Optimal condition of cannabis maceration to obtain the high cannabidiol and Δ9-tetrahydrocannabinol content

CHAOWALIT MONTON FAMEERA MADAKA SUKANYA SETTHARAKSA THANIYA WUNNAKUP JIRAPORNCHAI SUKSAEREE THANAPAT SONGSAK About the authors

Abstract

Abstract: The aim of this work was to optimize a maceration condition of cannabis (Cannabis sativa L.). A circumscribed central composite experimental design was applied in this work. Temperature and time were varied from 40-80 °C and 30-90 min, respectively. The three responses (i.e., extraction yield, cannabidiol content, and Δ9- tetrahydrocannabinol content) were predicted by computer software. The yield was high when cannabis was macerated using ethanol at high temperature and long duration time. While cannabidiol and Δ9- tetrahydrocannabinol content was high when macerating at a low heating temperature and short duration time. The optimal condition provided the simultaneous high of cannabidiol and Δ9- tetrahydrocannabinol content was 40 °C for 30 min. The prediction was accurate due to low percent error. This optimal condition could be used as a guide for maceration of cannabis to obtain the extract containing a high content of cannabidiol and Δ9- tetrahydrocannabinol.

Key words
Cannabis sativa; cannabidiol; Δ9-tetrahydrocannabinol; optimization


INTRODUCTION

Cannabis sativa L. is a plant in Family Cannabaceae. In Thailand, it is categorized as a narcotic drug. Cannabis contains at least 750 identDENT M, DRAGOVIĆ-UZELAC V, PENIĆ M, BRNČIĆ M, BOSILJKOV T and LEVAJ B. 2013. The effect of extraction solvents, temperature and time on the composition and mass fraction of polyphenols in Dalmatian wild sage (Salvia officinalis L.) extracts. Food Technol Biotechnol 51: 84-91.ified chemical constituents, among these, 104 compounds are cannabinoids (RadwanRADWAN MM et al. 2015. Isolation and pharmacological evaluation of minor cannabinoids from high-potency Cannabis sativa. J Nat Prod 78: 1271-1276. et al. 2015). According to the survey from 31 countries in 953 subjects, cannabis is mostly used for the treatment of chronic pain, anxiety, loss of appetite, depression, and insomnia (HazekampHAZEKAMP A, WARE MA, MULLER-VAHL KR, ABRAMS D and GROTENHERMEN F. 2013. The medicinal use of cannabis and cannabinoids--an international cross-sectional survey on administration forms. J Psychoactive Drugs 45: 199-210. et al. 2013). There are many systematic reviews and meta- analyses reveal that cannabis can be used in several diseases and for symptoms such as cancer-pain (AviramAVIRAM J and SAMUELLY-LEICHTAG G. 2017. Efficacy of cannabis-based medicines for pain management: A systematic review and meta-analysis of randomized controlled trials. Pain Physician 20: E755-E796. and Samuelly-Leichtag 2017), chronic non-cancer pain (Aviram and Samuelly-Leichtag 2017, Martin-SanchezMARTIN-SANCHEZ E, FURUKAWA TA, TAYLOR J and MARTIN JL. 2009. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med 10: 1353-1368. et al. 2009, StockingsSTOCKINGS E, CAMPBELL G, HALL WD, NIELSEN S, ZAGIC D, RAHMAN R, MURNION B, FARRELL M, WEIER M and DEGENHARDT L. 2018a. Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Pain 159: 1932-1954. et al. 2018a, WhitingWHITING PF et al. 2015. Cannabinoids for medical use: A systematic review and meta-analysis. JAMA 313: 2456-2473. et al. 2015), chemotherapy-induced nausea and vomiting (MachadoMACHADO ROCHA FC, STEFANO SC, DE CASSIA HAIEK R, ROSA OLIVEIRA LM and DA SILVEIRA DX. 2008. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care 17: 431-443. Rocha et al. 2008, Whiting et al. 2015), epilepsy (PamplonaPAMPLONA FA, DA SILVA LR and COAN AC. 2018. Potential clinical benefits of CBD-rich cannabis extracts over purified CBD in treatment-resistant epilepsy: Observational data meta-analysis. Front Neurol 9. et al. 2018, Stockings et al. 2018bSTOCKINGS E, ZAGIC D, CAMPBELL G, WEIER M, HALL WD, NIELSEN S, HERKES GK, FARRELL M and DEGENHARDT L. 2018b. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry 89: 741-753.), insomnia (Whiting et al. 2015), neuropathic pain (Aviram and Samuelly-Leichtag 2017, NugentNUGENT SM et al. 2017. The effects of cannabis among adults with chronic pain and an overview of general harms: A systematic review. Ann Intern Med 167: 319-331. et al. 2017, WareWARE MA, WANG T, SHAPIRO S, ROBINSON A, DUCRUET T, HUYNH T, GAMSA A, BENNETT GJ and COLLET J-P. 2010. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. Can Med Assoc J 182: E694-E701. et al. 2010), spasticity (Whiting et al. 2015), Tourette syndrome (Whiting et al. 2015), and weight loss (Whiting et al. 2015), etc.

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) are the most well-known cannabis active compounds. Δ9-THC is a primary psychoactive compound, while CBD is a non-psychoactive compound. CBD and Δ9-THC are derived from their acidic precursors in plants; cannabidiolic acid (CBDA) and Δ9-tetrahydrocannabinolic acid (THCA), respectively. The two acidic precursors are both derived from cannabigerolic acid (CBGA), which was converted to CBDA and THCA by CBDA synthase or THCA synthase, respectively. According to CBDA and THCA, they are decarboxylated to CBD and Δ9-THC by light exposure, heating, or aging (World Health Organization 2017WHO - WORLD HEALTH ORGANIZATION. 2017. Cannabidiol (CBD) Pre-review report. Cited January 28th, 2019. Available from: https://www.who.int/medicines/access/controlled-substances/5.2_CBD.pdf.
https://www.who.int/medicines/access/con...
). There are two major cannabinoid receptors; CB1 and CB2 receptors. CB1 receptors are mostly located in a central nervous system with some peripheral tissues, while CB2 receptors are mostly located periphery on immune cells and gastrointestinal tract. Δ9-THC is a partial agonist to CB1 and CB2 receptors, while CBD act as an antagonist of CB1 and CB2 receptors agonists with apparently low affinity (PertweePERTWEE RG. 2008. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol 153: 199-215. 2008). The effects of Δ9-THC are muscle relaxation, analgesia, and antiemesis. However, it induces psychosis, anxiety, and sedation. CBD is anxiolytic, antipsychotic, and antisedating. CBD can reduce the effect of Δ9-THC by inhibition of metabolism of Δ9-THC to 11-hydroxytetrahydrocannabinol, a more psychoactive metabolite (HowardHOWARD P, TWYCROSS R, SHUSTER J, MIHALYO M and WILCOCK A. 2013. Cannabinoids. J Pain Symptom Manag 46: 142-149. et al. 2013). Combination of Δ9-THC and CBD can improve the efficacy and tolerability profile of Δ9-THC. Nowadays, there are cannabis-based commercial products containing natural cannabinoids; Sativex® and Epidiolex®. Sativex® is an oromucosal spray, each 100 μL contains 2.7 mg Δ9-THC and 2.5 mg CBD. It is used for the treatment of spasticity due to multiple sclerosis (eMCEMC. 2018. Sativex oromucosal spray. Cited on January 28th, 2019. Available from: https://www.medicines.org.uk/emc/product/602/smpc.
https://www.medicines.org.uk/emc/product...
2018). While Epidiolex® is an oral solution, it contains 100 mg/mL CBD. It is used for treatment of epilepsy associated with Lennox-Gastaut syndrome or Dravet syndrome (FDAFDA. 2018. Epidiolex®. Cited on January 28th, 2019. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.
https://www.accessdata.fda.gov/drugsatfd...
2018).

Extraction is an essential first step in the analysis of chemical compounds in plants. This step is required to extract the desired chemical compounds from plant materials for further use. Proper extraction must be taken to assure the plant chemical compounds are not destroyed during the extraction process (SasidharanSASIDHARAN S, CHEN Y, SARAVANAN D, SUNDRAM KM and YOGA LATHA L. 2010. Extraction, isolation and characterization of bioactive compounds from plants’ extracts. Afr J Tradit Complement Altern Med 8: 1-10. et al. 2010). Furthermore, the proper extraction condition can provide the highest content of active chemical compounds. The aim of this work was to optimize a maceration condition of seized cannabis. A validated high performance liquid chromatography was used for determination of CBD and Δ9-THC. A circumscribed central composite experimental design was applied in this work to evaluate the effect of maceration temperature and duration time on extraction yield, CBD content, and Δ9-THC content. We expected that the optimal condition obtained from this work could be used as a guide for maceration of cannabis to obtain the extract containing a high content of CBD and Δ9-THC.

MATERIALS AND METHODS

MATERIALS

CBD (purity 97.4%, HPLC) and Δ9-THC (purity 98.9%, HPLC) isolated from seized cannabis bar were used as a standard marker for analysis of CBD and Δ9-THC containing in cannabis extract. They were certified by NMR and GC-MS. Methanol (HPLC grade) was purchased from Honeywell Burdick & Jackson, USA. Absolute ethanol was purchased from QRëC, New Zealand.

CANNABIS SAMPLE AND EXTRACTION PROCEDURE

Seized cannabis bars were obtained from the Narcotics Suppression Bureau with the permission of Office of the Narcotics Control Board, Thai Food and Drug Administration, Ministry of Public Health. They were deposited at College of Pharmacy, Rangsit University. Seized cannabis bar was cut into small piece, ground, and passed through a 20-mesh sieve.

The 10 g of cannabis powder was added to 250-mL Erlenmeyer flask. Then, absolute ethanol (100 mL) was added. It was macerated under specific temperature and duration time according to the circumscribed central composite experimental design as shown in Table I. The maceration was done using a water bath (WNB 14, Memmert, Germany). After maceration, the filtrate was collected by vacuum filtration. The marc was macerated again using the same condition for an additional two times. The three filtrates were pooled and the solvent was eliminated by a rotary evaporator (Buchi R-100, Büchi Labortechnik AG, Switzerland). Extraction yield data was collected and the extracts were kept in a desiccator until use.

TABLE I
Coded and actual value of model conditions of the circumscribed central composite experimental design.

OPTIMIZATION OF MACERATION OF CANNABIS

The circumscribed central composite experimental design was applied in this work. Two factors were varied; temperature (X1) and duration time (X2). Temperature and time were varied from 40-80 °C and 30-90 min, respectively. Ten conditions (eight non-center points and two center points) according to the circumscribed central composite experimental design are shown in Table I. Cannabis powders were individually extracted following the ten conditions and the extracts from different conditions were analyzed for CBD and Δ9-THC content using high performance liquid chromatography (HPLC). Three responses; extraction yield (Y1), CBD content in the extract (Y2), and Δ9-THC content in the extract (Y3) were monitors. The above data was analyzed by Design-Expert version 11.0. Contour plots, response surfaces, and desirability plot were constructed. The equations for prediction of each response were reported. In addition, analysis of variance was performed for each response. The correlations between the factors were determined using SPSS version 22. The optimal condition that gave the highest content of CBD and Δ9-THC was selected based on desirability value (BezerraBEZERRA MA, SANTELLI RE, OLIVEIRA EP, VILLAR LS and ESCALEIRA LA. 2008. Response surface methodology (RSM) as a tool for optimization in analytical chemistry. Talanta 76: 965-977. et al. 2008). This optimal condition was used to extract cannabis powder again. The extraction yield, CBD content, and Δ9-THC content were reported. The percent error of the prediction was reported for each response. This value was used to confirm the accuracy of the prediction.

QUANTITATIVE ANALYSIS OF CBD AND Δ9-THC IN CANNABIS EXTRACT

The analysis of CBD and Δ9-THC content was done by HPLC instrument (Agilent 1260 Infinity, Agilent, USA). ACE® C18-PFP (250×4.6 mm, i.d., 5 µm) (Advanced Chromatography Technologies Ltd., UK) connected to guard column (SecurityGuard Cartridge C18, 4.0×3.0 mm, i.d.) (Phenomenex Inc., USA) was used for the isocratic separation. Column temperature was controlled at 25 °C. Mobile phase consisted of water and methanol in a ratio of 10:90 v/v. Mobile phase flow rate was set at 1 mL/min and injection volume was 10 μL. The response signal was monitored at 222 nm. The total analysis time for each injection was 25 min.

RESULTS AND DISCUSSION

CBD and Δ9-THC in cannabis extract were quantified by reversed-phase HPLC. The HPLC method was validated to ensure the reliability of the analysis. The HPLC chromatograms of CBD, Δ9-THC, and cannabis extract are shown in Fig. 1. CBD and Δ9-THC were eluted at retention time of 5.1 and 9.8 min, respectively.

Figure 1
HPLC chromatograms of (a) CBD (100 μg/mL), (b) Δ9-THC (100 μg/mL), and (c) cannabis extract (500 μg/mL).

Our work found that the extraction yield of the ten conditions was in the range of 18.63-22.39%. Condition 5 and Condition 8 had the lowest and highest extraction yield, respectively. CBD and Δ9-THC content in the extract was in the range of 6.98-8.10% and 25.90-30.67%, respectively. Condition 8 and Condition 5 had the lowest and highest CBD content as well as Δ9-THC content, respectively. However, a narrow range of CBD and Δ9-THC content in raw material extracted from the ten conditions was observed; 1.49-1.65% and 5.51-6.05%, respectively. Recently, there was a high efficient technique to extract the CBD and Δ9-THC such as supercritical fluid extraction (ElkinsELKINS AC, DESEO MA, ROCHFORT S, EZERNIEKS V and SPANGENBERG G. 2019. Development of a validated method for the qualitative and quantitative analysis of cannabinoids in plant biomass and medicinal cannabis resin extracts obtained by super-critical fluid extraction. J Chromatogr B 1109: 76-83. et al. 2019, Gallo-MolinaGALLO-MOLINA AC, CASTRO-VARGAS HI, GARZÓN-MÉNDEZ WF, MARTÍNEZ RAMÍREZ JA, RIVERA MONROY ZJ, KING JW and PARADA-ALFONSO F. 2019. Extraction, isolation and purification of tetrahydrocannabinol from the Cannabis sativa L. plant using supercritical fluid extraction and solid phase extraction. J Supercrit Fluids 146: 208-216. et al. 2019). However, the extraction of crude extract by maceration was still necessary to concentrate the CBD and Δ9-THC yield before supercritical fluid extraction was done.

Contour plots and response surfaces of model conditions of extraction yield, CBD content and Δ9-THC content are shown in Fig. 2. They were fitted with linear mathematic models. Increasing temperature as well as duration time provided high extraction yield (Fig. 2a). According to CBD and Δ 9-THC content in the extract, increasing temperature and duration time provided low content of CBD and Δ 9-THC (Fig. 2b and 2c). The coded and actual equations for prediction of extraction yield, CBD content, and Δ9-THC content are shown below. The equations revealed that temperature and time had a positive effect on extraction yield, while they had a negative effect on CBD and Δ9-THC content. From the equations, the coefficient of maceration temperature had higher value compared to maceration time, so maceration temperature had a major effect on CBD and Δ9-THC content rather than maceration time.

Figure 2
Contour plots (left) and response surfaces (right) of model conditions of (a) yield, (b) CBD content, and (c) Δ9-THC content.

Coded equations

Y 1 = 21.00 + 0.76 ( X 1 ) + 0.41 ( X 2 ) (1)
Y 2 = 7.52 0.30 ( X 1 ) 0.16 ( X 2 ) (2)
Y 3 = 27.84 1.15 ( X 1 ) 0.49 ( X 2 ) (3)

Actual equations

Yield = 16.617 + 0.054 ( Temp. ) + 0.019 ( Time ) (4)
CBD content = 9.228 0.021 ( Temp. ) 0.008 ( Time ) (5)
Δ 9 THC content = 34.122 0.082 ( Temp. ) 0.023 ( Time ) (6)

Extraction temperature and time were two of several factors that affected the extraction efficiency of active chemical compounds of various plants. Much research has investigated the effect of extraction temperature and extraction time on plant chemical compounds. YapoYAPO BM, ROBERT C, ETIENNE I, WATHELET B and PAQUOT M. 2007. Effect of extraction conditions on the yield, purity and surface properties of sugar beet pulp pectin extracts. Food Chem 100: 1356-1364. et al. (2007) isolated pectin from sugar beet pulp, and found that extraction time had a positive effect on pectin yield compared to extraction temperature. Vergara-SalinasVERGARA-SALINAS JR, PEREZ-JIMENEZ J, TORRES JL, AGOSIN E and PEREZ-CORREA JR. 2012. Effects of temperature and time on polyphenolic content and antioxidant activity in the pressurized hot water extraction of deodorized thyme (Thymus vulgaris). J Agric Food Chem 60: 10920-10929. et al. (2012) determined the effect of temperature and time on the polyphenolic content of Thymus vulgaris. They reported that the content of polyphenols was diverse with regard to different extraction temperatures and extraction times. The higher temperature and longer time could decrease the diversity of hydroxycinnamic acids, flavones, flavonols/flavanones, and total polyphenols. The phenolic compounds that mostly extracted at high temperature were 3,4-dihydroxyphenyllactic acid. In case of nonphenolic antioxidant, it was highly extracted at the high temperature and long extraction time. Dent et al. (2013) showed that extraction temperature had a positive effect on mass fractions of total polyphenols, rosmarinic acid, and luteolin-3-glucuronide of Salvia officinalis, while extraction time had no effect on mass fractions of total polyphenols and rosmarinic acid. MartinsMARTINS FS and DA CONCEICAO EC. 2015. Evaluation of extraction method on the chemical composition in Apeiba tibourbou Aubl’s extracts. Pharmacogn Mag 11: 368-373. and da Conceicao (2015) showed that extraction temperature had a non-significant effect on rosmarinic acid and caffeic acid of Apeiba tibourbou, while extraction time had a significant effect on both rosmarinic acid and caffeic acid. KuzmanovićKUZMANOVIĆ M, TIŠMA M, BUCIĆ-KOJIĆ A, CASAZZA AA, PAINI M, ALIAKBARIAN B and PEREGO P. 2015. High-pressure and temperature extraction of phenolic compounds from corn silage. Chem Eng Trans 43: 133-138. et al. (2015) reported that the temperature was the most significant factor affected phenolic compound content of corn silage. Our previous work investigated the effect of extraction temperature and time on centelloids content of Centella asiatica. We found that extraction temperature and time had a positive effect on centelloids content of Centella asiatica (MontonMONTON C, SETTHARAKSA S, SONGSANGSIRISAK C, CHUENWISET N, SUKSAEREE J and LUPRASONG C. 2018. Estimation of centelloids and total phenolic content of Centella asiatica (L.) Urb. using computer software and their correlation with antioxidant activity. Bull Health Sci Technol 16: 50-59. et al. 2018). However, the long extraction time perhaps led to decomposition of some plant chemical compounds such as phenolic compounds of Centella asiatica (ChewCHEW KK, NG SY, THOO YY, KHOO MZ, AIDA WMW and HO CW. 2011. Effect of ethanol concentration, extraction time and extraction temperature on the recovery of phenolic compounds and antioxidant capacity of Centella asiatica extracts. Int Food Res J 18: 571-578. et al. 2011), polysaccharides fromHovenia dulcispeduncles (LiuLIU Y, QIANG M, SUN Z and DU Y. 2015. Optimization of ultrasonic extraction of polysaccharides from Hovenia dulcis peduncles and their antioxidant potential. Int J Biol Macromol 80: 350-357. et al. 2015), and polysaccharide from Angelica sinensis (TianTIAN S, HAO C, XU G, YANG J and SUN R. 2017. Optimization conditions for extracting polysaccharide from Angelica sinensis and its antioxidant activities. J Food Drug Anal 25: 766-775. et al. 2017). The dual high temperature with long duration time led to degradation of some thermo-labile compounds (i.e., amygdalin of apricot-kernel and Prunus tomentosa) (Lv et al. 2005LV WF, DING MY and ZHENG R. 2005. Isolation and quantitation of amygdalin in Apricot-kernel and Prunus tomentosa Thunb. by HPLC with solid-phase extraction. J Chromatogr Sci 43: 383-387.), polysaccharides of mulberry fruit (ChenCHEN C, YOU L-J, ABBASI AM, FU X and LIU RH. 2015. Optimization for ultrasound extraction of polysaccharides from mulberry fruits with antioxidant and hyperglycemic activity in vitro. Carbohydr Polym 130: 122-132. et al. 2015), polysaccharides of Tricholoma mongolicum (WangWANG J, ZHAO Y, LI W, WANG Z and SHEN L. 2015. Optimization of polysaccharides extraction from Tricholoma mongolicum Imai and their antioxidant and antiproliferative activities. Carbohydr Polym 131: 322-330. et al. 2015), and polysaccharides of Astragalus cicer (ShangSHANG H, WANG M, LI R, DUAN M, WU H and ZHOU H. 2018. Extraction condition optimization and effects of drying methods on physicochemical properties and antioxidant activities of polysaccharides from Astragalus cicer L. Sci Rep 8: 3359. et al. 2018). The above reports revealed that the optimal condition for the extraction of a specific plant should be optimized to ensure that the selected extraction condition provided the highest amount of active chemical compounds. Furthermore, it perhaps influences the biological and pharmacological effect of the plants.

Table II shows correlations between extraction yield, CBD content, and Δ9-THC content. The correlation between extraction yield vs. CBD content or extraction yield vs. Δ9-THC had a negative value with a significant manner. According to the correlation between CBD and Δ9-THC content, it had a high correlation with significant value. This result indicated that while CBD was extracted, Δ9-THC was extracted as well. This phenomenon perhaps related to the similar physicochemical properties of both compounds similarly affected extracted during the extraction process.

TABLE II
Correlations between extraction yield, CBD content, and Δ9-THC content.

The optimal condition obtained from Design-Expert that provided the simultaneous high of CBD and Δ9-THC content was the temperature of 40 °C and duration time of 30 min. The desirability value of this condition was 0.946. The desirability plot (Fig. 3) showed that increasing temperature and duration time could decrease desirability value, indicating that temperature and duration time of the maceration had a negative effect on content of CBD and Δ9-THC in the cannabis extract, according to Equations 2, 3, 5, and 6. This optimal condition was used to extract the cannabis to check the accuracy of the prediction by Design-Expert. Results showed that prediction by Design-Expert was accurate since the percent error was low (Table III).

Figure 3
Desirability plot.
TABLE III
Predicted value, experimental value, and percent error of the prediction.

CONCLUSIONS

The circumscribed central composite experimental design was applied to determine the effect of maceration temperature and duration time on extraction yield, CBD content, and Δ9-THC content. The content of CBD and Δ9-THC had a negative correlation to the extraction yield. The high content of CBD and Δ9-THC were achieved when macerating using ethanol at the low heating temperature and short duration time. The optimal condition provided the simultaneous high of CBD and Δ9-THC content was a temperature of 40 °C and duration time of 30 min. The prediction was accurate and could be used as a guide for maceration of cannabis to obtain the extract containing a high content of CBD and Δ9-THC.

ACKNOWLEGMENTS

This work is supported by Research Institute of Rangsit University under Grant No. 98/2560. We would like to acknowledge College of Pharmacy, Rangsit University for facilities support. We also acknowledge Professor J. E. Moreton, University of Maryland at Baltimore, USA for his assistance in editing the English language in this paper. The authors declare that they have no conflicts of interest.

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Publication Dates

  • Publication in this collection
    14 Oct 2019
  • Date of issue
    2019

History

  • Received
    6 June 2019
  • Accepted
    25 July 2019
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