(1) How is Sana Therapeutics ’s oil characterized as Full Spectrum, despite lacking in THC?

The full classes spectrum THC-free hemp oil by Sana Therapeutics consists of predominantly these chemical

• Cannabidiol (CBD), and other trace cannabinoids
• 30+ terpenes, including, β-Bisabolene, β-Farnesene, Guaiol, β-Maaliene, Calarene, β- Caryophyllene, α-Humulene, Cadinene, α-Gurjunene, d-Limonene, Nerolidol, α-Pinene, Aristolene, Eucalyptol, Camphene, β-Farnesene, Farnesol, α-Bisabolol, P-Cymene, Linalool, Myrcene, Phytol, Isopulegol, Terpinene, Geraniol, Myrcene, γ-Terpinene, δ-3-Carene Flavanoids
• Anti-oxidants
• Fatty acids and glycerides
• Omega acids

While the extraction and purification process is carried out at low temperature to preserve the terpenes and volatile molecules, its enclosed and continuous nature ensures that none of the desirable natural molecules are lost. There is no Tetrahydrocannabinol (THC) present as a result of a complete removal by a chromatographic purification system.

Some minor cannabinoids are partially lost while THC is removed, leading to their presence only at trace levels in the oil. However, the therapeutic effects of the THC-free hemp oil are not impacted as they are a result of CBD working synergistically with a diverse mix of mono- and sesquiterpenes6-10, as well as other plant lipids known to facilitate the transport and absorption through various routes of administration, when the finished product is consumed.

The extent of contribution of THC towards the entourage effect from a full-spectrum oil has been misunderstood. Since THC is the only psychoactive molecule in hemp oil, its effects have been generally confused as the cause of the relief as opposed to correlated with it. In a CBD:THC mix, the medicinal effects observed in most cases are similar if THC were to be removed, except measuring it is difficult because of the psychoactivity that confounds the measurement and analysis of relief/benefit. Dedicated studies based on CBD without THC have shown that it is not necessary for THC to be in the hemp oil as the relief from pain, anxiety, insomnia, epilepsy, and nausea can be brought upon by CBD alone working synergistically with terpenes.1-5

Sana’s THC-free hemp oil and finished products are based on the scientific belief that clinical effects are solely due to CBD and terpenes in its full-spectrum oil. The impact on patients and consumers is superior compared to THC-containing oil because it avoids the adverse effects and undesirable outcomes typically associated with THC. The THC-free products can be used without fear of getting high, and across pets, kids, older adults, and various consumer segments wanting to avoid the ‘drug-like effects’.

The purity of the THC-free hemp oil also means that there is less than detectable levels of solvents; propane, isobutane, butane, ethanol, pentane, isopropanol, hexane, and acetone, as well as heavy metals; cadmium, arsenic, lead, and mercury.

The complete chemical environment of the hemp oil, without the undesirable presence of THC, combined with extreme purity with respect to solvents and heavy metals, ensures expected benefits from the products made with it and offers a broad array of consumer and medical applications that can be developed.

References:

1. Taming THC, Ethan Russo, British Journal of Pharmacology, Jan 2011.
2. Chemistry and Biodiversity, Raphael Machoulam, Vol 4, Issue 8, Aug 2007, P 1678.
3. Safety and Side Effects of Cannabidiol, Machado Bergamaschi, Current Drug Safety, Vol 6, No 4, Sept 2011, P 237.
4. Cannabidiol Claims and Misconceptions, Ethan Russo, Trends in Pharmacological Sciences, Vol 38, Issue 5, 2017.
5. CBD for Opioid Addiction, Yasmin Hurd, TRands in Neurosciences, Vol 40, Issue 3, Mar 2017, P 124.
6. Evidence-Based Complementary and Alternative Medicine, Volume 2012, Article ID 872394, β-Caryophyllene, a Compound Isolated from the Biblical Balm of Gilead (Commiphora gileadensis), Is a Selective Apoptosis Inducer for Tumor Cell Lines
7. Phytochemistry, Volume 67, Issue 22, November 2006, Pages 2469-2473, Caryophyllene-rich rhizome oil of Zingiber nimmonii from South India: Chemical characterization and antimicrobial activity.
8. Effects of anti-nociceptive and anti-inflammatory component of limonene in herbal drugs, Cheraghi, J. ; Valadi, A., Iranian Journal of Medicinal and Aromatic Plants, 2010 Vol.26 No.3 pp.Pe415-Pe422 ref.15
9. Antifungal activity of essential oils from several medicinal plants against four postharvest citrus pathogens, Chebli Bouchra, Achouri Mohamed, Idrissi Hassani Mina and Mohamed Hmamouchi, Phytopathology Mediterranea, 42, No. 3 (December 2003), pp. 251-256.
10. Bioorganic & Medicinal Chemistry Letters, Volume 23, Issue 3, 1 February 2013, Pages 864-868, Novel limonene and citral based 2,5-disubstituted-1,3,4-oxadiazoles: A natural product coupled approach to semicarbazones for antiepileptic activity

(2) How are we different than Charlotte’s Web, CV Sciences, and Prime my Body (Quick Silver).

GENETICS: Our unique genetics is rich in CBD and other minor cannabinoids, and abundant with 30+ terpenes. CBD is more than 90% of all cannabinoids and primary terpenes are beta-caryophyllene, humulene, linalool, pinene, and bisabolol, all of them medicinal and synergistic with CBD.

ZERO-THC: Our proprietary manufacturing uses chromatography to remove THC but retains all other synergistic molecules in hemp oil. The removal of THC combined with preservation of diverse cannabinoids, terpenes, lipids, and flavonoids, ensures that the full spectrum nature of our oil is preserved. The full-spectrum oil is what is responsible for the entourage effect, which makes our hemp oil medicinal in nature.

PROPRIETARY PRODUCT TECHNLOGIES:
Our flagship technology is based on making the PCR hemp oil water soluble. This technology isn’t like other liposome-based technology.
The water soluble hemp oil is a nanoemulsion (very small hemp oil droplets dispersed in the formula), which ensure very high absorption efficiency in the blood upon ingestion. Sana’s softgels are made with this water soluble hemp oil and customization of a formula by adding additional ingredient is very easy as the softgel customization manufacturing is done on site. The nanoemulsion based softgels are absorbed into the blood stream four-times higher than hemp oil and work quickly in full or empty stomach.

(3) Is this legal for me to do and what’s going on with all the regulations?

Sana Therapeutics is a legal entity. Our farms are licensed by CO State Dept. of Agriculture and compliant with Federal Farm Bill 2014, Section 7606. Sana Therapeutics’s THC-free PCR hemp oil are legal to be sold within and outside the USA.

However, in light of the recent warning letters by FDA to some CBD suppliers, it is essential that no medical claims that have not been approved, are put on the product, package, or any marketing documents.

(4) What is special about our extraction process?

Extraction:

• Uses food-grade ethanol or supercritical CO2
• High CBD, low THC, high terpene plant genetics leads to high-quality extract
• No external additive
• Closed, enclosed process to preserve terpenes

Purification:

• THC is completely removed
• All other components, minor cannabinoids, terpenes, flavonoids, are preserved.
• NO solvents

• NO heavy metals
• NO pesticides

(5) What do phytocannabinoids do and how do they work?

Phytocannabinoids can be used to supplement or replace chemicals inside our bodies, called endocannabinoids. When the nervous system or immune system do not work as intended because of endocannabinoid deficiency, phytocannabinoids used as supplements help with restoring the proper functionality of the central nervous system and immune system.

This is primarily due to the phytocannabinoids activating CB1 and CB2 receptors, which in turn regulate cognitive and immune functions.

Also refer to the catalog and all of the Cannabinoids and what they are helpful with.

(6) What is Sana Therapeutics’s unique technology for soft gels?

Sana’s soft gels are made by solubilizing hemp oil by converting it into an oil-in-water type nanoemulsion. The unique advantage of this formulation is the enhanced surface area of cannabinoids resulting in higher bioavailability (4-6 times higher for CBD compared with oil form), consistency of the biological effects, and independence from fed vs. fasting effects. The soft gels can be taken with or without food, without much impact on its efficacy.

This technology platform is depicted by the schematic below where the customization of the formulation can lead to addition of synergistic botanical or pharmaceutical ingredients. For example, cannabidiol and curcumin can be combined to address inflammation through independent pathways, making the resulting product a lot more effective, not to mention curcumin is up to 200 times more bioavailable in a water-soluble nanoemulsion form than its oil form.

Another example of synergistic ingredients in a soft gel is CBD combined with melatonin, where sleep is induced due to melatonin and sleep quality is preserved through CBD.

(7) How is Sana Therapeutics’s water soluble technology superior to other water-soluble technology, liposomal or micelle-based, in the market?

Sana 's nanoemulsions are a finely-engineered formula that uses optimized composition and a unique process to manufacture. The average size of the hemp oil droplet is 25 nanometers, compared with 100-5000 nanometers that is usually obtained by using the industry standard liposomal delivery method. The small size of the Sana nanoemulsion leads to a much larger surface area of the hemp oil droplets in soft gels, leading to much higher absorption in blood. Hemp oil nanoemulsions can also be used in a number of commercial areas, including the cosmetic, pharmaceutical and food industries. Their lipophilic (oily) interior (i.e. ability to dissolve in fats, oils, lipids, and non-polar solvents) makes them a much better option for transporting lipophilic compounds compared to liposomes, and as such they more efficiently enable the skin penetration of active ingredients. Furthermore, due to their transparent properties and extremely small droplet size, nanoemulsions do not lead to phase-separation (oil separating from water), and thus enable the formulation of sprayable products.

(8) How is Full-Spetcrum Phytocannabinoid Hemp Oil better than using purified Cannabidiol isolate?

The cannabidiol in a phytocannabinoid-rich full-spectrum hemp oil is much more effective than a pure cannabidiol isolate, when used at the same level (mg/kg), controlled for the delivery and routes of administration for the following reasons: (1) Scientific evidence, see references 1-6, exist to show that CBD in the presence of other plant constituents improves the dose-response in a standardized hemp extract, showing it is more potent or efficacious than pure CBD isolate. Various research groups have studied a range of physiological parameters, such as analgesic effects, and have concluded that the higher efficiency of plant extract can be explained by additive or synergistic interactions between CBD, terpenes, and the minor

phytocannabinoids or non-cannabinoids presented in the extracts. This is because other phytocannabinoids, including Tetrahydrocannabivarin, Cannabigerol and Cannabichromene, as well as mono- and sesqui-terpenes, exert additional effects of therapeutic interest and the therapeutic synergy observed with plant extracts results in the requirement for a lower amount of active components, with consequent reduced adverse effects. (2) A full spectrum PCR hemp oil is easier to manufacture since it can be emulsified, dissolved, and homogenized much more effectively, compared with an isolate. Since the isolates are difficult to dissolve in water-containing media during manufacturing or consumption, they pose a risk of inconsistent delivery of active for consumers and patients alike. Although an insufficient dispersion of isolate in a supplement, vape, or food product is difficult to observe, experimental evidence point to a a better consistency, delivery, and efficiency (bioavailability) when a PCR hemp oil is used to manufacture the finished product. (3) Isolate CBD has been used for various Investigational New Drug (IND) applications. GW Pharmaceuticals has an approval pending with Food and Drug Administration for a drug with CBD as the active ingredient. Historically, the active ingredients in their purified form are not allowed in any consumer or drug product upon FDA-approval. Therefore, designing a product with purified CBD that will soon be illegal to use, presents a challenge for manufacturers. However, designing consumer products or supplements with full-spectrum hemp oil with up to 80% CBD and no THC provides a solution to those who would want a viable and legal supply of CBD raw material in the form of a botanical extract.

[1] Ruth Gallily, Zhannah Yekhtin, Lumír Ondřej Hanuš, Overcoming the Bell‐Shaped Dose‐Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol, Pharmacology & Pharmacy, 2015, 6, 75‐85 [2] Romano, B., Borrelli, F., Pagano, E., Cascio, M.G., Pertwee, R.G. and Izzo, A.A. (2014) Inhibition of Colon Carcinogenesis by a Standardized Cannabis Sativa Extract with High Content of Cannabidiol. Phytomedicine, 21, 631-639. http://dx.doi.org/10.1016/j.phymed.2013.11.006 [3] Capasso, R., Aviello, G., Borrelli, F., Romano, B., Ferro, M., Castaldo, L., Montanaro, V., Altieri, V. and Izzo, A.A., (2011) Inhibitory Effect of Standardized Cannabis Sativa Extract and Its Ingredient Cannabidiol on Rat and Human Bladder Contractility. Urology, 77, 1006.e9- 006e15. http://dx.doi.org/10.1016/j.urology.2010.12.006 [4] De Petrocellis, L., Ligresti, A., Schiano Moriello, A., Iappelli, M., Verde, R., Stott, C.G., Cristino, L., Orlando, P. and Di Marzo, V. (2013) Non-THC Cannabinoids Inhibit Prostate Carcinomahttp://dx.doi.org/10.1111/j.1476-5381.2012.02027.xGrowth in Vitro and in Vivo: Pro-Apoptotic Effects and Underlying Mechanisms. British Journal of Pharmacology, 168, 79-102.[5] Russo, E.B. (2011) Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects. British Journal of Pharmacology, 163, 1344-1364. http://dx.doi.org/10.1111/j.1476- 5381.2011.01238.x [6] Wagner, H. and Ulrich-Merzenich, G. (2009) Synergy Research: Approaching a New Generation of Phytopharmaceuticals. Phytomedicine, 16, 97-110. http://dx.doi.org/10.1016/j.phymed.2008.12.018

(9) How is Sana Therapeutics’s Full-Spetcrum Phytocannabinoid Hemp Oil extracted? How is THC-removed from this oil?

The hemp plant material is dried and milled into a powdered form. This allows for higher surface area which in turn results in an efficient extraction in shorter time. The extraction is carried out either in supercritical CO2 or ethanol. The solvent allows for preferential extraction of cannabinoids, waxes, terpenes and some of the impurities while discouraging the exchange of impurities such as plant carbohydrates and other impurities. The liquid extract or slurry containing plant material is processed through a custom designed filtration process in which almost all of the undissolved solids are retained while solid-free clean extract is able to permeate through the filter membrane. The solvent from clean hemp extract is recovered using distillation. This converts liquid extract into an oil form. This oil is further treated to preferentially remove waxes. It is then processed through a unique chromatography media which removes THC. The final oil has total phytocannabinoids in 75-85% range with total terpenes between 1 to 4%.

(10) Does Sana Therapeutics practice organic farming? Does it have an organic certification?

Folium Biosciences believes in a cultivation approach that is compliant with organic farming practices as defined by the standards captured in the Organic Food Production Act, USDA organic regulations, and the National Organic Program. The farms at Folium practice an organic cultivation or handling system plan that intends to meet the requirements below: (1) A description exists of practices and procedures to be performed and maintained; (2) A list exists of each substance to be used as a production or handling input, indicating its composition, source, and where it will be used; (3) A description exists of the monitoring practices and procedures to be performed and maintained,

including the frequency with which they will be performed, to verify that the plan is effectively implemented; (4) A description exists of the record-keeping system implemented to comply with the requirements; (5) A description exists of the management practices and physical barriers established to prevent commingling of organic and non-organic products on a split operation and to prevent contact of organic production and handling operations and products with prohibited substances.

Sana does not possess a certification to demonstrate that these organic farming practices have been reviewed and approved by a certification agency but expects to have one by 2019. This declaration intends to inform the parties concerned that the practices leading to an organic-certification in future are already in place and therefore, result in an equivalent product that could be expected from a certified-organic farm.

(11) Why is our THC-Free PCR Oil is so high in CBD content? (plant genetics high in CBD, extraction and selective purification process etc)

Sana’s unique plant genetics contain 15-18% CBD and < 0.3% THC, qualifying it as industrial hemp. Sana’s unique proprietary process removes the unwanted materials, waxes, chlorophyll, and pigments that are non-medicinal in nature form the cannabinoids, lipids, vitamins, and terpenes in the hemp extract. Because the refining and THC-removal process is so selective, removing only the components that do not have any nutritional or medicinal value, the resulting oil becomes very enriched, 70-85% CBD by content, and less is needed for a finished product formulation.

(12) What is the difference between supercritical hemp oil vs. ethanol extracted hemp oil?

Sana produces phytocannabinoid-Rich Hemp Oil by two separate processes. The first process utilizes supercritical CO2 to produce an extract rich in terpenes, CBD, and other cannabinoids. This extract is further subjected to winterization in ethanol and solvent removal through vacuum distillation. After the chlorophyll, waxes, and THC are removed, the resulting product is called PCR hemp oil with 60-80% CBD, minor cannabinoids, and terpenes.

The second solvent-extraction process utilizes ethanol for extraction, followed by the same purification processes as the first, to remove chlorophyll, waxes, and THC. The only difference between the two processes is that the first step, extraction, utilizes different solvents; CO2 and ethanol, respectively.

Irrespective of the process, the critical attributes of the oil (CBD %, terpenes, minor cannabinoids) are a result of post extraction purification processes and not necessarily the extraction itself. Since the extract from both processes undergo the same set of purification steps, the resulting hemp oil attributes remain comparable and similar from the two approaches. Any minor differences may be solely due to aesthetics and sensory qualities, such as color, viscosity etc.

Sana uses both types of oils to fulfill orders. As they are comparable and interchangeable, the resulting products possess the same level of quality without any inconsistency. The PCR hemp oils are the same irrespective of the extraction solvents as the manufacturing is designed to arrive at the same quality attributes that are critical to our customers.

(13) What evidence is there that nanoemulsions increase bioavailability of cannabinoids?

The increased bioavailability of cannabinoids is inferred from scientific literature published over the past 20 years that substantiate the enhanced bioavailability of botanical and pharmaceutical actives due to water miscibility and emulsion droplet size. Some of these articles are:

https://www.sciencedirect.com/science/article/abs/pii/S0939641106002839 https://www.sciencedirect.com/science/article/pii/S0378517307005534 https://jnanobiotechnology.biomedcentral.com/track/pdf/10.1186/1477-3155-6-8 https://pubs.acs.org/doi/abs/10.1021/jf300609p https://www.sciencedirect.com/science/article/pii/S0378517308005279 http://jpharmsci.org/article/S0022-3549(15)32398-4/pdf https://www.tandfonline.com/doi/abs/10.1080/10611860802473402 https://www.researchgate.net/profile/Thomas_Wilson15/publication/247920347_Bioavailability_of_a_ Nanoemulsion_of_Lutein_is_Greater_than_a_Lutein_Supplement/links/56d49df908ae9e9dea65b5cb.p df https://onlinelibrary.wiley.com/doi/full/10.1111/j.1750-3841.2009.01457.x https://www.sciencedirect.com/science/article/abs/pii/S0924224414001873 https://link.springer.com/article/10.1208/s12249-009-9268-4 https://www.sciencedirect.com/science/article/pii/S1359644610000723 https://www.sciencedirect.com/science/article/pii/S0378517312001755 https://www.sciencedirect.com/science/article/pii/S0308814613013538 https://www.sciencedirect.com/science/article/pii/S0268005X14002549 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302540/