This lecture gives an overview of the state of the cannabis science, the North American markets and our cannabis research.
Bridging the gap between analytical chemistry, machine learning, and synthetic chemistry, this compilation of studies explores the multifaceted nature of cannabis compounds. We begin with advancements in extraction techniques, utilizing machine learning to optimize yield predictions in large-scale botanical recovery, specifically focusing on cannabis. This approach significantly enhances the efficiency and precision of extraction processes. We then transitions to molecular analysis, examining the stability and transformation of CBD derivatives, highlighting the need for robust quality control in product development. Additionally, the lecture addresses the critical aspect of safety in cannabis use by exploring innovative strategies for heavy metal testing, demonstrating how pooling methods can reduce testing resources while maintaining safety standards. The lecture will answer the question of how to build the best joint, the implications of joint architecture on cannabis consumption, offering insights into optimizing product efficacy and consumer experience.
Overall, this lecture encapsulates the collaborative efforts between academia and innovative research, providing a comprehensive understanding of the complexities and potential of cannabis chemistry.
2. • Who is Markus Roggen?
• What is Cannabis, Weed, Marijuana, the Devil’s Lettuce?
• Why Research; Fundamental and Applied?
From Leaf to Lab
3. • Imperial College (IC), London, UK
• M/Sci in chemistry, minors in mathematics and finance (Dr. Chris Braddock)
• Chemometrics & Sugars to Synthetic Building Blocks
• Federal Institute of Technology (ETH), Zürich, CH
• PhD in organic chemistry (Prof. Dr. Erick Carreira)
• Iridium-Catalyzed Allylic Substitution
• The Scripps Research Institute (TSRI), San Diego, USA
• Postdoc in physical organic chemistry (Prof. Dr. Donna Blackmond)
• Enantioselective Organocatalytic Selenylation
Academic Background
4. • CSO of analytical laboratory
• DaVinci Laboratory of California, San Luis Obispo, CA, USA
• Built an analytical testing laboratory from scratch, in an ever-changing cannabis
regulation environment
• VP of extraction and production operation
• OutCo, San Diego, CA, USA
• Built an extraction facility from scratch, R&D of methods and products
• Founder/CEO/CSO of R&D laboratory
• CBDV / Delic Labs / Controlled Chemistry, Vancouver, BC, Canada
• Cannabis R&D as CRO for international companies
• Built from scratch, sold to Delic, bought back assets, setting up again…
• Public-private partnership for cannabis research funding
Cannabis Industry Background
5. Research Genealogy
Sajni Shah
Kendra Payne
Dr. Tom Dupree
Dr. Eric Janusson
Dr. Duane Hean
Sean Ryan
Gursaanj Bajaj
Luiz Geraldo
Callum MacPhee
Klara Wyse
Bofeng Cheng
Rachel de Souza
Seth Hinz
Ziqing (Stella) Zhu
Katie O’Connell
Soheil Nasseri
Matthew Ke
Rehmanali Jiwani
Nat Juthaprachakul
Vanessa Clarke
Denys Dzuibii
Duo Lu
Wesley Sequeira
Hank Chen
Ali Wasti
Amanda Assen
Dingding Xuan
Tim Sun
Thomas Ford
Prof. Sammis
Prof. Reid
Prof. Huan
Prof. Kennepohl
Prof. Bizzoto
Brodie Thomson
Will Chappell
Joey Lai
Paul Foth
Isaiah O. Betinol
Pirouz Kiani
Weiying He
Alyssa Hui
UBC
CBDV/Delic
Markus Roggen
Imperial College
Dr. Chris Braddock
ETH Zürich
Prof. Erick Carreira
Scripps Research
Prof. Donna Blackmond
LinkedIn
8. Cannabis History
1611
Jamestown
settlers bring
cannabis to
North America
1911
Massachusetts
becomes the
first state to
outlaw cannabis
1970s
Substance Control
Act classifies
Cannabis as
Schedule I
2000s
>7 million
arrests for
cannabis
possession in
USA
1996
California
legalize
medical
marijuana
2018
Canada
legalizes
recreational
cannabis
2018
USA Farm Bill
legalizes hemp
(<0.5%wt. THC)
1500 BC
Earliest written
reference to
medical
cannabis in
the Chinese
pharmacopeia
700 BC
Medical use of
cannabis in the
Middle East
recorded in the
Venidad
10. Cannabis Business
• Sales are mixed, established markets are declining, new markets see
steady growth
• Many companies struggle to achieve profitability, large layoffs and
downsizing
• Industry is challenged by the illicit market and regulations
Size of Global Cannabis Industry: $51bil
Size of USA Cannabis Industry: $34bil
Year over Year Growth: 13%
Legal vs. Illicit (CAN): 33% illegal
Gaming cosmetics $50bil
YouTube Ad Rev. $29bil
YoY growth California: 3%
Illicit markets: 12% tobacco / 26% alcohol
11. Cannabis as Medicine
• Chronic pain and spasticity: moderate-quality evidence
• Nausea and vomiting due to chemotherapy: low-quality
• Sleep disorders: low-quality evidence
• Anti-cancer: no evidence
• Cancer-causing: no evidence
• Deadly overdose: no evidence
Time to intoxication:
• Inhalation: seconds to minutes
• Ingestion: 0.5 to 2 hours
DOI:10.1001/jama.2015.6358; DOI: 10.17226/24625
12. • Discovery of CBN in 1940 by Robert S. Cahn
• Isolation of CBD and THC in 1942 by Robert Adams
• Rediscovered & corrected in 1964 by Raphael Mechoulam
• Why did it take so long:
• Cannabinoids are not alkaloids!
Cannabis Chemistry
R. Adams, Bull. N. York Acad. Med. 1942, 18, 705–30.
13. Cannabis Biochemistry
• 1988 to 1993: Identification of cannabinoid binding sites CB1 and CB2
receptor
• CB1 found in brain, peripheral neurons, adipocytes, hepatocytes, etc.
• CB2 found in immune cells (B lymphocytes, macrophages)
DOI: 10.1016/j.cell.2016.10.004
14. Cannabis Biochemistry
• 1992 to 1997: Identification of anandamide and 2-AG as
neurotransmitters
• Work spearheaded by Mechoulam
Anandamide
From Sanskrit ”ananda” for Joy, Bliss
2-Arachidonoylglycerol
Present in relatively high levels
25. Rapture’s Quadrant
Fundamental
Knowledge
Immediate Application
Framework spans curiosity-driven
to application-focused research
• Fundamental research without
immediate practical use
• Applied research for new
technologies, not fundamental
understanding
• Applied Fundamental:
Knowledge pursuit with specific
practical applications
Tinkering
27. Why Is THCA Decarboxylation
Faster than CBDA? An in silico
Perspective.
He, W.; Foth, P. J.; Roggen, M.; Sammis, G. M.; Kennepohl, P.
https://doi.org/10.26434/chemrxiv.12909887.
Fundamental
Research
28. Decarboxylation Theory
• An integral step in cannabis production
• The plant produces cannabinoid acids
• The consumer wants neutral cannabinoids
THCA
Produced by plant
THC
Makes you high
29. Decarboxylation Observation (Question Time!)
Not all decarboxylations are equal
0
20
40
60
80
100
0 5 10 15 20 25 30 35 40 45
Decarb
%
Minutes
Decarboxylation at 110˚C
CBDA/CBD
THCA/THC
THCA THC
CBDA CBD
30. Computational Studies (Question Time!)
Steric vs. Electronic: Exploring the rate difference in THCA and CBDA
decarboxylation
32. Computational Studies
Key Findings:
• Rate determining step is the
intermolecular protonation
• Rate difference is due to steric rather
than electronic effects
33. CBD Hydroxyquinone
Photo-Isomerises to a Highly
Reactive Intermediate.
Thomson, B.J., Hanna, S., Schwarzenberg, A., Kiani, P., Bizzotto, D.,
Kennepohl, P., Davies, A., Roggen, M., & Sammis, G.M.
(2023) Sci. Rep. 13, 6967.
Fundamental
Research
35. The Purple Problem
• CBD vape cartridges turn purple
• Reddit knows, peer reviewed does not
• Beam Test identifies cannabis (presence of CBD or CBG)
• Beam, W. Fourth Report of Wellcome Tropical Research
Laboratories, part B. Khartoum, 1911; pp 25
• DOI: 10.1016/0040-4020(68)88159-1
Purple Colour
36. When and Why does CBD turn purple?
CBD degrades 20% in 30 days at 37°C
15% CBD degradation in 30 days
Stabile CBD storage at pH 4-6
Light
Heat
Acid / Base
DOI: 10.1038/s41598-020-60477-6; DOI: 10.1089/can.2021.0004 36
38. Isolation of HU-331 and its Anion
1H NMR (300 MHz, DMSO-d6)
1H NMR (300 MHz, DMSO-d6)
39. Computational Investigation of Absorption
• TD-DFT-calculations of visible light
absorption of HU-331 and its anion
• Why are there anions in neutral solutions?
43. Everything is Possible!
• Photoexcitation of
hydroxyquinones
• Hydroxyquinol 5:
unstable in air
• 5 quickly degrades to
host of new quinones
• O2
- and H2O2 as by-
products, which start
more degradation
44. • What about toxicology?
• What are the pathways for other cannabinoids?
• Tobacco companies need more stability data!
Everything is Possible!
47. Fast, Easy, and Reliable Monitoring of
THCA and CBDA Decarboxylation in
Cannabis Flower and Oil Samples
Using Infrared Spectroscopy
Shah, S., Wasti, A., Kozadjian, G., Cabral, J.-L., Wang, Y., & Roggen, M.
Agilent White Paper
Applied
Research
48. • Important in most cannabis processing
• There is no standard method
Decarboxylation Control
Before extraction
Biomass
After extraction
Oils
49. Problems with excessive heat:
• Instrument time
• High costs
• Side reactions and degradation
• Low yield
Don‘t Decarboxylate too Long
0
10
20
30
40
50
60
70
80
0
0.5
1
1.5
2
2.5
3
3.5
0 1000 2000 3000 4000 5000 6000
THC
THC
(%)
CBN
&
d8-THC
(%)
d8-THC
CBN
Elapsed Time (Minutes)
50. In-situ tracking via FTRI
50
Oil Decarb Ratio
THCA to THC
Y-axis: IR Prediction
X-axis: HPLC Concentration
Biomass Decarb Ratio
CBDA to CBD
• Small sample
• Fast and cheap
• Easy to use
51. Simulations of Test Reduction
Using Pooled Heavy Metals
Analysis in Cannabis.
Dupree, T.B., Assen, A.D., Janusson, E., Wise, A.R., Swider, J.M., & Roggen, M.
(2022) J. AOAC Int. 106, 484–489.
Applied
Research
52. The Problem of Compliant Testing
Heavy Metal Conundrum:
• Cannabis bioaccumulates heavy metals
• Extractor suffers from contaminated raw material
• Heavy metal testing is mandated
• Failed batches are expensive
• How to reduce product failure?
53. The Problem of Compliant Testing
Heavy Metal Conundrum:
• Late detection = loss / cross-contamination
• Test early / often = $$$
• How testing costs low for producers?
• And still make a profit as a testing lab?
54. Qualitative Pooled Testing
• How to test large number of people for a new virus?
• 133,816 patient samples / ~30,000 tests
• 20x more test for same budget
55. Quantitative Pooled Testing
DOI: 10.1097/QAI.0b013e3181ba37a7
• Pooling used to reduce costs of polymerase chain
reaction-based screening for acute HIV infection
• Variety of pooling strategies for prevalence of HIV
1% - 25%
56. Project Goals
• Save costs
• Increase product safety
• Reduce strain on the industry
• Increase sample throughput in cannabis testing labs
• Demonstrate that pooling strategies works
67. Pooled Testing Conclusion
Outcomes
• 3 sample pool = 23.8% fewer tests (WA)
• 4 sample pool = 54.1% fewer tests (CA)
• Developed case-by-case to reduce time, effort, cost
68. What is Next for Cannabis Analysis?
DOI: 10.1186/s42238-021-00064-2
Reported %THC value from commerical laboratories
• THC %wt. is the only
important metric
• So much more
research potential
70. Extraction Yield Prediction for
the Large-Scale Recovery of
Cannabinoids.
Plommer, H., Betinol, I.O., Dupree, T., Roggen, M., & Reid, J.P.
(2024) Digit. Discov. 3 155-162.
Applied
Fundamental
71. Extracting Cannabis
• Cannabis companies are not doing well:
• Cumulative private-sector losses exceed C$16 bil.
• Operating cannabis extraction is costly
• Cannabis oil prices are falling
CAN
Cannabis
USA
Cannabis CPG Pharma
Avg. Cost
Margin
68% 51% 30% 26%
72. Extracting Cannabis
• Researched cannabis extraction since 2016
• Design of Experiment
• Solvent Kinetics and Thermodynamics
• Consulting for many producers
• Piecemeal solutions: slow, costly, not translatable
• How can extraction optimization be generalised?
• Unique extraction database
• Different instruments
• Variety of cultivars
• Various process conditions
• Yields of cannabinoids
• Amplifying a single large-scale experiment to predict outcomes of untested
conditions
73. Extracting Cannabis with Machine Learning
Random Forest ML
• Ensemble Learning Method
• Handles Various Data Types
• Feature Randomness
• Bagging Technique
• Automatic Feature
Selection
74. Extracting Cannabis with Machine Learning
Random Forest ML
• Ensemble Learning Method
• Handles Various Data Types
• Feature Randomness
• Bagging Technique
• Automatic Feature
Selection
75. Extracting Cannabis: AI + Manual Work
• Harmonizing information from different individual reports
• Multiple result types to increase information density
76. Extracting Cannabis: AI + Manual Work
• Harmonizing information from different individual reports
• Multiple result types to increase information density
• Brute force translation of producer data into database
• Cannabis extractions are also reactions: input ≠ output
77. AI for Extraction
• No extra experiments or costs
• Multi-Factor optimization solution
• Extraction Improvements
• Yield: +10%
• Throughput: +100%
• Quality: improved
• Waste: -50%
78. What is Next for Extraction AI?
• More data and systems
• LLM?
81. Does Size Matter for Performance? A
Study of How Particle Size Influences
Joint Smoking
Sun, T., Plommer, H., Shah, S., & Roggen, M. (2023)
Cann. Sci. Tech.
Applied
Fundamental
85. Aerosol Sample Collection
• Using a Smoke Cycle Simulator
• Aerosols from three puffs collected on glass microfiber filters
• Volatile compounds, i.e. terpenes and toxicants caught in impinger
86. Quantitative Sample Analysis
• Full decarboxylation observed
• Smoke temperature: 44˚C
• THC b.p.: 157˚C at 0.05mmHg
• Myrcene b.p.: 167˚C at 1 atm
• Humulene b.p.: 106˚C at 5 mmHg
87. Experimental Setup
• Pre-Rolls various particle sizes (1- and 5-mm)
• Pre-rolls infused with kief and/or oil
• Analysis for cannabinoids and terpenes
88. 0
10
20
30
40
50
60
70
First 1/3 Second 1/3 Third 1/3
THC
(mg/g)
THC by Puff Position
Inconsistent THC Delivery
• THC inhalation builds throughout consumption
• Highest delivery at end of a joint’s lifecycle
DOI: 10.1089/can.2023.0123
1/3 2/3 3/3
89. Effect of Particle Size on THC Delivery
• Fine grind: More THC per puff
• Coarse grind: More THC per Pre-Roll
• Highest delivery at end of a joint’s lifecycle
0
10
20
30
40
50
60
THC/puff (mg*20) THC/joint (mg) Puff count
THC 1-mm THC 5-mm
90. Infused: Same but Different
• Infused Pre-Rolls deliver
• More THC (~3x)
0
200
400
600
800
1000
1 g Regular Pre-
Rolls
1 g Kief Coated Pre-
Rolls
1 g Distillate
Infused Pre-Rolls
THC
(µg/mL)
THC per Pre-Roll
91. Infused: Same but Different
• Infused Pre-Rolls deliver
• More THC (~3x)
• But not on a per-puff basis!
0
1
2
3
4
5
6
7
1 g Regular Pre-Rolls 1 g Kief Coated Pre-
Rolls
1 g Distillate Infused
Pre-Rolls
THC
(µg/mL)
THC per Puff
92. Infused: Same but Different
Infused Pre-Rolls deliver
• More THC (~3x)
• More Terpenes (>4x)
• More flavor
• Different flavor
0
500
1000
1500
2000
2500
3000
3500
4000
4500
1 g Regular Pre-
Rolls
1 g Kief Coated
Pre-Rolls
1 g Distillate
Infused Pre-
Rolls
Terpenes
(µg)
Menthol
(+)-Valencene
α-Humulene
(-)-trans-Caryophyllene
Terpineol (mixture of isomers)
(1R)-endo-(+)-Fenchyl alcohol
(+)-Linalool
(R)-(+)-Limonene
β-myrcene
β-Pinene
Camphene
Sabinene
0
500
1000
1500
2000
2500
3000
3500
4000
4500
1 g Regular Pre-
Rolls
1 g Kief Coated
Pre-Rolls
1 g Distillate
Infused Pre-
Rolls
Terpenes
(µg)
Men
(+)-V
α-Hu
(-)-tr
Terp
(1R)-
(+)-L
(R)-(
β-my
β-Pin
Cam
Sabin
0
500
1000
1500
2000
2500
3000
3500
4000
4500
1 g Regular Pre-
Rolls
1 g Kief Coated
Pre-Rolls
1 g Distillate
Infused Pre-
Rolls
Terpenes
(µg)
0
500
1000
1500
2000
2500
3000
3500
4000
4500
1 g Regular Pre-
Rolls
1 g Kief Coated
Pre-Rolls
1 g Distillate
Infused Pre-
Rolls
Terpenes
(µg)
Menthol
(+)-Valencene
α-Humulene
(-)-trans-Caryophyl
Terpineol (mixture
(1R)-endo-(+)-Fenc
(+)-Linalool
(R)-(+)-Limonene
β-myrcene
β-Pinene
Camphene
Sabinene
93. 0
100
200
300
400
500
600
700
800
900
1000
1 g Regular Pre-Rolls 1 g Kief Coated Pre-
Rolls
1 g Distillate Infused
Pre-Rolls
Toxicants
(μg)
Average Toxicants by Test Group
Benzaldehyde
Phenol
Benzonitrile
Infused: Toxicants, Watch Out!
• Infused Pre-Rolls deliver
• More THC (~3x)
• More Terpenes (>4x)
• More flavor
• More Toxicants!!!
94. Want a Sequel to Our Smoky Saga?
• Real-life inhalation profile
• Spliffs: Mixing cannabis with tobacco is a potent mix!?
• Cultivation: Effects on cannabis smoke composition
• What about vape cartridges? And dabs?
95. Summary
• Cannabis is a chaotic industry
• Cannabis can, maybe, help medicinally
• Cannabis can do a lot, but we don’t know why
• There is a lot of chemistry left to discover and research
- Process analysis
- Reaction mechanism
- Decomposition of cannabinoids
- Chemistry of consumption
96. Cannabis Accolades are Different
Academic:
• Scholarship of the Swiss Chemical Industry
• German DAAD Scholarship
Cannabis:
• ElSohly Award by ACS
• 40 under 40 by Marijuana Venture
• The Cannabis Scientist Power List, three years running
97. Cannabis Accolades are Different
Academic:
• Scholarship of the Swiss Chemical Industry
• German DAAD Scholarship
Cannabis:
• 40 under 40 by Marijuana Venture
• ElSohly Award, ACS
• The Cannabis Scientist Power List, three years running
98. Cannabis Accolades are Different
Academic:
• Scholarship of the Swiss Chemical Industry
• German DAAD Scholarship
Cannabis:
• 40 under 40 by Marijuana Venture
• ElSohly Award, ACS
• The Cannabis Scientist Power List, three years running
99. Thank you very much!
Questions?
Dr. Markus Roggen
markus@complexbiotech.com