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Pre-clinical Studies to Determine Safety
Conclusion and Direction
5-MeO-DMT Research Interest
5-MeO-DMT vs. Psilocybin (psilocin)
CLINICAL CONSIDERATION OF 5-MeO-DMT
Alexander M. Sherwood,1Kristi W. Kaylo,1Robert B. Kargbo,1Alan K. Davis,2Rafael L. Lancelotta,3Malin V. Uthaug,4Robert B. Barrow1
1 Medicinal Chemistry, Usona Institute, Madison, WI
2Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD
3Innate Path, Lakewood, CO
4Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
DESIGN
BACKGROUND
REFERENCES
PLAN
ACKNOWLEDGEMENTS
1. Davis, A. K.; Barsuglia, J. P.; Lancelotta, R.; Grant, R. M.; Renn, E. J Psychopharmaco. 2018, 1-14.
2. Ray, T. S. PLoS ONE. 2010, 5, e9019
3. Dakic, V.; Nascimento, J. M.; Sartore, R. C.; de Moraes Maciel, R.; de Araujo, D. B.; Ribeiro, S.; Martins-de-Souza, D.;
Rehen, S. K. Sci Rep. 2017, 7, 12863.
4. Szabo, A.; Kovacs, A.; Frecska, E.; Rajnavolgyi, E. PloS ONE. 2014, 9, e106533.
5. Barsuglia, J.; Davis, A. K.; Palmer, R.; Lancelotta, R.; Windham-Herman, A. M.; Peterson, K.; Polanco, M.; Grant, R.;
Griffiths, R. R. Front Psychol. 2018, 9, 2459.
6. Uthaug, M. V.; Lancelotta, R.; van Oorsouw, K.; Kuypers, K. P. C.; Mason, N.; Rak, J.; Šuláková, A.; Jurok, R.; Maryška,
M.; Kuchař, M.; Páleníček, T.; Riba, J.; Ramaekers, J. G. Psychopharmaco. 2019, 1-14.
▪Potent Naturally Occurring Psychoactive Alkaloid
▪Potential to induce acute and profound altered consciousness1
▪Found in parotid gland secretions of Incilius alvarius
▪Present in virola resin, peregrina seeds, Dictyoloma incanescens
▪5-MeO-DMT-containing snuff used as an entheogen by
indigenous South American peoples for centuries
▪Mechanism of Action Not Well Described
▪Interacts with many CNS receptors (polypharmacology)
▪Uniquely selective for 5-HT1A receptor subtype2
▪Potentially active metabolite (bufotenine)
▪Promotes neurogenesis and reduces inflammation in vitro3,4
▪Subjectively Unique Psychedelic
▪Short duration, typically less than 1h; poor oral bioavailability
▪Reported to induce a unique state of altered consciousness and
awareness which may support a number of potential therapeutic
utilities.5,6
Initiating 5-MeO-DMT Clinical Study
“First-in-Man” Clinical Study Approach
5-MeO-DMT has unique pharmacology and a
history of anecdotal human use suggesting
potential psychotherapeutic utility. To
empirically determine measures of safety and
efficacy, controlled studies to support human
clinical trials are necessary.
FDA Investigational New Drug (IND) Application Enabling Activities
Synthetic Design
Figure 2: 5-MeO-DMT synthesis by Fischer Indole route
Clinical trials to evaluate the therapeutic efficacy of psilocybin are
currently underway. Despite similarity in structure, several key
differences distinguish 5-MeO-DMT from psilocybin (or its active
metabolite psilocin).
A
B
Figure 1 A) Approximate subjective experience time course for 5-MeO-DMT (red) versus psilocybin (blue). B)
Normalized CNS receptor binding affinity profile for 5-MeO-DMT (top) versus psilocin (bottom).2
▪Drug-related
✓Identify Scalable Synthetic Route
✓Develop Analytical Methods
✓Fully Characterize Compound
✓Identify Route of Administration and
Formulation
▪Preclinical Studies
▪Toxicology
▪Safety Pharmacology
▪Genotoxicity
▪Primary / Secondary Pharmacodynamics
▪ADME / Drug-drug Interactions
Route of Administration Selection
Route / Dosage Form Pros Cons
Intramuscular Injection
•Avoid first pass metabolism
•High bioavailability
•Precise control of dosage
•Gentle onset, slightly longer duration of effects
•Additional burden on manufacturing sterile product
Intravenous Injection •Avoid first pass metabolism
•Complete bioavailability
•Precise control of dosage
•Additional burden on manufacturing sterile product
•Very rapid onset
•High dose-sensitivity
Metered Dose Inhalation •Favorable route for patient acceptance
•Ease of administration
•Avoid first pass metabolism
•Similar route / exposure compared to anecdotal use
•More complex drug delivery systems
•Very rapid onset
•Challenging to control dosage
Dry Powder Inhalation
Buccal / Sublingual •Ease of administration
•Avoid first pass metabolism •Intrinsic dose/absorption limits
•Absorption may not be rapid enough
Oral •Ease of administration
•Ease of formulation
•First pass metabolism –5-MeO-DMT not orally
active
•Elongated PK curve
Figure 3: UPLC chromatogram and high-purity 5-MeO-DMT crystal
5-MeO-DMT
99.8% purity
5-MeO-DMT is subject to rapid first-pass metabolism by monoamine oxidase and is not orally active.
The most commonly reported route of administration is by vaporization of the freebase drug, which is
not a pharmaceutically acceptable approach. An intramuscular injection of 5-MeO-DMT has been
identified as the most preferable dosage form.
Toxicology •Safe Dose (animal)
Safety
Pharmacology
•Respiratory
•CNS
•hERG
•ECG/CV
Genotoxicity
•LeadScope/DEREK
•Ames
•Micronucleus
•Chromosomal aberration
Primary PD •Target binding/affinity
Secondary PD •Off-target binding
Absorption,
Distribution,
Metabolism,
Excretion
(ADME)
•Plasma protein binding
•Blood partitioning
•Pharmacokinetic Study
•Transporter substrate
•Hepatocyte met ID
Drug-Drug
Interactions (DDI)
•CYP induction
•CYP inhibition
•Transporter inhibition
Patient Population Experienced psychedelic users
Objectives
1. Determine the human safety of 5-MeO-DMT
2. Determine the human PK & metabolic profile of 5-MeO-DMT
3. Determine the mystical experience occasioned by 5-MeO-DMT
4. Determine the 5HT receptor binding of 5-MeO-DMT
Safety Physical Examination, Vital Signs, Labs (CBC, CMP, Urinalysis), UPT,
Holter ECG
Pharmacokinetics Serial blood and urine sampling
PD-biomarker 5-HT1A and/or 5HT2A PET imaging
Pharmacodynamic
Activity
PROs: Hallucinogen Rating Scale, revised 5-Dimension Altered States
of Consciousness questionnaire, Mystical Experience Questionnaire,
Challenging Experiences Questionnaire, and Psychological Insight
Questionnaire.
Investigator-Completed: Brief Psychiatric Rating Scale, the Scale for
Assessment of Negative Symptoms, Scale for Assessment of Positive
Symptoms
Doses tbd
Controls Randomized (5:1), Double-Blind
▪5-MeO-DMT may hold potential as a novel psychotherapeutic tool
▪Initiation of human clinical trials with 5-MeO-DMT will require a multi-pronged effort to:
1) Provide consistent high-quality cGMP 5-MeO-DMT
2) Formulate 5-MeO-DMT appropriately for intramuscular injection
3) Conduct preclinical experiments to rigorously ensure patient safety
4) Effectively design the clinical program to assess safety, PK/PD and clinical activity
To all of the Shamans, Therapists, Psychonauts, and Scientists advancing the field.