’ Development Programs OTCQB:GBLX • Phytomedicine-based Drug Development • Extensive Research Network: multiple universities, hospitals & CROs • GBS’ Discovery Platform: unique APIs and IP • APIs: Synthetic homologues identical to plant compounds • Oral delivery formulations: ODT, OTF, nanoparticles, gel capsules • Parkinson’s Disease (PD): Patent issued; IND ready Q2 2022 • Neuropathic Pain (NP): Patent issued; Animal study at NRC Canada • Anti-Inflammatory (AI): Patent issued; Animal P of C ready • Cytokine Release Syndrome (CRS): Patent filed; P of C study at MSU Drug Development Pipeline Pre - IND CLINICAL TRIALS

First-in-Man/ Combined FDA Rx PROGRAMS DISCOVERY PRECLINICAL Phase III Phase I Phase I-II APPROVAL

Parkinson's Disease (PD)

Neuropathic Pain (NP)

Heart Failure (HF)

Cytokine Release KEY Syndrome (CRS)

Mast Cell Activation Completed Syndrome (MCAS) In-Process Inflammatory Bowel Disease (IBD) Drug Discovery Platform High Throughput Screening System HTS Disease-specific cell & animal models

In Silico Convergence Analysis ISCA Data Analytics & Machine Learning

Plant-inspired, Optimized Therapeutic Mixtures CTM Synthetic cannabinoid API & IP (comp and use) Intellectual Property Portfolio Strategy • Plant-Inspired, Optimized Therapeutic Mixtures • Novel API composed of natural or synthetic homologs of plant- derived ingredients • Composition of Matter and Field of Use Claims • Combinations of Novel API and Delivery • Current Portfolio (USPTO & WIPO/PCT) • 5 Issued US Patents & 3 Issued International Patents • 7 Nonprovisional US Patent Applications & 35 International Patent Applications • 3 Provisional US Patent Applications Parkinson’s Therapeutics Optimized Therapeutic Mixture (OTM) Development Mixtures More Effective Than Individual Ingredients

70 Individual Ingredients Complex Mixtures Complex Mixtures Complex Mixtures (no major plus CBD plus CBN cannabinoids) 60

50

KEY 40 Neuroprotection induced cytotoxicity cytotoxicity induced - Dopamine Secretion 30

20

10

% Protection from MPTP/MPP+ from Protection % release DOPA in Increase % 0 CBC CBD CBG CBN THC* THCA CBDV CBDA CBGA CCCM1 CCCM2 CCCM3 CCCM4 CCCM5 CCCM6 CCCM7 CCCM8 CCCM9 Geriniol Phytol A CCCM10 CCCM11 CCCM12 Myrcene b- Nerolidol Isopulegol Eucalyptol Camphene g-Terpinene a-Humulene CCCM1 +CCCM1 CBD +CCCM2 CBD +CCCM3 CBD +CCCM4 CBD +CCCM5 CBD +CCCM6 CBD +CCCM7 CBD +CCCM8 CBD +CCCM9 CBD CCCM1 +CCCM1 CBN +CCCM2 CBN +CCCM3 CBN +CCCM4 CBN +CCCM5 CBN +CCCM6 CBN +CCCM7 CBN +CCCM8 CBN +CCCM9 CBN B-carophylene CCCM10 +CCCM10 CBD +CCCM11 CBD +CCCM12 CBD CCCM10 +CCCM10 CBN +CCCM11 CBN +CCCM12 CBN Figure 1. Mixtures were more effective than Individual Ingredients in cell models of Parkinson’s disease Statistically Significant PD-Symptom Reduction Parkinson’s Animal Study—NRC Canada • Zebrafish model of Parkinson’s Disease-72 hr OHDA Exposure • Restored overall movement levels (measured based on total distance moved) • Normal startle response (Light/Dark) • Reduced “resting tremor”(measured frequency & duration of shifts in activity states) • Tested Multiple OTMs • Safety/Toxicology • Proof of Concept: Acute Symptomatic Relief • Mechanism of Action: Neurostimulatory, Neuroprotectant, Anti-Inflammatory • Animal Data to support IND application to US FDA and Health Canada Statistically Significant PD-Symptom Reduction Frequency of Switching & Duration of Activity State

A. Total Freq Avg B. High + Mod Cumul Avg C. 0 to 90min

200 25 10000 * control 20 control 8000 150 ** PD-like ** 15 6000 100 PD-like 10 PD-like 4000

50 (mm)Distance 5 2000

0 0 0

Drug Drug OHDA OHDA OHDA

CC MeOH CC MeOH Drug+OHDA Drug+OHDA 0.1uM+OHDA 0.5uM +O H D A 0.25uM+OHDA Figure 2. Statistically significant reduction in PD-like symptoms was achieved when 0.5 µM of OTM.PD119 was exposed to the PD-like animals (Drug + OHDA); Panel A. Total frequency of activity state switching; Panel B. % Time in the “ON” (or not low) Activity State, Panel C. Total distance traveled; * = t-test p < 0.05 for OHDA + Drug vs OHDA; ** = t-test p < 0.01 for OHDA + Drug vs OHDA PD Clinical: Orally Disintegrating Tablets (ODT) Zydis™ Orally Disintegrating Tablets (ODT) • Unique, freeze-dried oral solid dosage • Instant oral dispersion – typically less than 3 seconds OTM.PDXXX in Zydis™ ODT • Convenient dosing solution for PD patients • Greater than 50% of PD patients have swallowing problems Clinical Advantages • Improved bioavailability • Increased patient compliance Figure 3. Zydis™ Orally • Rapid onset through Buccal/Sublingual Absorption Disintegrating Tablets (ODT) Parkinson’s OTM Study Synopsis Name of Sponsor/Company: GB Sciences, Inc. Name(s) of Investigational Products: OTM.PD119, OTM.PD205, OTM.PD361 Title of Study: A Randomized, Double-Blinded, Cross-Over Study Designed to Evaluate the Safety and Preliminary Efficacy of OTM.PD119, OTM.PD205, GBS.PD361 in Mild to Moderate Parkinson's Disease (PD). Study Center(s): Two potential sites identified, pending further discussions. Study Type: Interventional Study Design: Allocation-Randomized; Interventional Model-Crossover Assignment; Masking-Double (Participant & Outcomes Assessor); Primary Purpose: Safety, Tolerability, and Preliminary Efficacy Total Duration of Study: For each subject, the duration of the treatment is 12 weeks (3 treatments x 4 weeks each). The estimated duration for the entire protocol is approximately 18 weeks based on a two-week run-in period and two, two-week wash out periods (TBD) between treatments. Phase of development: Phase 0/First-in-Man Parkinson’s OTM Study Synopsis Randomized to one of three study groups (1:1:1) • Group A (n = 8) • Group B (n = 8) • Group C (n = 8) Cross-over Design

Group Run-in Treatment 1 Wash-out Treatment 2 Wash-out Treatment 3

A placebo OTM.PD119 placebo OTM.PD205 placebo OTM.PD361

B placebo OTM.PD205 placebo OTM.PD361 placebo OTM.PD119

C placebo OTM.PD361 placebo OTM.PD119 placebo OTM.PD205

Weeks 1 & 2 3, 4, 5, 6 7 & 8 9, 10, 11, 12 13 & 14 15, 16, 17, 18 Neuropathic Pain OTM Proof of Concept: Extended-Relief Nanoparticles Esther Berrocoso, PhD, Raquel Rey-Brea, MS, Mercedes Fernández-Arévalo, PhD, Juan Antonio Micó, MD, PhD, Lucía Martín-Banderas, PhD. 2017. Single oral dose of cannabinoid derivate loaded PLGA nanocarriers relieves neuropathic pain for eleven days. Nanomedicine: Nanotechnology, Biology, and Medicine. 13 (2017) 2623-2632.

180 Cannabinoid-containing Nanoparticle Oral 170

Administration 160 Control (one dose) 150

140 Free Cannabinoids 130 Empty Nanoparticles 120

110 Cannabinoid Containing- 100 Nanoparticles

PAIN WITHDRAWAL THRESHOLD (G) THRESHOLD WITHDRAWAL PAIN 90 0 0.5 3 9 24 72 120 168 216 264 HOURS AFTER ORAL DOSAGE Figure 4. Single oral doses of cannabinoid-containing nanoparticles relieve pain for up to 11 days compared to less than 1 day of pain relief from free (unencapsulated) cannabinoids at the same dosage. The peak effectiveness of the free cannabinoids was between 0.5 and 9 hours; whereas, the cannabinoid-containing nanoparticles remained maximally effective between 1 and 9 days. Pain:TRP Channel Responses to Compounds Figure 5. NS veh Positive Control NS veh Strain mixture A. B. contribute significantly to 65 110 calcium fluxes via TRPV1 60 100 4) 4) induced by Cannabis- - 55 - equivalent mixtures relative 50 90 to the effects of the whole 45 HEK TRPV1 HEK wild type 80 strain, the cannabinoid RFU (Fluo 40 RFU (Fluo 70 mixture and a Capsaicin 35 control 30 60 0 20 40 60 80 100 120 0 30 60 90 120 150 180 C. Time (sec) D. Time (sec) Starkus, J., Jansen, C., Shimoda, L.M.N., NS veh Cannabinoids NS veh mixture 110 110 Stokes, A.J., Small-Howard, A.L., Turner, H. mixture (2019) Diverse TRPV1 responses to cannabinoids. Channels 13(1):172-191. 100 100

doi: 10.1080/19336950.2019.1619436. 4) 4) - 90 - 90

80 80 Jansen, C., Shimoda, L.M.N., Ang, L., Bacani,

A.J., Baker, J.D., Speck, M., Badowski, C., RFU (Fluo RFU (Fluo Stokes, A.J., Small-Howard, A.L., Turner, H. 70 70 (2019) Myrcene and Terpene Regulation of TRPV1. Channels 13(1):344-366. doi: 60 60 10.1080/19336950.2019.1654347 0 30 60 90 120 150 180 0 30 60 90 120 150 180 Time (sec) Time (sec) Pain: Myrcene dominant TRPV1 responses

Jansen, C., Shimoda, L.M.N., Ang, L., Bacani, A.J., Baker, J.D., Speck, M., Badowski, C., Stokes, A.J., Small-Howard, A.L., Turner, H. (2019) Myrcene and Terpene Regulation of TRPV1. Channels 13(1):344-366. doi: 10.1080/19336950.2019.1654347 Figure 6. Myrcene and Nerolidol ■All terpenes are the major contributors. 60 ■Matched vehicle Individual terpenes contribute ■Myrcene 50 differentially to terpene mixture- ■Nerolidiol ■Caryophyllene induced calcium responses. HEK- 40 ■Limonene TRPV1 were ■αBisabool

loaded with Fluo-4 and RFU - 4 30 ■Linalool population-based calcium assays ■Humulene Fluo 20 ■αPinene were conducted in the presence ■βPinene of 1mM external calcium. After a 10 ■Camphene matched vehicle exposure ■ (veh) period to establish a 0 baseline, cells were stimulated at 0 60 120 180 240 300 -10 20s with the indicated terpenes. Time (sec) Neuropathic Pain Strategy

Within a Conventional nocioceptive capsaicin pain sensory neuron therapy targets only bundle, different TRPV1 and leaves other neurons express neurons in the bundle multiple TRP untouched channels, so they are able to respond to different stimuli

Figure 7. In silico network pharmacology and wet lab experiments reveal that OTM.NP mixtures have the potential to target multiple receptors in the bundle to increase their net effectiveness. . Surface-Modified PLGA Nanoparticles

Figure 8. Schematic representing the encapsulation process for creating Poly-Lactic-co- Glycolic Acid (PLGA) Nanoparticles containing cannabinoids and/or .

El-Hammadi M, Small-Howard A, Fernández-Arévalo M, Martín-Banderas L. Development of enhanced drug delivery vehicles for three cannabis-based terpenes using poly(lactic-co-glycolic acid) based nanoparticles. Industrial Crops and Products. 2021:164. 113345. 10.1016/j.indcrop.2021.113345. Pain: Terpene-Encapsulated Nanoparticles

Addition of stimulant 1000

Figure 9. Encapsulated 800 Ionomycin terpenoids trigger larger calcium flux at TRPV1 than non- 600 Free myrcene encapsulated terpenoids. Fluorescence changes measured Free Nerolidol using Fluo-4 calcium signaling 400 Free Caryophyllene assay after treatment of RFU Myrcene NPs inducible HEK TRPV1 cells with 200 both free and encapsulated Nerolidol NPs terpenes. 0 Caryophyllene NPs 0 280 560 840 1120 1400 1680 1960 2240 2520 2800 3080 3360 3640 Time (sec) Synergy: Terpene-Encapsulated Nanoparticles

Addition of stimulant Addition of stimulant 1000 Figure 10. Synergies are 1000 revealed between 800 800 B. 600 encapsulated NPs. 600 A. 400 Calcium responses of 400 RFU

RFU 200 individual terpenes NPs 200 0

in comparison with their 0 0 0 200 400 600 800 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 corresponding 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 Time (sec) combinations. A: Time (sec) Myrcene NPs Nerolidol NPs Myrcene NPs Caryo. NPs Myrcene+Caryo. NPs Myrcene NPs, nerolidol Myrcene+Nerolidol NPs

NPs, and their Addition of stimulant Addition of stimulant 1000 1000 combination; B: Myrcene 800 800 NPs, caryophyllene NPs, C. D. 600 600 and their combination; C: 400 400 RFU

Nerolidol NPs, RFU 200 caryophyllene NPs, and 200 0 0 0 0

their combination; D: NPs 200 400 600 800 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 of the three terpenes, Time (sec) Time (sec) Myrcene+Nerolidol NPs Myrcene+Caryo. NPs and their combination. Nerolidol NPs Caryo. NPs Nerolidol+Caryo. NPs Nerolidol+Caryo. NPs Myr.+Nero.+Caryo. NPs In Vivo: Terpene-Encapsulated Nanoparticles Ellis, L.D., Berrue, F., Morash, M., Achenbach, J.C., Hill, J., McDougall, J.J. (2018) Comparison of cannabinoids with known analgesics using a novel high throughput zebrafish larval model of nociception. Behavioral Brain Research 337:151-159. Neuropathic Pain NP o Testing Single Compounds • Within nanoparticles • Non-encapsulated o Testing Complex Mixtures • Danio rerio • Within nanoparticles • High throughput screening • Non-encapsulated • Hundreds of larvae per female o 2 zebrafish nociceptive models 200 • Place preference 150 • Nociception • Light Phase

100

• Body patterning established by 5dpf (mm) Distance 50 • Dark periods

0 59 Time (m) 119 • Stimulus induced behavioral responses : Key Milestones Highlights from 2020

Parkinson’s disease US Patent Issued OTM.PD119, OTM.PD205, Statistically-significant reduction of OTM.PD361 Parkinsonian movement in animal model Neuropathic pain US Patent Issued OTM.NP110, OTM.NP121, Promising Preclinical Results in Midterm OTM.NP139 Research Report Mast Cell Activation Syndrome US Patent Issued OTM.MC122, OTM.MC128 Rare disease, Regulatory Advantages Cytokine Release Syndrome US Patent Application Filed Multiple OTM.MCAS Preclinical Proof-of-Concept Studies PhAROS™ Drug Discovery Platform Phytomedical Analytics for Research Optimization at Scale

Science Gateway & Virtual Research Environment for Drug Discovery o Transformative data integration, analytic methods, & visualization tools for the meta- analysis of non-Western medical knowledge systems o In Silico Convergence Analysis o Pre-validates efficacy o Drug-target-indication relationships o US patent application filed Oct 16, 2020

Jansen C, Baker JD, Kodaira E, Ang L, Bacani AJ, Aldan JT, Shimoda LMN, Salameh M, Small- Howard AL, Stokes AJ, Turner H, Adra CN. Medicine in motion: Opportunities, challenges and data analytics-based solutions for traditional medicine integration into western medical practice. J Ethnopharmacol. 2021 Mar 1;267:113477. doi: 10.1016/j.jep.2020.113477. Epub 2020 Oct 21. PMID: 33098971; PMCID: PMC7577282. Research & Development Partners SUMMARY

• Novel drugs for unmet clinical needs & major markets • Proprietary discovery engine: plant-inspired, optimized therapeutic mixtures (OTM) • Active ingredients = synthetic copies of plant compounds • First drug expected to enter clinic Q3 2022 • Four drugs in preclinical phase • Experienced team, lean operations, outsourcing strategy Contact Information Andrea Small-Howard, Ph.D., M.B.A. Chief Science Officer & Director

GB Sciences, Inc. 3550 West Teco Avenue Las Vegas, Nevada 89118 www.gbsciences.com [email protected]

Michael Farley, Ph.D. President & Director

GBS Global Biopharma Inc. 200-900 Morrison Drive Ottawa, Ontario, CANADA K2H 8K7 www.gbsglobalbiopharma.com [email protected]