experience more powerful effects with psilocybin,^[8] because tobacco smoke exposure decreases the activity of MAO in the brain and peripheral organs.^[67]

Pharmacology

Pharmacodynamics

Psilocybin is rapidly dephosphorylated in the body to psilocin, which is a partial agonist for several serotonin receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors. Psilocin has a high affinity for the 5-HT_2B and 5-HT_2C receptors in the human brain, and with a slightly lower affinity for the 5-HT_2A receptor. Psilocin binds with low affinity to 5-HT1 receptors, including 5-HT_1A and 5-HT_1D.^[1] Serotonin receptors are located in numerous parts of the brain, including the cerebral cortex, and are involved in a wide range of functions, including regulation of moodand motivation.^[68] The psychotomimetic (psychosis-mimicking) effects of psilocin can be blocked in a dose-dependent fashion by the 5-HT_2Aantagonist drug ketanserin.^[51] Various lines of evidence have shown that interactions with non-5-HT₂ receptors also contribute to the subjective and behavioral effects of the drug.^{[62][nb 5]} For example, psilocin indirectly increases the concentration of the neurotransmitter dopamine in the basal ganglia, and some psychotomimetic symptoms of psilocin are reduced by haloperidol, a non-selective dopamine receptor antagonist. Taken together, these suggest that there may be an indirect dopaminergic contribution to psilocin’s psychotomimetic effects.^[21] Unlike LSD, which binds to D2-like dopamine receptors in addition to having strong affinity for several 5-HT receptors, psilocybin and psilocin have no affinity for the dopamine D2 receptors.^[1]

Pharmacokinetics

The effects of the drug begin 10–40 minutes after ingestion, and last 2–6 hours depending on dose, species, and individual metabolism.^[70] The half life of psilocybin is 163 ± 64 minutes when taken orally, or 74.1 ± 19.6 minutes when injected intravenously.^[1] A dosage of 4–10 mg, corresponding roughly to 50–300 micrograms per kilogram (µg/kg) of body weight, is required to induce psychedelic effects. A typical recreational dosage is 10–50 mg psilocybin, which is roughly equivalent to 10–50 grams of fresh mushrooms, or 1–5 grams of dried mushrooms.^[8] A small number of people are unusually sensitive to psilocybin, such that a normally threshold-level dose of about 2 mg can result in effects usually associated with medium or high doses. In contrast, there are some who require relatively high doses to experience noticeable effects. Individual brain chemistry and metabolism play a large role in determining a person’s response to psilocybin.^[70]

Psilocybin is metabolized mostly in the liver. As it becomes converted to psilocin, it undergoes a first-pass effect, whereby its concentration is greatly reduced before it reaches the systemic circulation. Psilocin is broken down by the enzyme monoamine oxidase to produce several metabolites that can circulate in the blood plasma, including 4-hydroxyindole-3-acetaldehyde, 4-hydroxytryptophol, and 4-hydroxyindole-3-acetic acid.^[1] Some psilocin is not broken down by enzymes and instead forms a glucuronide; this is a biochemical mechanism animals use to eliminate toxic substances by linking them with glucuronic acid, which can then be excreted in the urine.^[71][72] Psilocin is glucuronated by the glucuronosyltransferase enzymes UGT1A9 in the liver, and by UGT1A10 in the small intestine.^[73] Based on studies using animals, about 50% of ingested psilocybin is absorbed through the stomach and intestine. Within 24 hours, about 65% of the absorbed psilocybin is excreted into the urine, and a further 15–20% is excreted in the bile and feces. Although most of the remaining drug is eliminated in this way within 8 hours, it is still detectable in the urine after 7 days.^[74] Clinical studies show that psilocin concentrations in the plasma of adults average about 8 µg/liter within 2 hours after ingestion of a single 15 mg oral psilocybin dose;^[75] psychological effects occur with a blood plasma concentration of 4–6 µg/liter.^[1]Psilocybin is about 100 times less potent than LSD on a weight per weight basis, and the physiological effects last about half as long.^[76]

Chemistry and biosynthesis

Psilocybin (O-phosphoryl-4-hydroxy-N,N–dimethyltryptamine, 4-PO-Psilocin, or 4-PO-HO-DMT) is a prodrug that is converted into the pharmacologically active compound psilocin in the body by a dephosphorylation reaction. This chemical reaction takes place under strongly acidic conditions, or under physiological conditions in the body, through the action of enzymes called alkaline phosphatases.^[77]

Psilocybin is a tryptamine compound with a chemical structure containing an indole ring linked to an ethylamine substituent. It is chemically related to the amino acid tryptophan, and is structurally similar to the neurotransmitter serotonin. Psilocybin is a member of the general class of tryptophan-based compounds that originally functioned as antioxidants in earlier life forms before assuming more complex functions in multicellular organisms, including humans.^[78] Other related indole-containing psychedelic compounds include dimethyltryptamine, found in many plant species and in trace amounts in some mammals, and bufotenine, found in the skin of psychoactive toads.^[79]

Psilocybin is an alkaloid that is soluble in water, methanol and aqueous ethanol, but insoluble in organic solvents like chloroform and petroleum ether.^[80] Its pKa values are estimated to be 1.3 and 6.5 for the two successive phosphate OH groups and 10.4 for the dimethylamine nitrogen, so in general it exists as a zwitterionic structure.^[81] Exposure to light is detrimental to the stability of aqueous solutions of psilocybin, and will cause it to rapidly oxidize—an important consideration when using it as an analytical standard.^[82] Osamu Shirota and colleagues reported a method for the large-scale synthesis of psilocybin without chromatographic purification in 2003.^[83] Starting with 4-hydroxyindole, they generated psilocybin from psilocin in 85% yield, a marked improvement over yields reported from previous syntheses.^[84][85][86] Purified psilocybin is a white, needle-like crystalline powder^[83]with a melting point between 220–228 °C (428–442 °F),^[45] and a slightly ammonia-like taste.^[81]

Biosynthetically, the biochemical transformation from tryptophan to psilocybin involves several enzyme reactions: decarboxylation, methylation at the N⁹ position, 4-hydroxylation, and O–phosphorylation. Isotopic labeling experiments suggest that tryptophan decarboxylation is the initial biosynthetic step and that O-phosphorylation is the final step.^[87][88]) The sequence of the intermediate enzymatic steps has been shown to involve 4 different enzymes (PsiD, PsiH, PsiK, and PsiM) in P. cubensis and P. cyanescens, although the biosynthetic pathway may differ between species.^[89][90]

Analytical methods

Several relatively simple chemical tests — commercially available as reagent testing kits — can be used to assess the presence of psilocybin in extracts prepared from mushrooms. The drug reacts in the Marquis test to produce a yellow color, and a green color in the Mandelin test.^[91] Neither of these tests, however, is specific for psilocybin; for example, the Marquis test will react with many classes of controlled drugs, such as those containing primary amino groups and unsubstituted benzene rings, including amphetamine and methamphetamine.^[92] Ehrlich’s reagent and DMACA reagent are used as chemical sprays to detect the drug after thin layer chromatography.^[93] Many modern techniques of analytical chemistry have been used to quantify psilocybin levels in mushroom samples. Although the earliest methods commonly used gas chromatography, the high temperature required to vaporize the psilocybin sample prior to analysis causes it to spontaneously lose its phosphoryl group and become psilocin — making it difficult to chemically discriminate between the two drugs. In forensic toxicology, techniques involving gas chromatography coupled to mass spectrometry (GC–MS) are the most widely used due to their high sensitivity and ability to separate compounds in complex biological mixtures.^[94] These techniques include ion mobility spectrometry,^[95] capillary zone electrophoresis,^[96] ultraviolet spectroscopy,^[97] and infrared spectroscopy.^[98] High performance liquid chromatography (HPLC) is used with ultraviolet,^[82] fluorescence,^[99] electrochemical,^[100] and electrospraymass spectrometric detection methods.^[101]

Various chromatographic methods have been developed to detect psilocin in body fluids: the rapid emergency drug identification system (REMEDi HS), a drug screening method based on HPLC;^[102] HPLC with electrochemical detection;^[100][103] GC–MS;^[71][102] and liquid chromatography coupled to mass spectrometry.^[104] Although the determination of psilocin levels in urine can be performed without sample clean-up (i.e., removing potential contaminants that make it difficult to accurately assess concentration), the analysis in plasma or serum requires a preliminary extraction, followed by derivatization of the extracts in the case of GC–MS. A specific immunoassay has also been developed to detect psilocin in whole blood samples.^[105] A 2009 publication reported using HPLC to quickly separate forensically important illicit drugs including psilocybin and psilocin, which were identifiable within about half a minute of analysis time.^[106] These analytical techniques to determine psilocybin concentrations in body fluids are, however, not routinely available, and not typically used in clinical settings.^[22]

Natural occurrence

Psilocybin is present in varying concentrations in over 200 species of Basidiomycota mushrooms which evolved to produce the compound from muscarine some 20 million years ago.^[4] In a 2000 review on the worldwide distribution of hallucinogenic mushrooms, Gastón Guzmán and colleagues considered these to be distributed amongst the following genera: Psilocybe (116 species), Gymnopilus (14), Panaeolus (13), Copelandia (12), Hypholoma (6), Pluteus (6), Inocybe (6), Conocybe (4), Panaeolina (4), Gerronema (2) and Agrocybe, Galerina and Mycena(1 species each).^[108] Guzmán increased his estimate of the number of psilocybin-containing Psilocybe to 144 species in a 2005 review. The majority of these are found in Mexico (53 species), with the remainder distributed in the US and Canada (22), Europe (16), Asia (15), Africa (4), and Australia and associated islands (19).^[109] In general, psilocybin-containing species are dark-spored, gilled mushrooms that grow in meadows and woods of the subtropics and tropics, usually in soils rich in humus and plant debris.^[110] Psilocybin mushrooms occur on all continents, but the majority of species are found in subtropical humid forests.^[108] Psilocybe species commonly found in the tropics include P. cubensis and P. subcubensis. P. semilanceata — considered by Guzmán to be the world’s most widely distributed psilocybin mushroom^[111] — is found in Europe, North America, Asia, South America, Australia and New Zealand, but is entirely absent from Mexico.^[109] Although the presence or absence of psilocybin is not of much use as a chemotaxonomical marker at the familial level or higher, it is used to classify taxa of lower taxonomic groups.^[112]

Psilocybin was first isolated from Psilocybe mexicana.

P. semilanceata is common in Europe, Canada, and the United States.

Both the caps and the stems contain the psychoactive compounds, although the caps consistently contain more. The spores of these mushrooms do not contain psilocybin or psilocin.^{[95][114][115]} The total potency varies greatly between species and even between specimens of a species collected or grown from the same strain.^[116] Because most psilocybin biosynthesis occurs early in the formation of fruit bodies or sclerotia, younger, smaller mushrooms tend to have a higher concentration of the drug than larger, mature mushrooms.^[117] In general, the psilocybin content of mushrooms is quite variable (ranging from almost nothing to 1.5% of the dry weight)^[118] and depends on species, strain, growth and drying conditions, and mushroom size.^[119] Cultivated mushrooms have less variability in psilocybin content than wild mushrooms.^[120] The drug is more stable in dried than fresh mushrooms; dried mushrooms retain their potency for months or even years,^[121] while mushrooms stored fresh for four weeks contain only traces of the original psilocybin.^[8]

The psilocybin contents of dried herbarium specimens of Psilocybe semilanceata in one study were shown to decrease with the increasing age of the sample: collections dated 11, 33, or 118 years old contained 0.84%, 0.67%, and 0.014% (all dry weight), respectively.^[122] Mature mycelia contain some psilocybin, while young mycelia (recently germinated from spores) lack appreciable amounts.^[123] Many species of mushrooms containing psilocybin also contain lesser amounts of the analog compounds baeocystin and norbaeocystin,^[124] chemicals thought to be biogenic precursors.^[125] Although most species of psilocybin-containing mushrooms bruise blue when handled or damaged due to the oxidization of phenolic compounds, this reaction is not a definitive method of identification or determining a mushroom’s potency.^[116][126]

History

Early

There is evidence to suggest that psychoactive mushrooms have been used by humans in religious ceremonies for thousands of years. Murals dated 9000 to 7000 BCE found in the Sahara desert in southeast Algeria depict horned beings dressed as dancers, clothed in garb decorated with geometrical designs, and holding mushroom-like objects. Parallel lines extend from the mushroom shapes to the center of the dancers’ heads.^[127] 6,000-year-old pictographs discovered near the Spanish town of Villar del Humo illustrate several mushrooms that have been tentatively identified as Psilocybe hispanica, a hallucinogenic species native to the area.^[128]

Archaeological artifacts from Mexico, as well as the so-called Mayan “mushroom stones” of Guatemala have also been interpreted by some scholars as evidence for ritual and ceremonial usage of psychoactive mushrooms in the Mayan and Aztec cultures of Mesoamerica.^[129] In Nahuatl, the language of the Aztecs, the mushrooms were called teonanácatl, or “God’s flesh”. Following the arrival of Spanish explorers to the New World in the 16th century, chroniclers reported the use of mushrooms by the natives for ceremonial and religious purposes. According to the Dominican friar Diego Durán in The History of the Indies of New Spain (published c. 1581), mushrooms were eaten in festivities conducted on the occasion of the accession to the throne of Aztec emperor Moctezuma II in 1502. The Franciscan friar Bernardino de Sahagúnwrote of witnessing mushroom usage in his Florentine Codex (published 1545–1590),^[130] and described how some merchants would celebrate upon returning from a successful business trip by consuming mushrooms to evoke revelatory visions.^[131] After the defeat of the Aztecs, the Spanish forbade traditional religious practices and rituals that they considered “pagan idolatry”, including ceremonial mushroom use. For the next four centuries, the Indians of Mesoamerica hid their use of entheogens from the Spanish authorities.^[132]

Although dozens of species of psychedelic mushrooms are found in Europe, there is little documented usage of these species in Old World history besides the use of Amanita muscaria among Siberian peoples.^[133][134] The few existing historical accounts about psilocybin mushrooms typically lack sufficient information to allow species identification, and usually refer to the nature of their effects. For example, Flemish botanist Carolus Clusius (1526–1609) described the bolond gomba (crazy mushroom), used in rural Hungary to prepare love potions. English botanist John Parkinson included details about a “foolish mushroom” in his 1640 herbal Theatricum Botanicum.^[135] The first reliably documented report of intoxication with Psilocybe semilanceata—Europe’s most common and widespread psychedelic mushroom—involved a British family in 1799, who prepared a meal with mushrooms they had picked in London’s Green Park.^[136]

Modern

American banker and amateur ethnomycologist R. Gordon Wasson and his wife Valentina studied the ritual use of psychoactive mushrooms by the native population in the Mazatecvillage Huautla de Jiménez. In 1957, Wasson described the psychedelic visions that he experienced during these rituals in “Seeking the Magic Mushroom“, an article published in the popular American weekly Life magazine.^[137] Later the same year they were accompanied on a follow-up expedition by French mycologist Roger Heim, who identified several of the mushrooms as Psilocybe species.^[138] Heim cultivated the mushrooms in France, and sent samples for analysis to Albert Hofmann, a chemist employed by the Swiss multinational pharmaceutical company Sandoz (now Novartis). Hofmann, who had in 1938 created LSD, led a research group that isolated and identified the psychoactive compounds from Psilocybe mexicana.^[139][140] Hofmann was aided in the discovery process by his willingness to ingest mushroom extracts to help verify the presence of the active compounds.^[131]He and his colleagues later synthesized a number of compounds chemically related to the naturally occurring psilocybin, to see how structural changes would affect psychoactivity. The new molecules differed from psilocybin in the position of the phosphoryl or hydroxyl group at the top of the indole ring, and in the numbers of methyl groups (CH₃) and other additional carbon chains.^[141]

Two diethyl analogs (containing two ethyl groups in place of the two methyl groups) of psilocybin and psilocin were synthesized by Hofmann: 4-phosphoryloxy-N,N-diethyltryptamine, called CEY-19, and 4-hydroxy-N,N-diethyltryptamine, called CZ-74. Because their physiological effects last only about three and a half hours (about half as long as psilocybin), they proved more manageable in European clinics using “psycholytic therapy“—a form of psychotherapy involving the controlled use of psychedelic drugs.^[141] Sandoz marketed and sold pure psilocybin under the name Indocybin to physicians and clinicians worldwide.^[142] There were no reports of serious complications when psilocybin was used in this way.^[1]

In the early 1960s, Harvard University became a testing ground for psilocybin, through the efforts of Timothy Leary and his associates Ralph Metzner and Richard Alpert (who later changed his name to Ram Dass). Leary obtained synthesized psilocybin from Hofmann through Sandoz pharmaceutical. Some studies, such as the Concord Prison Experiment, suggested promising results using psilocybin in clinical psychiatry.^[6][143] According to a 2008 review of safety guidelines in human hallucinogenic research, however, Leary and Alpert’s well-publicized termination from Harvard and later advocacy of hallucinogen use “further undermined an objective scientific approach to studying these compounds”.^[144] In response to concerns about the increase in unauthorized use of psychedelic drugs by the general public, psilocybin and other hallucinogenic drugs suffered negative press and faced increasingly restrictive laws. In the United States, laws were passed in 1966 that prohibited the production, trade, or ingestion of hallucinogenic drugs; Sandoz stopped producing LSD and psilocybin the same year.^[74] Further backlash against LSD usage swept psilocybin along with it into the Schedule I category of illicit drugs in 1970. Subsequent restrictions on the use of these drugs in human research made funding for such projects difficult to obtain, and scientists who worked with psychedelic drugs faced being “professionally marginalized”.^[145]

Despite the legal restrictions on psilocybin use, the 1970s witnessed the emergence of psilocybin as the “entheogen of choice”.^[146] This was due in large part to a wide dissemination of information on the topic, which included works such as those by author Carlos Castaneda, and several books that taught the technique of growing psilocybin mushrooms. One of the most popular of this latter group was published in 1976 under the pseudonyms O.T. Oss and O.N. Oeric by Jeremy Bigwood, Dennis J. McKenna, K. Harrison McKenna, and Terence McKenna, entitled Psilocybin: Magic Mushroom Grower’s Guide. Over 100,000 copies were sold by 1981.^[147] As ethnobiologist Jonathan Ott explains, “These authors adapted San Antonio’s technique (for producing edible mushrooms by casing mycelial cultures on a rye grain substrate; San Antonio 1971) to the production of Psilocybe [Stropharia] cubensis. The new technique involved the use of ordinary kitchen implements, and for the first time the layperson was able to produce a potent entheogen in his own home, without access to sophisticated technology, equipment or chemical supplies.”^[148]

Because of a lack of clarity about laws about psilocybin mushrooms, retailers in the late 1990s and early 2000s (decade) commercialized and marketed them in smartshops in the Netherlands and the UK, and online. Several websites^{[nb 6]} emerged that have contributed to the accessibility of information on description, use, effects and exchange of experiences among users. Since 2001, six EU countries have tightened their legislation on psilocybin mushrooms in response to concerns about their prevalence and increasing usage.^[41] In the 1990s, hallucinogens and their effects on human consciousness were again the subject of scientific study, particularly in Europe. Advances in neuropharmacology and neuropsychology, and the availability of brain imaging techniques have provided impetus for using drugs like psilocybin to probe the “neural underpinnings of psychotic symptom formation including ego disorders and hallucinations”.^[11] Recent studies in the United States have attracted attention from the popular press and thrust psilocybin back into the limelight.^[149][150]

Society and culture

Legal status

In the United States, psilocybin (and psilocin) were first subjected to federal regulation by the Drug Abuse Control Amendments of 1965, a product of a bill sponsored by Senator Thomas J. Dodd. The law—passed in July 1965 and effected on February 1, 1966—was an amendment to the federal Food, Drug and Cosmetic Act and was intended to regulate the unlicensed “possession, manufacture, or sale of depressant, stimulant and hallucinogenic drugs”.^[151] The statutes themselves, however, did not list the “hallucinogenic drugs” that were being regulated.^[151] Instead, the term “hallucinogenic drugs” was meant to refer to those substances believed to have a “hallucinogenic effect on the central nervous system”.^[151]

Despite the seemingly strict provisions of the law, many people were exempt from prosecution. The statutes “permit … people to possess such drugs so long as they were for the personal use of the possessor, [for] a member of his household, or for administration to an animal”.^[151] The federal law that specifically banned psilocybin and psilocin was enacted on October 24, 1968. The substances were said to have “a high potential for abuse”, “no currently accepted medical use,” and “a lack of accepted safety”.^[152] On October 27, 1970, both psilocybin and psilocin became classified as Schedule I drugs and were simultaneously labeled “hallucinogens” under a section of the Comprehensive Drug Abuse Prevention and Control Act known as the Controlled Substances Act.^[153] Schedule I drugs are illicit drugs that are claimed to have no known therapeutic benefit.

The United Nations Convention on Psychotropic Substances (adopted in 1971) requires its members to prohibit psilocybin, and parties to the treaty are required to restrict use of the drug to medical and scientific research under strictly controlled conditions. However, the mushrooms containing the drug were not specifically included in the convention, due largely to pressure from the Mexican government.^[154]

Most national drug laws have been amended to reflect the terms of the convention; examples include the UK Misuse of Drugs Act 1971, the US Psychotropic Substances Act of 1978,^[153] Australia Poisons Standard (October 2015),^[155] the Canadian Controlled Drugs and Substances Act of 1996,^[156] and the Japanese Narcotics and Psychotropics Control Law of 2002.^[157] The possession and use of psilocybin is prohibited under almost all circumstances, and often carries severe legal penalties.^[154]

Possession and use of psilocybin mushrooms, including the bluing species of Psilocybe, is therefore prohibited by extension. However, in many national, state, and provincial drug laws, there has been a great deal of ambiguity about the legal status of psilocybin mushrooms, as well as a strong element of selective enforcement in some places.^[120][158] Most US state courts have considered the mushroom a ‘container’ of the illicit drugs, and therefore illegal. A loophole further complicates the legal situation—the spores of psilocybin mushrooms do not contain the drugs, and are legal to possess in many areas. Jurisdictions that have specifically enacted or amended laws to criminalize the possession of psilocybin mushroom spores include Germany (since 1998),^{[157] <.span>and California, Georgia, and Idaho in the United St`tes. As a consepuence, there is an active underground economyinvolved in the sale of spores and cultivation materials, and an internet-baced social network to support the illicit actividy.[159]}

Usage

A 2009 national survey of drug use by the US Department of Health and Human Services concluded that the number of first-time psilocybin mushroom users in the United States was roughly equivalent to the number of first-time users of cannabis.^[154] In European countries, the lifetime prevalence estimates of psychedelic mushroom usage among young adults (15–34 years) range from 0.3% to 14.1%.^[160]

In modern Mexico, traditional ceremonial use survives among several indigenous groups, including the Nahuas, the Matlatzinca, the Totonacs, the Mazatecs, Mixes, Zapotecs, and the Chatino. Although hallucinogenic Psilocybe species are abundant in low-lying areas of Mexico, most ceremonial use takes places in mountainous areas of elevations greater than 1,500 meters (4,900 ft). Guzmán suggests this is a vestige of Spanish colonial influence from several hundred years earlier, when mushroom use was persecuted by the Catholic Church.^[161]

Research and potential for use in medicine

After a long interruption in the use of psilocybin in research, there has been a general shift in attitudes regarding research with hallucinogenic agents. Many countries are revising their positions and have started to approve studies to test the physiological and therapeutic effects of hallucinogens.^[13]

Psilocybin has been a subject of medical research since the early 1960s, when Leary and Alpert ran the Harvard Psilocybin Project, in which they carried out a number of experiments to evaluate the therapeutic value of psilocybin in the treatment of personality disorders, or to augment psychological counseling.^[162] In the 2000s (decade), there was a renewal of research concerning the use of psychedelic drugs for potential clinical applications, such as to address anxiety disorders, major depression, and various addictions.^[163][164] In 2008, the Johns Hopkins research team published guidelines for responsibly conducting medical research trials with psilocybin and other hallucinogens in humans. These included recommendations on how to screen potential study volunteers to exclude those with personal or family psychiatric histories that suggest a risk of adverse reactions to hallucinogens.^[144] A 2010 study on the short- and long-term subjective effects of psilocybin administration in clinical settings concluded that despite a small risk of acutereactions such as dysphoria, anxiety, or panic, “the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk”; the authors note, however, that the safety of the drug “cannot be generalized to situations in which psilocybin is used recreationally or administered under less controlled conditions.”^[11]

The first clinical study of psilocybin approved by the U.S. Food and Drug Administration (FDA) since 1970^[165]—led by Francisco Moreno at the University of Arizona and supported by the Heffter Research Institute and the Multidisciplinary Association for Psychedelic Studies—studied the effects of psilocybin on patients with obsessive–compulsive disorder(OCD). The pilot study found that, when administered by trained professionals in a medical setting, the use of psilocybin was associated with substantial reductions in OCD symptoms in several of the patients.^[166][167] This effect is caused largely by psilocybin’s ability to reduce the levels of the 5-HT_2A receptor, resulting in decreased responsiveness to serotonin.^[62]

The chemical structures of psilocybin and related analogs have been used in computational biology to help model the structure, function, and ligand-binding properties of the 5-HT_2CG-protein-coupled receptor.^[168][169]

PAPER

Concise Large-Scale Synthesis of Psilocin and Psilocybin, Principal Hallucinogenic Constituents of “Magic Mushroom”

SYNTHESIS

https://erowid.org/archive/rhodium/chemistry/psilocybin.html

http://www.ch.ic.ac.uk/ectoc/echet98/pub/039/index.htm

Notes

References

Cited literature[edit]

Psilocybin

Names
IUPAC name [3-(2-Dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate
Identifiers
CAS Number	520-52-5
3D model (JSmol)	Interactive image
Beilstein Reference	273158
ChEBI	CHEBI:8614
ChemSpider	10178
ECHA InfoCard	100.007.542
EC Number	208-294-4
KEGG	C07576
MeSH	Psilocybine
PubChem CID	10624
RTECS number	NM3150000
InChI[show]
SMILES[show]
Pharmacology
Dependence liability	Low
Routes of administration	Oral, intravenous
Pharmacokinetics:
Metabolism	Hepatic
Biological half-life	oral: 163±64 min intravenous: 74.1±19.6 min[1]
Excretion	Renal
Legal status	AU: S9 (Prohibited) CA: Schedule III UK: Class A US: Schedule I
Properties
Chemical formula	C12H17N2O4P
Molar mass	284.25 g·mol−1
Melting point	220–228 °C (428–442 °F)[2]
Solubility in water	soluble
Solubility	soluble in methanol slightly soluble in ethanol negligible in chloroform, benzene
Hazards
Lethal dose or concentration (LD, LC):
LD50 (median dose)	285 mg/kg (mouse, i.v.) 280 mg/kg (rat, i.v.) 12.5 mg/kg (rabbit, i.v.)[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).