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• Research article
• Open access
• Published: 04 February 2020

Marijuana legalization and historical trends in marijuana use among US residents aged 12–25: results from the 1979–2016 National Survey on drug use and health

• Xinguang Chen 1 ,
• Xiangfan Chen 2 &
• Hong Yan 2  

BMC Public Health volume  20 , Article number:  156 ( 2020 ) Cite this article

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Marijuana is the most commonly used illicit drug in the United States. More and more states legalized medical and recreational marijuana use. Adolescents and emerging adults are at high risk for marijuana use. This ecological study aims to examine historical trends in marijuana use among youth along with marijuana legalization.

Data ( n  = 749,152) were from the 31-wave National Survey on Drug Use and Health (NSDUH), 1979–2016. Current marijuana use, if use marijuana in the past 30 days, was used as outcome variable. Age was measured as the chronological age self-reported by the participants, period was the year when the survey was conducted, and cohort was estimated as period subtracted age. Rate of current marijuana use was decomposed into independent age, period and cohort effects using the hierarchical age-period-cohort (HAPC) model.

After controlling for age, cohort and other covariates, the estimated period effect indicated declines in marijuana use in 1979–1992 and 2001–2006, and increases in 1992–2001 and 2006–2016. The period effect was positively and significantly associated with the proportion of people covered by Medical Marijuana Laws (MML) (correlation coefficients: 0.89 for total sample, 0.81 for males and 0.93 for females, all three p values < 0.01), but was not significantly associated with the Recreational Marijuana Laws (RML). The estimated cohort effect showed a historical decline in marijuana use in those who were born in 1954–1972, a sudden increase in 1972–1984, followed by a decline in 1984–2003.

The model derived trends in marijuana use were coincident with the laws and regulations on marijuana and other drugs in the United States since the 1950s. With more states legalizing marijuana use in the United States, emphasizing responsible use would be essential to protect youth from using marijuana.

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Introduction

Marijuana use and laws in the united states.

Marijuana is one of the most commonly used drugs in the United States (US) [ 1 ]. In 2015, 8.3% of the US population aged 12 years and older used marijuana in the past month; 16.4% of adolescents aged 12–17 years used in lifetime and 7.0% used in the past month [ 2 ]. The effects of marijuana on a person’s health are mixed. Despite potential benefits (e.g., relieve pain) [ 3 ], using marijuana is associated with a number of adverse effects, particularly among adolescents. Typical adverse effects include impaired short-term memory, cognitive impairment, diminished life satisfaction, and increased risk of using other substances [ 4 ].

Since 1937 when the Marijuana Tax Act was issued, a series of federal laws have been subsequently enacted to regulate marijuana use, including the Boggs Act (1952), Narcotics Control Act (1956), Controlled Substance Act (1970), and Anti-Drug Abuse Act (1986) [ 5 , 6 ]. These laws regulated the sale, possession, use, and cultivation of marijuana [ 6 ]. For example, the Boggs Act increased the punishment of marijuana possession, and the Controlled Substance Act categorized the marijuana into the Schedule I Drugs which have a high potential for abuse, no medical use, and not safe to use without medical supervision [ 5 , 6 ]. These federal laws may have contributed to changes in the historical trend of marijuana use among youth.

Movements to decriminalize and legalize marijuana use

Starting in the late 1960s, marijuana decriminalization became a movement, advocating reformation of federal laws regulating marijuana [ 7 ]. As a result, 11 US states had taken measures to decriminalize marijuana use by reducing the penalty of possession of small amount of marijuana [ 7 ].

The legalization of marijuana started in 1993 when Surgeon General Elder proposed to study marijuana legalization [ 8 ]. California was the first state that passed Medical Marijuana Laws (MML) in 1996 [ 9 ]. After California, more and more states established laws permitting marijuana use for medical and/or recreational purposes. To date, 33 states and the District of Columbia have established MML, including 11 states with recreational marijuana laws (RML) [ 9 ]. Compared with the legalization of marijuana use in the European countries which were more divided that many of them have medical marijuana registered as a treatment option with few having legalized recreational use [ 10 , 11 , 12 , 13 ], the legalization of marijuana in the US were more mixed with 11 states legalized medical and recreational use consecutively, such as California, Nevada, Washington, etc. These state laws may alter people’s attitudes and behaviors, finally may lead to the increased risk of marijuana use, particularly among young people [ 13 ]. Reported studies indicate that state marijuana laws were associated with increases in acceptance of and accessibility to marijuana, declines in perceived harm, and formation of new norms supporting marijuana use [ 14 ].

Marijuana harm to adolescents and young adults

Adolescents and young adults constitute a large proportion of the US population. Data from the US Census Bureau indicate that approximately 60 million of the US population are in the 12–25 years age range [ 15 ]. These people are vulnerable to drugs, including marijuana [ 16 ]. Marijuana is more prevalent among people in this age range than in other ages [ 17 ]. One well-known factor for explaining the marijuana use among people in this age range is the theory of imbalanced cognitive and physical development [ 4 ]. The delayed brain development of youth reduces their capability to cognitively process social, emotional and incentive events against risk behaviors, such as marijuana use [ 18 ]. Understanding the impact of marijuana laws on marijuana use among this population with a historical perspective is of great legal, social and public health significance.

Inconsistent results regarding the impact of marijuana laws on marijuana use

A number of studies have examined the impact of marijuana laws on marijuana use across the world, but reported inconsistent results [ 13 ]. Some studies reported no association between marijuana laws and marijuana use [ 14 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ], some reported a protective effect of the laws against marijuana use [ 24 , 26 ], some reported mixed effects [ 27 , 28 ], while some others reported a risk effect that marijuana laws increased marijuana use [ 29 , 30 ]. Despite much information, our review of these reported studies revealed several limitations. First of all, these studies often targeted a short time span, ignoring the long period trend before marijuana legalization. Despite the fact that marijuana laws enact in a specific year, the process of legalization often lasts for several years. Individuals may have already changed their attitudes and behaviors before the year when the law is enacted. Therefore, it may not be valid when comparing marijuana use before and after the year at a single time point when the law is enacted and ignoring the secular historical trend [ 19 , 30 , 31 ]. Second, many studies adapted the difference-in-difference analytical approach designated for analyzing randomized controlled trials. No US state is randomized to legalize the marijuana laws, and no state can be established as controls. Thus, the impact of laws cannot be efficiently detected using this approach. Third, since marijuana legalization is a public process, and the information of marijuana legalization in one state can be easily spread to states without the marijuana laws. The information diffusion cannot be ruled out, reducing the validity of the non-marijuana law states as the controls to compare the between-state differences [ 31 ].

Alternatively, evidence derived based on a historical perspective may provide new information regarding the impact of laws and regulations on marijuana use, including state marijuana laws in the past two decades. Marijuana users may stop using to comply with the laws/regulations, while non-marijuana users may start to use if marijuana is legal. Data from several studies with national data since 1996 demonstrate that attitudes, beliefs, perceptions, and use of marijuana among people in the US were associated with state marijuana laws [ 29 , 32 ].

Age-period-cohort modeling: looking into the past with recent data

To investigate historical trends over a long period, including the time period with no data, we can use the classic age-period-cohort modeling (APC) approach. The APC model can successfully discompose the rate or prevalence of marijuana use into independent age, period and cohort effects [ 33 , 34 ]. Age effect refers to the risk associated with the aging process, including the biological and social accumulation process. Period effect is risk associated with the external environmental events in specific years that exert effect on all age groups, representing the unbiased historical trend of marijuana use which controlling for the influences from age and birth cohort. Cohort effect refers to the risk associated with the specific year of birth. A typical example is that people born in 2011 in Fukushima, Japan may have greater risk of cancer due to the nuclear disaster [ 35 ], so a person aged 80 in 2091 contains the information of cancer risk in 2011 when he/she was born. Similarly, a participant aged 25 in 1979 contains information on the risk of marijuana use 25 years ago in 1954 when that person was born. With this method, we can describe historical trends of marijuana use using information stored by participants in older ages [ 33 ]. The estimated period and cohort effects can be used to present the unbiased historical trend of specific topics, including marijuana use [ 34 , 36 , 37 , 38 ]. Furthermore, the newly established hierarchical APC (HAPC) modeling is capable of analyzing individual-level data to provide more precise measures of historical trends [ 33 ]. The HAPC model has been used in various fields, including social and behavioral science, and public health [ 39 , 40 ].

Several studies have investigated marijuana use with APC modeling method [ 17 , 41 , 42 ]. However, these studies covered only a small portion of the decades with state marijuana legalization [ 17 , 42 ]. For example, the study conducted by Miech and colleagues only covered periods from 1985 to 2009 [ 17 ]. Among these studies, one focused on a longer state marijuana legalization period, but did not provide detailed information regarding the impact of marijuana laws because the survey was every 5 years and researchers used a large 5-year age group which leads to a wide 10-year birth cohort. The averaging of the cohort effects in 10 years could reduce the capability of detecting sensitive changes of marijuana use corresponding to the historical events [ 41 ].

Purpose of the study

In this study, we examined the historical trends in marijuana use among youth using HAPC modeling to obtain the period and cohort effects. These two effects provide unbiased and independent information to characterize historical trends in marijuana use after controlling for age and other covariates. We conceptually linked the model-derived time trends to both federal and state laws/regulations regarding marijuana and other drug use in 1954–2016. The ultimate goal is to provide evidence informing federal and state legislation and public health decision-making to promote responsible marijuana use and to protect young people from marijuana use-related adverse consequences.

Materials and methods

Data sources and study population.

Data were derived from 31 waves of National Survey on Drug Use and Health (NSDUH), 1979–2016. NSDUH is a multi-year cross-sectional survey program sponsored by the Substance Abuse and Mental Health Services Administration. The survey was conducted every 3 years before 1990, and annually thereafter. The aim is to provide data on the use of tobacco, alcohol, illicit drug and mental health among the US population.

Survey participants were noninstitutionalized US civilians 12 years of age and older. Participants were recruited by NSDUH using a multi-stage clustered random sampling method. Several changes were made to the NSDUH after its establishment [ 43 ]. First, the name of the survey was changed from the National Household Survey on Drug Abuse (NHSDA) to NSDUH in 2002. Second, starting in 2002, adolescent participants receive $30 as incentives to improve the response rate. Third, survey mode was changed from personal interviews with self-enumerated answer sheets (before 1999) to the computer-assisted person interviews (CAPI) and audio computer-assisted self-interviews (ACASI) (since 1999). These changes may confound the historical trends [ 43 ], thus we used two dummy variables as covariates, one for the survey mode change in 1999 and another for the survey method change in 2002 to control for potential confounding effect.

Data acquisition

Data were downloaded from the designated website ( https://nsduhweb.rti.org/respweb/homepage.cfm ). A database was used to store and merge the data by year for analysis. Among all participants, data for those aged 12–25 years ( n  = 749,152) were included. We excluded participants aged 26 and older because the public data did not provide information on single or two-year age that was needed for HAPC modeling (details see statistical analysis section). We obtained approval from the Institutional Review Board at the University of Florida to conduct this study.

Variables and measurements

Current marijuana use: the dependent variable. Participants were defined as current marijuana users if they reported marijuana use within the past 30 days. We used the variable harmonization method to create a comparable measure across 31-wave NSDUH data [ 44 ]. Slightly different questions were used in NSDUH. In 1979–1993, participants were asked: “When was the most recent time that you used marijuana or hash?” Starting in 1994, the question was changed to “How long has it been since you last used marijuana or hashish?” To harmonize the marijuana use variable, participants were coded as current marijuana users if their response to the question indicated the last time to use marijuana was within past 30 days.

Chronological age, time period and birth cohort were the predictors. (1) Chronological age in years was measured with participants’ age at the survey. APC modeling requires the same age measure for all participants [ 33 ]. Since no data by single-year age were available for participants older than 21, we grouped all participants into two-year age groups. A total of 7 age groups, 12–13, ..., 24–25 were used. (2) Time period was measured with the year when the survey was conducted, including 1979, 1982, 1985, 1988, 1990, 1991... 2016. (3). Birth cohort was the year of birth, and it was measured by subtracting age from the survey year.

The proportion of people covered by MML: This variable was created by dividing the population in all states with MML over the total US population. The proportion was computed by year from 1996 when California first passed the MML to 2016 when a total of 29 states legalized medical marijuana use. The estimated proportion ranged from 12% in 1996 to 61% in 2016. The proportion of people covered by RML: This variable was derived by dividing the population in all states with RML with the total US population. The estimated proportion ranged from 4% in 2012 to 21% in 2016. These two variables were used to quantitatively assess the relationships between marijuana laws and changes in the risk of marijuana use.

Covariates: Demographic variables gender (male/female) and race/ethnicity (White, Black, Hispanic and others) were used to describe the study sample.

Statistical analysis

We estimated the prevalence of current marijuana use by year using the survey estimation method, considering the complex multi-stage cluster random sampling design and unequal probability. A prevalence rate is not a simple indicator, but consisting of the impact of chronological age, time period and birth cohort, named as age, period and cohort effects, respectively. Thus, it is biased if a prevalence rate is directly used to depict the historical trend. HAPC modeling is an epidemiological method capable of decomposing prevalence rate into mutually independent age, period and cohort effects with individual-level data, while the estimated period and cohort effects provide an unbiased measure of historical trend controlling for the effects of age and other covariates. In this study, we analyzed the data using the two-level HAPC cross-classified random-effects model (CCREM) [ 36 ]:

Where M ijk represents the rate of marijuana use for participants in age group i (12–13, 14,15...), period j (1979, 1982,...) and birth cohort k (1954–55, 1956–57...); parameter α i (age effect) was modeled as the fixed effect; and parameters β j (period effect) and γ k (cohort effect) were modeled as random effects; and β m was used to control m covariates, including the two dummy variables assessing changes made to the NSDUH in 1999 and 2002, respectively.

The HAPC modeling analysis was executed using the PROC GLIMMIX. Sample weights were included to obtain results representing the total US population aged 12–25. A ridge-stabilized Newton-Raphson algorithm was used for parameter estimation. Modeling analysis was conducted for the overall sample, stratified by gender. The estimated age effect α i , period β j and cohort γ k (i.e., the log-linear regression coefficients) were directly plotted to visualize the pattern of change.

To gain insight into the relationship between legal events and regulations at the national level, we listed these events/regulations along with the estimated time trends in the risk of marijuana from HAPC modeling. To provide a quantitative measure, we associated the estimated period effect with the proportions of US population living with MML and RML using Pearson correlation. All statistical analyses for this study were conducted using the software SAS, version 9.4 (SAS Institute Inc., Cary, NC).

Sample characteristics

Data for a total of 749,152 participants (12–25 years old) from all 31-wave NSDUH covering a 38-year period were analyzed. Among the total sample (Table  1 ), 48.96% were male and 58.78% were White, 14.84% Black, and 18.40% Hispanic.

Prevalence rate of current marijuana use

As shown in Fig.  1 , the estimated prevalence rates of current marijuana use from 1979 to 2016 show a “V” shaped pattern. The rate was 27.57% in 1979, it declined to 8.02% in 1992, followed by a gradual increase to 14.70% by 2016. The pattern was the same for both male and female with males more likely to use than females during the whole period.

Prevalence rate (%) of current marijuana use among US residents 12 to 25 years of age during 1979–2016, overall and stratified by gender. Derived from data from the 1979–2016 National Survey on Drug Use and Health (NSDUH)

HAPC modeling and results

Estimated age effects α i from the CCREM [ 1 ] for current marijuana use are presented in Fig.  2 . The risk by age shows a 2-phase pattern –a rapid increase phase from ages 12 to 19, followed by a gradually declining phase. The pattern was persistent for the overall sample and for both male and female subsamples.

Age effect for the risk of current marijuana use, overall and stratified by male and female, estimated with hierarchical age-period-cohort modeling method with 31 waves of NSDUH data during 1979–2016. Age effect α i were log-linear regression coefficients estimated using CCREM (1), see text for more details

The estimated period effects β j from the CCREM [ 1 ] are presented in Fig.  3 . The period effect reflects the risk of current marijuana use due to significant events occurring over the period, particularly federal and state laws and regulations. After controlling for the impacts of age, cohort and other covariates, the estimated period effect indicates that the risk of current marijuana use had two declining trends (1979–1992 and 2001–2006), and two increasing trends (1992–2001 and 2006–2016). Epidemiologically, the time trends characterized by the estimated period effects in Fig. 3 are more valid than the prevalence rates presented in Fig. 1 because the former was adjusted for confounders while the later was not.

Period effect for the risk of marijuana use for US adolescents and young adults, overall and by male/female estimated with hierarchical age-period-cohort modeling method and its correlation with the proportion of US population covered by Medical Marijuana Laws and Recreational Marijuana Laws. Period effect β j were log-linear regression coefficients estimated using CCREM (1), see text for more details

Correlation of the period effect with proportions of the population covered by marijuana laws: The Pearson correlation coefficient of the period effect with the proportions of US population covered by MML during 1996–2016 was 0.89 for the total sample, 0.81 for male and 0.93 for female, respectively ( p  < 0.01 for all). The correlation between period effect and proportion of US population covered by RML was 0.64 for the total sample, 0.59 for male and 0.49 for female ( p  > 0.05 for all).

Likewise, the estimated cohort effects γ k from the CCREM [ 1 ] are presented in Fig.  4 . The cohort effect reflects changes in the risk of current marijuana use over the period indicated by the year of birth of the survey participants after the impacts of age, period and other covariates are adjusted. Results in the figure show three distinctive cohorts with different risk patterns of current marijuana use during 1954–2003: (1) the Historical Declining Cohort (HDC): those born in 1954–1972, and characterized by a gradual and linear declining trend with some fluctuations; (2) the Sudden Increase Cohort (SIC): those born from 1972 to 1984, characterized with a rapid almost linear increasing trend; and (3) the Contemporary Declining Cohort (CDC): those born during 1984 and 2003, and characterized with a progressive declining over time. The detailed results of HAPC modeling analysis were also shown in Additional file 1 : Table S1.

Cohort effect for the risk of marijuana use among US adolescents and young adults born during 1954–2003, overall and by male/female, estimated with hierarchical age-period-cohort modeling method. Cohort effect γ k were log-linear regression coefficients estimated using CCREM (1), see text for more details

This study provides new data regarding the risk of marijuana use in youth in the US during 1954–2016. This is a period in the US history with substantial increases and declines in drug use, including marijuana; accompanied with many ups and downs in legal actions against drug use since the 1970s and progressive marijuana legalization at the state level from the later 1990s till today (see Additional file 1 : Table S2). Findings of the study indicate four-phase period effect and three-phase cohort effect, corresponding to various historical events of marijuana laws, regulations and social movements.

Coincident relationship between the period effect and legal drug control

The period effect derived from the HAPC model provides a net effect of the impact of time on marijuana use after the impact of age and birth cohort were adjusted. Findings in this study indicate that there was a progressive decline in the period effect during 1979 and 1992. This trend was corresponding to a period with the strongest legal actions at the national level, the War on Drugs by President Nixon (1969–1974) President Reagan (1981–1989) [ 45 ], and President Bush (1989) [ 45 ],and the Anti-Drug Abuse Act (1986) [ 5 ].

The estimated period effect shows an increasing trend in 1992–2001. During this period, President Clinton advocated for the use of treatment to replace incarceration (1992) [ 45 ], Surgeon General Elders proposed to study marijuana legalization (1993–1994) [ 8 ], President Clinton’s position of the need to re-examine the entire policy against people who use drugs, and decriminalization of marijuana (2000) [ 45 ] and the passage of MML in eight US states.

The estimated period effect shows a declining trend in 2001–2006. Important laws/regulations include the Student Drug Testing Program promoted by President Bush, and the broadened the public schools’ authority to test illegal drugs among students given by the US Supreme Court (2002) [ 46 ].

The estimated period effect increases in 2006–2016. This is the period when the proportion of the population covered by MML progressively increased. This relation was further proved by a positive correlation between the estimated period effect and the proportion of the population covered by MML. In addition, several other events occurred. For example, over 500 economists wrote an open letter to President Bush, Congress and Governors of the US and called for marijuana legalization (2005) [ 47 ], and President Obama ended the federal interference with the state MML, treated marijuana as public health issues, and avoided using the term of “War on Drugs” [ 45 ]. The study also indicates that the proportion of population covered by RML was positively associated with the period effect although not significant which may be due to the limited number of data points of RML. Future studies may follow up to investigate the relationship between RML and rate of marijuana use.

Coincident relationship between the cohort effect and legal drug control

Cohort effect is the risk of marijuana use associated with the specific year of birth. People born in different years are exposed to different laws, regulations in the past, therefore, the risk of marijuana use for people may differ when they enter adolescence and adulthood. Findings in this study indicate three distinctive cohorts: HDC (1954–1972), SIC (1972–1984) and CDC (1984–2003). During HDC, the overall level of marijuana use was declining. Various laws/regulations of drug use in general and marijuana in particular may explain the declining trend. First, multiple laws passed to regulate the marijuana and other substance use before and during this period remained in effect, for example, the Marijuana Tax Act (1937), the Boggs Act (1952), the Narcotics Control Act (1956) and the Controlled Substance Act (1970). Secondly, the formation of government departments focusing on drug use prevention and control may contribute to the cohort effect, such as the Bureau of Narcotics and Dangerous Drugs (1968) [ 48 ]. People born during this period may be exposed to the macro environment with laws and regulations against marijuana, thus, they may be less likely to use marijuana.

Compared to people born before 1972, the cohort effect for participants born during 1972 and 1984 was in coincidence with the increased risk of using marijuana shown as SIC. This trend was accompanied by the state and federal movements for marijuana use, which may alter the social environment and public attitudes and beliefs from prohibitive to acceptive. For example, seven states passed laws to decriminalize the marijuana use and reduced the penalty for personal possession of small amount of marijuana in 1976 [ 7 ]. Four more states joined the movement in two subsequent years [ 7 ]. People born during this period may have experienced tolerated environment of marijuana, and they may become more acceptable of marijuana use, increasing their likelihood of using marijuana.

A declining cohort CDC appeared immediately after 1984 and extended to 2003. This declining cohort effect was corresponding to a number of laws, regulations and movements prohibiting drug use. Typical examples included the War on Drugs initiated by President Nixon (1980s), the expansion of the drug war by President Reagan (1980s), the highly-publicized anti-drug campaign “Just Say No” by First Lady Nancy Reagan (early 1980s) [ 45 ], and the Zero Tolerance Policies in mid-to-late 1980s [ 45 ], the Anti-Drug Abuse Act (1986) [ 5 ], the nationally televised speech of War on Drugs declared by President Bush in 1989 and the escalated War on Drugs by President Clinton (1993–2001) [ 45 ]. Meanwhile many activities of the federal government and social groups may also influence the social environment of using marijuana. For example, the Federal government opposed to legalize the cultivation of industrial hemp, and Federal agents shut down marijuana sales club in San Francisco in 1998 [ 48 ]. Individuals born in these years grew up in an environment against marijuana use which may decrease their likelihood of using marijuana when they enter adolescence and young adulthood.

This study applied the age-period-cohort model to investigate the independent age, period and cohort effects, and indicated that the model derived trends in marijuana use among adolescents and young adults were coincident with the laws and regulations on marijuana use in the United States since the 1950s. With more states legalizing marijuana use in the United States, emphasizing responsible use would be essential to protect youth from using marijuana.

Limitations

This study has limitations. First, study data were collected through a household survey, which is subject to underreporting. Second, no causal relationship can be warranted using cross-sectional data, and further studies are needed to verify the association between the specific laws/regulation and the risk of marijuana use. Third, data were available to measure single-year age up to age 21 and two-year age group up to 25, preventing researchers from examining the risk of marijuana use for participants in other ages. Lastly, data derived from NSDUH were nation-wide, and future studies are needed to analyze state-level data and investigate the between-state differences. Although a systematic review of all laws and regulations related to marijuana and other drugs is beyond the scope of this study, findings from our study provide new data from a historical perspective much needed for the current trend in marijuana legalization across the nation to get the benefit from marijuana while to protect vulnerable children and youth in the US. It provides an opportunity for stack-holders to make public decisions by reviewing the findings of this analysis together with the laws and regulations at the federal and state levels over a long period since the 1950s.

Availability of data and materials

The data of the study are available from the designated repository ( https://nsduhweb.rti.org/respweb/homepage.cfm ).

Abbreviations

Audio computer-assisted self-interviews

Age-period-cohort modeling

Computer-assisted person interviews

Cross-classified random-effects model

Contemporary Declining Cohort

Hierarchical age-period-cohort

Historical Declining Cohort

Medical Marijuana Laws

National Household Survey on Drug Abuse

National Survey on Drug Use and Health

Recreational Marijuana Laws

Sudden Increase Cohort

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Additional file 1: table s1..

Estimated Age, Period, Cohort Effects for the Trend of Marijuana Use in Past Month among Adolescents and Emerging Adults Aged 12 to 25 Years, NSDUH, 1979-2016. Table S2. Laws at the federal and state levels related to marijuana use.

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Yu, B., Chen, X., Chen, X. et al. Marijuana legalization and historical trends in marijuana use among US residents aged 12–25: results from the 1979–2016 National Survey on drug use and health. BMC Public Health 20 , 156 (2020). https://doi.org/10.1186/s12889-020-8253-4

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ORIGINAL RESEARCH article

Cannabis for medical use: analysis of recent clinical trials in view of current legislation.

• Department of Drug Science and Technology, University of Turin, Turin, Italy

Cannabis has long been regarded as a recreational substance in the Western world. The recent marketing authorization of some medicinal products of industrial origin and the introduction onto the market of inflorescences for medical use mean that medical doctors can now prescribe Cannabis -based medicines in those countries which allow it. Nevertheless, there is still considerable controversy on this topic in the scientific community. In particular, this controversy concerns: the plant species to be used; the pathologies that can be treated and consequently the efficacy and safety of use; the routes of administration; the methods of preparation; the type and dosage of cannabinoids to be used; and, the active molecules of interest. As such, although medical Cannabis has been historically used, the results of currently completed and internationally published studies are inconclusive and often discordant. In light of these considerations, the aim of this work is to analyse the current legislation in countries that allow the use of medical Cannabis , in relation to the impact that this legislation has had on clinical trials. First of all, a literature search has been performed (PubMed and SciFinder) on clinical trials which involved the administration of Cannabis for medical use over the last 3 years. Of the numerous studies extrapolated from the literature, only about 43 reported data on clinical trials on medical Cannabis , with these mainly being performed in Australia, Brazil, Canada, Denmark, Germany, Israel, Netherlands, Switzerland, the United Kingdom and the United States of America. Once the reference countries were identified, an evaluation of the legislation in relation to Cannabis for medical use in each was carried out via the consultation of the pertinent scientific literature, but also of official government documentation and that of local regulatory authorities. This analysis provided us with an overview of the different legislation in these countries and, consequently, allowed us to analyse, with greater awareness, the results of the clinical trials published in the last 3 years in order to obtain general interest indications in the prosecution of scientific research in this area.

1 Introduction

Cannabis was widely used in the past for its curative properties. The earliest records of its medicinal use date back to China where Cannabis has been cultivated for millennia for use as a fiber, food, and medicine. Over time, it spread to the whole of Asia, the Middle East, and Africa. In the West, the plant started to attract scientific interest only in the 20th century. However, in the last century, the cultivation, sale, and use of Cannabis was made illegal in the majority of countries ( Lafaye, et al., 2017 ; Pisanti and Bifulco, 2019 ; Romano and Hazekamp, 2019 ; Arias, et al., 2021 ).

In the last few decades, there has been revived support for its decriminalisation, and legalisation for medical uses thanks to new and scientifically founded indications of its potential therapeutic value. This is partly due to the support gained in the media, and to the high expectations for its efficacy, even though these hopes, for many diseases, are not sufficiently supported by scientific research ( Hill, 2015 ; Whiting, et al., 2015 ).

The phytocomplex of Cannabis plants is made up of more than 500 molecules, of which about a hundred belong to the Cannabinoid chemical class. Among these molecules, even small variations in molecular structure can produce significantly different effects. The molecules of greatest interest to pharmacologists are the decarboxylated forms of 9-tetrahydracannabinol (THC) and cannabidiol since these are easily absorbed in the intestine ( Grotenhermen, 2003 ; Gould, 2015 ; Baratta, et al., 2019 ; Baratta, et al., 2021 ).

Recently, Cannabis based industrial medicines have been approved for sale, and medical use inflorescences have been made available. This has given medical doctors, in those countries which allow it, the option to prescribe Cannabis -based products. At present, the most widely available products are: Marinol ® (AbbVie Inc) and Syndros ® (Benuvia Therapeutics) which contain dronabinol, an isomer of delta-9-tetrahydrocannabinol; Cesamet ® based on nabilone (Meda Pharmaceuticals Inc.), another synthetic cannabinoid; Sativex ® (GW Pharma Ltd.), based on an ethanol extraction of Cannabis sativa ; and Epidiolex ® 1 (Greenwich Biosciences), which contains CBD ( Casiraghi, et al., 2018 ).

A variety of pharmaceutical-grade inflorescence products are also available on the market. Usually, the label only indicates the concentrations of THC and CBD. This is a critical point as the phytocomplex of medical Cannabis contains many active molecules which contribute to the “Entourage effect,” a hypothesis postulating a positive synergic action between cannabinoids and terpenes ( Stella, et al., 2021 ; Baratta, et al., 2022 ).

Given the increasing availability of the above products, many countries have introduced specific legislation, regulations, and guidelines regarding the use of medical use Cannabis in the treatment of various pathologies. Nevertheless, debate continues around this subject within the scientific community. The main points of contention are the correct plant varieties to be used, the pathologies to be treated, and, consequently, the efficacy and safety of their use. There are no universally shared indications on the optimum administration route, the preparation methodology, the definitive types of cannabinoids and dosages to recommend, or even the identity of the active molecule of interest. This controversy stems in large part from the findings of the clinical trials conducted till now. Although the number of studies and publications is growing rapidly, for many diseases the results are often contradictory or inconclusive. All too often, these trials were performed on a non-homogeneous population, and utilising diverse plant material, extraction methods, dosages, pharmaceutical forms, and administration routes. Moreover, the trials were often conducted without a control group ( Stella, et al., 2021 ).

In light of all these considerations, the objective of this work is to analyse the current legislation and regulations in a number of countries where medical use Cannabis is permitted in order to evaluate any relationship of these on the design of clinical trials carried out there.

2 Materials and Methods

We carried out a literature search (PubMed and SciFinder) for clinical trials with medical Cannabis published in the last 3 years (2019/01/01–2021/12/15). We excluded literature reviews, non-clinical trials, and articles about non-medical use Cannabis . We also considered published articles about clinical trial protocols to be carried out. The key search terms used were clinical trials, medical Cannabis , and medical use.

After the publications had been selected, the countries of origin were identified in order to perform an evaluation of the current regulations in each regarding medical Cannabis . The scientific literature, and relevant official publications from government and local authorities were consulted for this analysis.

Finally, the characteristics and the results of the clinical studies were analysed to evaluate any possible link to the state legislation where the studies had been carried out.

Of the 400 matches from the literature search, only 10% (43) of the publications reported data from trials or clinical protocols regarding medical Cannabis . The relevant trials were carried out in: Australia, Brazil, Canada, Denmark, Germany, Israel, Netherlands, Switzerland, the United Kingdom, and the United States of America. Given their geographical distribution, these countries can be considered of interest despite the small number of studies available.

For each of the countries in question, the current legislation on medical Cannabis was analysed, and some specific features are reported such as: prescription procedure, indicated pathologies for medical Cannabis , products available for sale, dispensation forms, authorisation to grow Cannabis for medical use, and reimbursement procedure.

3.1 Current Legislation

3.1.1 australia.

Although there are some regulatory differences among the federal states regarding the importation of products, and the qualification required to write a prescription, medical Cannabis may be prescribed after receiving authorisation from the Therapeutic Goods Administration, through the Special Access Scheme for an individual patient, or through the Authorized Prescriber Scheme for a group of patients with the same condition. Products of industrial origin are exempt from these schemes as approval for sale has already been granted (Sativex ® and Epidiolex ® ).

As well as Sativex ® and Epidiolex ® , indicated for the treatment of spasticity in multiple sclerosis and paediatric epilepsy, herbal- Cannabis based products may also be prescribed. The most common conditions are spasticity in multiple sclerosis, nausea or vomiting caused by anti-tumoral chemotherapy, pain or anxiety in patients with terminal diseases, and refractory child epilepsy. The physician may in any case write a prescription for pathologies other than those indicated.

Pharmacies are authorised to dispense medical Cannabis -based products.

The cost of the therapy is not subsidised by the government.

Alcohol and Drug Foundation, 2021 ; Australian Capital Territory Government, 2021 ; Australian Government, 2017a ; Australian Government, 2017b ; Australian Government, 2018 ; Australian Government, 2020 ; Australian Government, 2021 ; Australian Institute of Health and Welfare, 2019 ; Castle, et al., 2019 ; Centre for Medicinal Cannabis Research and Innovation, 2021 ; Health Direct, 2019 ; Mersiades, et al., 2019 ; The Health Products Regulatory Authority, 2017 ; The Office of Drug Control, 2021 )

3.1.2 Brazil

Various products of industrial origin are available such as Epidiolex ® and Sativex ® , and the importation of Cannabis -derived products is generally authorised. However, the importation of the raw plant or parts of the plant is not permitted. Products with a concentration of THC greater than 0.2% may only be prescribed when no alternative therapy is available, and the patient has reached the irreversible or terminal stage of their disease. Prescription is under the responsibility of the prescribing medical doctor. The medication may be taken either orally or by inhalation.

The cost of the treatment is generally high and is completely at the patient’s expense.

The dispensation may take place in a pharmacy, where Cannabis may not be processed, however.

( Crippa, et al., 2018 ; Marketrealist, 2019 ; Ministério da Saúde, 2019 ; Reuters, 2019 ; Brazilian Government, 2021 )

3.1.3 Canada

The situation in Canada is quite different, medical Cannabis (with the exception of approved industrial products) is not considered as a medicine; hence, it is not dispensed in pharmacies. Medical doctors or nurses may prescribe it for individual patients. The patient can then acquire it from a licensed vendor; grow a quantity sufficient for personal use in residence after registering with the Ministry for Health; nominate a grower in their place (a grower can only cultivate for two people); or acquire it from a provincial or area level licensed retailer. The patient is allowed to prepare Cannabis -based products, but the use of organic solvents such as butane, benzene, methyl-chloride, or chlorinated hydrocarbons is forbidden.

Regarding industrial products, Sativex ® is available for sale; it is indicated for the treatment of spasticity in multiple sclerosis. Other recommended uses include additional pain relief for neuropathic pain in adult patients with multiple sclerosis, and additional pain relief for patients with late-stage cancer who experience moderate to serious pain when already undergoing palliative care with the highest tolerable dosages of opioids. Nabilone is approved for treatment of serious nausea and vomiting associated with chemotherapy, while dronabinol is approved for the treatment of AIDS-related anorexia, and for serious nausea and vomiting associated with chemotherapy. Dronabinol was withdrawn for the Canadian market by the producer in February 2012, but not for health risks.

Generally, Cannabis may be used for any symptom without demonstrating the inefficacy of the previous therapies.

The approved industrial products may be reimbursed by health insurance companies, while all the others are non-reimbursable.

( Fischer, et al., 2015 ; Ablin, et al., 2016 ; Health Canada, 2016 ; The Health Products Regulatory Authority, 2017 ; Abuhasira, et al., 2018 ; Conseil fédéral, 2018 ; Government of Canada, 2019 ; Health Canada, 2022 )

3.1.4 Denmark

All medical doctors are authorised to prescribe Cannabis -based products as part of a 4 years pilot project launched in January 2018. As part of this project, a medical doctor may prescribe medicines that are not approved for distribution or sale in Denmark. However, the medical doctor must take full responsibility for the products they prescribe and must determine the proper dosage for each patient. Medical doctors may refer to the guidelines laid out by the Danish Medicines Agency. The imported plant products available for prescription may vary in content, but they must comply with strict standards and regulations governing the cultivation of the plant species, and the production and standardisation of the Cannabis -based product.

Herbal Cannabis is available by prescription only in pharmacies, which may also prepare magistral preparations.

Regarding industrial products, neurologists may prescribe Sativex ® to treat spasticity from multiple sclerosis. In general, medical doctors may prescribe imported Cannabis -derived medicines that have not been approved for sale in Denmark, such as Marinol ® and Cesamet ® on compassionate grounds, but only if the request is approved by the Danish Medicines Agency.

In general, the Danish Medicines Agency indicates that medical Cannabis be considered as a therapy only for the following conditions: painful spasticity in multiple sclerosis, painful spasticity caused by spinal cord damage, chemotherapy-induced nausea, and neuropathic pain. As part of the pilot project, Cannabis may, however, be prescribed to any patient even outside of the guidelines. The use of Cannabis is not recommended for patients under 18 years of age.

The prices of the prescribed products within the pilot project are set freely by the manufacturers. It is possible to obtain a reimbursement as of 01/01/2019 (retroactive for 2018). Patients in the terminal stages of a disease are fully reimbursed, while patients with other illnesses receive a 50% reimbursement, up to annual maximum of 10,000 Danish Krone. The reimbursement is automatically deducted at the time of the purchase in a pharmacy.

For prescriptions that are not part of the pilot project, the medical doctor may request a reimbursement for an individual patient from the Danish Medicines Agency. It will consider the request for those patients with pathologies where Cannabis -based treatment appears to be effective, and for those whom all other treatments with approved medicines have been used without effect.

( The Health Products Regulatory Authority, 2017 ; Abuhasira, et al., 2018 ; Krcevski-Skvarc, et al., 2018 ; Danish Medicines Agency, 2020 ; Gustavsen, et al., 2021 )

3.1.5 Germany

Medical doctors may prescribe medical Cannabis using a specific “narcotics” prescription form. The prescription may be for any condition that has no standard treatment, or the standard treatment cannot be used owing to reactions, or based on the patient’s specific condition. Among the industrial products available is Sativex ® , which is indicated for spasticity in refractory multiple sclerosis. In addition, it is possible to prescribe dronabinol without particular restrictions regarding its indicated use. Nabilone is approved for nausea and vomiting associated with chemotherapy and unresponsive to conventional therapies. Finally, Epidiolex ® and many types of Cannabis inflorescences may also be prescribed. Magisterial preparations may be prescribed, and pharmacies may dispense extracts of Cannabis and inflorescences.

In the past, Cannabis could also be theoretically grown in residence by private individuals if conventional therapies had been inefficacious, no other alternative treatments were available, and/or to reduce the cost of therapy. Actually, this possibility has never been really applied. Since 2019, however, a system of checks on the production and supply of Cannabis has been introduced by the government.

The patients may request a reimbursement from health insurance companies. For this purpose the prescribing medical doctor has the task of certifying the seriousness of the disease, that the standard therapies have been ineffective, or cannot be used due to the patient’s specific condition, or that there is a reasonable likelihood that medical Cannabis will be effective for that subject.

( Grotenhermen and Müller-Vahl, 2012 ; Ablin, et al., 2016 ; The Health Products Regulatory Authority, 2017 ; Abuhasira, et al., 2018 ; Conseil fédéral, 2018 ; Federal Institute for Drugs and Medical Devices, 2018 ; Krcevski-Skvarc, et al., 2018 ; Rasche, et al., 2019 ; Federal Institute for Drugs and Medical Devices, 2022a ; Federal Institute for Drugs and Medical Devices, 2022b ; Federal Institute for Drugs and Medical Devices, 2022c ; Federal Institute for Drugs and Medical Devices, 2022d ; German Institute for Medical Cannabis , 2022 )

3.1.6 Israel

In Israel, patients with a prescription may use a licensed pharmacy to obtain medical Cannabis . There is a list of conditions for which Cannabis may be used, but the medical doctor may also prescribe it for other pathologies: in any case, it may only be used when other therapies have proved ineffective. The list includes neuropathic pain, serious cachexia in AIDS patients, spasticity from multiple sclerosis, pain associated with Parkinson’s disease, Tourette’s syndrome, treatment of metastatic cancer or chemotherapy-induced symptoms, inflammatory intestinal diseases and post-traumatic stress disorders.

In general, the products available are Cannabis inflorescences, Sativex ® and Epidiolex ® . The number of medical Cannabis patients among the Israeli population is one of the highest in the world (on February 2022 about 100,000 Israelis -about 1% of the population-were allowed to consume medical Cannabis ).

Sativex ® is recommended for spasticity from multiple sclerosis unresponsive to other treatments, or as an additional analgesic therapy in adult patients with advanced stage cancer with moderate to severe pain despite being administered the highest tolerable dosage of opioids; Epidiolex ® is used to treat convulsions in Dravet syndrome, and Lennox-Gastaut syndrome.

As for herbal Cannabis , a government-run programme produces and distributes this product. Medical Cannabis is supplied in two forms: as an oil extract for oral administration or sub-lingual deposition, and as the inflorescence which may be smoked or inhaled with vaporisers. The cost of the therapy is reimbursed in part by some private and state health insurance schemes.

( abcNEWS, 2022 ; Ablin, et al., 2016 ; Abuhasira, et al., 2018 ; Krcevski-Skvarc, et al., 2018 ; State of Israel - Minister of Health, 2017 ; State of Israel - Minister of Health, 2022 ; The Health Products Regulatory Authority, 2017 )

3.1.7 Netherlands

In Netherlands, all medical doctors may prescribe medical Cannabis . The pharmacies may also produce extracts using the plant material produced by the Office of Medical Cannabis . These are usually oil extracts to be taken orally or deposited under the tongue. Some types of inflorescences are available for this purpose: the concentration of the active molecules and granulation properties may vary. The inflorescences may also be taken in the decoction form or inhaled through vaporisers.

Sativex ® is approved for the treatment of spasticity from multiple sclerosis refractory to conventional therapies.

Cannabis is indicated for the treatment of pain (multiple sclerosis, or spinal cord injuries), chronic pain, nausea and vomiting (in chemotherapy or radiotherapy, HIV therapies, adverse reactions to hepatitis C medication), palliative care for cancer or AIDS (to increase appetite and alleviate pain, nausea and weight loss), Tourette’s syndrome, and refractory glaucoma, epilepsy and epileptic syndromes (even in children). In addition, its use is indicated in the reduction in symptomology of the following pathologies: Crohn’s disease, ulcerative colitis, itching, migraine, rheumatic conditions, ADHD, post-traumatic stress disorders, agitation in Alzheimer’s disease and cerebral trauma. Medical doctors are in any case authorised to prescribe these therapies for other conditions if they consider it fit. Cannabis -based products must, however, be considered only in cases where authorised medicines have inefficacious or provoked unacceptable adverse reactions.

As concerns the available herbal Cannabis species, Bediol ® (THC 6.3%; CBD 8%) is usually recommended as the first-choice therapy to alleviate pain or as an anti-inflammatory therapy. Bedrocan ® (THC 22%; CBD <1.0%), Bedica ® (THC 14%; CBD <1.0%) and Bedrobinol ® (THC 13.5%; CBD <1.0%) are considered more effective for the treatment of symptoms such as appetite loss, weight loss, nausea, vomiting, anorexia, cachexia, emesis, Tourette’s syndrome, and glaucoma. Bedrolite ® (THC <1.0%; CBD 7.5%) is employed for certain forms of epilepsy.

The healthcare system does not reimburse the cost of Cannabis -based medicines. In some cases, the patient may be able to claim from private insurance schemes.

( The Health Products Regulatory Authority, 2017 ; Abuhasira, et al., 2018 ; Conseil fédéral, 2018 ; Krcevski-Skvarc, et al., 2018 ; Bedrocan, 2021 ; Office of Medicinal Cannabis, 2022 )

3.1.8 Switzerland

The prescription and use of Cannabis -based magistral preparations is authorised for spasticity (multiple sclerosis), chronic pain, appetite loss in AIDS, and nausea, pain, and appetite loss from cancer.

The magistral preparations are prepared in a pharmacy.

Medical doctors may prescribe Cannabis -based medicines only after receiving authorisation from the Federal office of the Public Health System.

The cost of the therapy is not reimbursed systematically, but on a case-by-case basis.

As well as the inflorescence, it is possible to use dronabinol and Epidiolex ® . Sativex ® is also authorised for use and available for treatment of spasticity from multiple sclerosis.

( Abuhasira, et al., 2018 ; Krcevski-Skvarc, et al., 2018 ; Swiss Confederation, Federal Office of Public Health, 2020 ; Swiss Confederation, Federal Office of Public Health, 2021a ; Swiss Confederation, Federal Office of Public Health, 2021b ; Swiss Confederation, Federal Office of Public Health, 2021c )

3.1.9 United Kingdom

In the United Kingdom, medical Cannabis is generally prescribed to adults and children with rare and serious forms of epilepsy, adults suffering from nausea or vomiting from chemotherapy, and adults with muscular stiffness or spasms from multiple sclerosis. This therapy is considered only in cases in which no alternative treatment is available, or other treatments have been inefficacious. The available products are Epidiolex ® , prescribed to patients with Lennox-Gastaut syndrome or Dravet syndrome; nabilone, which is authorised for nausea and vomiting associated with chemotherapy; dronabinol is also available, but it has no marketing authorization; and Sativex ® , which is prescribed for muscular spasms in multiple sclerosis unresponsive to other treatments (even though it is discouraged by NICE in that it is not cost-effective).

The medical Cannabis therapy cannot be obtained from a general practitioner but must be prescribed by a hospital specialist registered with the General Medical Council. The medical doctor may collect data on adverse reactions, which can also be signalled directly by the patient through a yellow card system.

( Department of Health and Social Care, 2018 ; Medicines and healthcare products Regulatory Agency, 2020 ; MS Society, 2021 ; National Health Service, 2021 ; General Medical Council, 2022 ; National Health Service, 2022 ; UK Government, 2022 )

3.1.10 United States of America

There are significant legislative differences among the states concerning Cannabis in the United States. In some states the legislation in force is extremely limiting, in others significantly less restrictive. Therefore, the state laws may not be completely harmonised with federal laws.

Regarding industrial products, the FDA has approved the prescription of dronabinol and nabilone for the treatment of chemotherapy-induced nausea and vomiting. Dronabinol may also be used for the treatment of appetite and weight loss in HIV patients. Epidiolex ® may be prescribed for the treatment of epileptic disorders, Lennox-Gastaut syndrome and Dravet’s syndrome.

Concerning herbal Cannabis , only 36 states have legalised or decriminalised its use. In general, in those states which have authorised the use of medical use Cannabis , there are restrictions on its prescription. Depending to the local laws, therefore, Cannabis may be prescribed for pain, anxiety, epilepsy, glaucoma, appetite and weight loss associated with AIDS, inflammatory intestinal disturbances irritable intestine syndrome, motor disturbances due to Tourette’s syndrome or multiple sclerosis, nausea and vomiting caused by chemotherapy, sleep disorders, posttraumatic stress disorders. Some states allow the addition, at the prescribing medical doctor’s discretion, of pathologies other than those expressly stated.

Generally, medical doctors do not need specific training to prescribe Cannabis , but in many states, it is necessary to register before doing so. In other states, medical doctors must attend a short training course to be able to register. In some states, it is enough that the medical doctor gives advice verbally to take medical Cannabis , or its use may be recommended by a health care professional who is not a medical doctor. On the other hand, in some states, it is necessary that two medical doctors confirm the need for a Cannabis -based treatment for a patient. Depending on the state, Cannabis may be supplied to the patient by licensed dispensaries, or it may be grown at home by the patient or by a caregiver.

Smoking medical Cannabis is prohibited in some states. Similarly even the edible forms are prohibited in some states. Generally, the administration is performed orally or by vaporiser.

Patients are generally registered so that the possession and use of medical Cannabis is not prosecuted.

Abuhasira, et al., 2018 ; Alharbi, 2020 ; Carliner, et al., 2017 ; Choo and Emery, 2017 ; Corroon and Kight, 2018 ; Johnson, et al., 2021 ; Mead, 2017 ; National Conferences of State Legislatures, 2022 ; ProCon, 2022 ; Ryan, et al., 2021 ; The Health Products Regulatory Authority, 2017 )

3.2 Study Protocols and Clinical Trials

There are 43 publications of proposed, or executed, clinical trial protocols in those countries whose legislation has been analysed; eight of these regarded proposed clinical trial protocols.

Hence, 35 publications regarded actual clinical trial data. These were sub-divided into three groups: the first, “positive outcome,” included those studies which demonstrated the efficacy of the preparation administered, or that the actual results were in line with those expected (18). The second group, “negative outcome,” included those studies where the authors reported that the administered product was no more efficacious than the placebo (5). Finally, the third group, “inconclusive outcome,” comprised those studies where the results were not conclusive (12).

The characteristics of the taken into account clinical studies are summarized in Table 1 .

TABLE 1 . Characteristics of the selected clinical trials.

3.2.1 Clinical Trials With a Positive Outcome

Of the 18 studies in this category, 4 were conducted in Australia, 4 in Israel, 1 in Switzerland, 5 in the United Kingdom, and 4 in the United States.

Regarding the study design, 2 were multi-centred, 13 used the double-blind method, 14 had a randomised control design, and 14 used a placebo control group.

The sample size varied greatly, from a minimum of 8 to a maximum of 128 enrolled subjects.

As for the products used in the trials, 12 studies administer CBD, 6 studied herbal Cannabis derivatives.

CBD was administered orally in 10 cases, topically and by inhalation in only one study. The herbal Cannabis derivatives were administered by inhalation in 3 cases, and by the oral route in 2 cases. One study considered products to be administered orally, by inhalation or topically.

In 9 studies, the Cannabis derivatives were administered in addition to a standard therapy.

The most commonly studied conditions were behaviour, cerebral activity, and memory (6), pain (4), addiction or abstinence to drugs (3), epilepsy (2), pharmacokinetic studies, safety, and tolerability (2), and nausea and vomiting (1). Two studies were carried out on a paediatric population.

In general, the studies involving the administration of CBD regarded epilepsy, addiction or abstinence to drugs, behaviour, cerebral activity and memory, peripheral neuropathy, pharmacokinetic studies, and safety and tolerability.

Instead, studies administering herbal Cannabis derivatives focused mainly about pain and then about nausea and vomiting, cerebral activity and Cannabis dependence. In most cases both THC and CBD were administered in different ratios. In some cases, a herbal Cannabis strain was used with a high concentration of THC.

( Almog, et al., 2020 ; Birnbaum, et al., 2019 ; Efron, et al., 2021 ; Freeman, et al., 2020 ; Grimison, et al., 2020 ; Hotz, et al., 2021 ; Hurd, et al., 2019 ; Izgelov, et al., 2020 ; Lintzeris, et al., 2020 ; Mitelpunkt, et al., 2019 ; O'Neill, et al., 2021 ; Perkins, et al., 2020 ; Pretzsch, et al., 2019a ; Pretzsch, et al., 2019c ; Wall, et al., 2019 ; Xu, et al., 2020 ; Yassin, et al., 2019 ; Zylla, et al., 2021 )

3.2.2 Clinical Trials With a Negative Outcome

Five trials had a negative outcome. Two of these were conducted in the United States, 1 in Australia, 1 in Brazil and 1 in the United Kingdom.

All of the trials had a randomised control, used a placebo control group, and a double-blind control. The sample size ranged from 14 to 105 enrolled subjects.

As for the products used, 3 studies administered oral preparations containing CBD. 2 studies were based on the administration of inflorescences by inhalation. 4 studies out of 5 administered the product in addition to a standard therapy.

The conditions studied in these trials with CBD were pain, COVID-19 infection, and the effects on neural correlates of reward anticipation and feedback. Herbal Cannabis , in three different forms and different ratios of THC/CBD), was administered to evaluate its efficacy in the treatment of Obsessive-Compulsive Disorder (OCD) and Post-Traumatic Stress Disorder (PTSD).

None of these studies demonstrated that the administered product was more efficacious than the placebo control.

( Kayser, et al., 2020 ; Lawn, et al., 2020 ; Bebee, et al., 2021 ; Bonn-Miller, et al., 2021 ; Crippa, et al., 2021 )

3.2.3 Clinical Trials With an Inconclusive Outcome

12 studies had an inconclusive outcome: 3 were conducted in Australia, 3 in Israel, 1 in the Netherlands, 1 in the United Kingdom and 4 in the United States.

Regarding study design, 10 included a double-blind system, 11 had a randomised control, and 10 utilised a placebo control group. The sample size ranged from a minimum of 6 subjects to a maximum of 150 individuals. Two of the studies were conducted on paediatric subjects.

Concerning the products used, 2 studies administered CBD alone, one study used THC alone, 1 study administered cannabidivarin, 2 studies administered THC and CBD, both alone and in a mixture, 5 studies administered herbal Cannabis derivatives, and 1 study administered both THC and CBD as well as a herbal Cannabis extract.

CBD and cannabidivarin were administered orally; THC, and the mixtures of THC and CBD were administered by inhalation. THC was also administered orally. The herbal Cannabis derivatives were administered by inhalation in 3 studies, while they were for oral use in 2 studies. 1 study used oral administration of a herbal Cannabis extract or an equivalent mixture of THC and CBD.

Six trials predicted that the administration was additional to standard therapy.

The conditions to be studied for the efficacy of CBD were anxiety and cognitive function in patients suffering from epilepsy. THC and/or CBD were administered to evaluate the active dosage or to study its effects on problems linked to appetite and metabolism, herbal Cannabis derivatives were studied to evaluate their activity in Crohn’s disease, ulcerative colitis, pain, haemolytic anaemia, markers of wellness and clinical biomarkers in obese patients. Trials related to autism were conducted with, as well as cannabidivarin, the administration of a herbal Cannabis extract or an equivalent mixture of THC and CBD.

When herbal Cannabis derivatives were administered, the concentration of THC and CBD, and the ratio of the two varied greatly among the trials. Some used products with a high concentration of THC, while others used products with a high concentration of CBD. In 1 trial, different types of inflorescences were administered to evaluate the most efficacious ratio of THC to CBD concentrations against pain.

( Pretzsch, et al., 2019b ; Solowij, et al., 2019 ; Van de Donk, et al., 2019 ; Abrams, et al., 2020 ; Farokhnia, et al., 2020 ; Liu, et al., 2020 ; Lopez, et al., 2020 ; Thompson, et al., 2020 ; Naftali, et al., 2021a ; Anderson, et al., 2021 ; Aran, et al., 2021 ; Naftali, et al., 2021b )

3.2.4 Study Protocols

There are 8 examples of published protocols that have not yet initiated the clinical trial phase. 4 are in Australia, and 1 each in Denmark, Canada, Germany, and Netherlands. The number of enrolled subjects is between 10 and 180 in total. One study will be carried out among the paediatric population.

Concerning the study design, 3 will be multi-centre studies, 7 use a double-blind system, 8 are randomised, and 7 use a placebo control group.

Regarding the products to be used, 4 protocols will use the oral administration of THC and CBD. The ratio between the components in question varies from study to study. In 2 protocols, the administration of CBD is also foreseen. One protocol foresees the administration of both CBD and a preparation containing a high concentration of THC.

For those studies using THC and CBD mixtures, the pathologies to be studied are, pain, dementia, spasms, and the activation of the immune system in HIV patients. Instead, the CBD alone preparations will be administered for behavioural problems and phobias. The herbal- Cannabis derived product will be administered for chronic tic disorder. The protocol that foresees the administration of both CBD and a preparation with a high concentration of THC will focus on the alleviation of pain.

( Costiniuk, et al., 2019 ; Hendricks, et al., 2019 ; Urbi, et al., 2019 ; Van der Flier, et al., 2019 ; Efron, et al., 2020 ; Hardy, et al., 2020 ; Jakubovski, et al., 2020 ; Timler, et al., 2020 )

4 Discussion

From the analysis of the current legislation in states where clinical trials and proposed protocols on medical Cannabis and derived products have been published in the last 3 years, many significant differences have been found regarding the products available, the indicated pathologies for which it may be prescribed, the production of the raw plant material, as well as its reimbursement and prescription. It was evaluated to consider the studies published in the last 3 years supposing that the researchers have benefited from the latest knowledge on medical Cannabis and to make an overview of the pathologies currently under study.

In particular, regarding industrial products, practically every country, with the exception of the United States, has approved the use of Sativex ® . However, Epidiolex ® , dronabinol.Netherlands, and nabilone are also quite common.

In all the countries, the use of herbal Cannabis is also authorised. The only exception is Brazil, which is certainly the country with the most restrictive legislation. Netherlands is the only country to provide directions for use, which are not binding, but quite strict, regarding the plant strain to be used for a determined pathology based on the concentration of active molecules (THC and CBD). Instead, for the other countries, it must be pointed out that the current legislation provides for the use of inflorescences or herbal Cannabis extracts without providing specific directions concerning the recommended concentration of active molecules to treat a determined condition.

Regarding the pathologies or symptoms associated with the more or less well-defined conditions, the most common are pain, nausea, vomiting, spasticity, and epilepsy followed by spasms, and weight and appetite loss. The less frequently indicated conditions in this case include Tourette’s syndrome, PTSD, and glaucoma. In many countries, additional conditions are considered in more or less detail.

In this regard, it is interesting to note that the country with the greatest number of specifically recommended pathologies not indicated in other countries is the Netherlands: perhaps based on the longstanding use of Cannabis both for medical use and recreational purposes. Although the legislation regarding medical Cannabis is quite comprehensive in all the countries considered, some of them, namely Australia, Canada, Denmark, Germany, Israel, Netherlands, and the United States, also permit the prescription of Cannabis for any therapeutic application at the discretion of the medical doctor. However, in Germany, Netherlands and Israel, this is limited to cases in which other therapies have proved ineffective, excessive adverse reactions to standard treatments have occurred, or valid alternative treatments are not available. Instead, in Australia, Canada, Denmark, and the United States, therapeutic strategies different from those specified are authorised regardless of any prior treatment. The prescription of medical Cannabis for any condition certainly does not conform to the procedures generally in force for other medicinal products, and especially products with a psychoactive effect such as those prepared containing THC.

It is interesting to note that in Canada, and in some states in the United States, the medical inflorescences may be grown directly by the patient, and the treatment may be recommended by a health worker, and not only a medical doctor; in the event that the plant species is not home-grown, it is distributed through a licensed dispensary. In Germany, Israel and Netherlands, herbal Cannabis is grown locally under the supervision of a government agency. This is significant if one considers that, in these three countries, the prescription process is highly deregulated regarding the recommended pathologies to be treated with Cannabis , but the same does not apply to its cultivation.

The normal administration routes are oral or by inhalation. Some countries, such as Israel, authorise smoking Cannabis inflorescences as a route of administration, something that is categorically banned in some states of the United States.

In addition, regarding prescription, it is noteworthy that the United Kingdom is the only country where this must be obtained from a hospital specialist. In some states in the United States, on the other hand, the prescribing medical doctor must be registered to prescribe this therapy and have attended a specific training course. In Australia and Switzerland, medical doctors may write the prescription only after receiving authorisation from a specific agency. Therefore, there is a different focus on the prescription process and hence inhomogeneity in this aspect too. The treatment costs are generally borne by the patient, and no reimbursement is foreseen, unless it is from a private health insurance scheme. This certainly restricts access to this kind of therapy to the more privileged members of society.

Concerning the results of the clinical trials, some interesting observations may be made. In the first place, a greater number of studies have been published in certain countries. These countries are the United States (11) and Australia (9), followed by Israel (7) and the United Kingdom (7). In general, the majority of the studies featured randomisation, the use of a double-blind method, and a placebo control group: these are factors which guarantee the quality of the data gathered. On the other hand, the majority of the studies took place with a small sample size. Moreover, the studies made use of a heterogeneous population: healthy and ill volunteers, adults and children, acute and chronically ill patients, and subjects who had previously used or had never used Cannabis prior to the study. Factors that, being so numerous, make it particularly challenging to draw any conclusive evaluations of the results of these trials, and more in general, the real efficacy of medical Cannabis .

Considering only the studies with a positive outcome, it should be noted that the studied pathologies are coherent with those provided for in current legislation i.e., pain, epilepsy, nausea, and vomiting; on the contrary, psychosis, behavioural problems, memory and cerebral activity represent a novelty. Furthermore, there is a net distinction between the products used based on the different conditions to be treated: the trials on pain, nausea and vomiting with positive outcomes administered herbal Cannabis derivatives in which, in 3 cases out of 4, both THC and CBD are present; the other studies with a positive outcome administered CBD alone. In those trials with a negative outcome, CBD was administered for pain, while herbal Cannabis derivatives were used for conditions such as OCD or PTSD. This consideration supports the use of herbal Cannabis in which both THC and CBD are present for pain, even though it should be stressed that the studies with a positive outcome for this pathology had a maximum of 30 enrolled subjects.

The studies with an inconclusive outcome regarded a variegated list of conditions including anxiety, Crohn’s syndrome, ulcerative colitis, pain, and appetite loss. Many of these are already included in some national regulations although the efficacy of Cannabis in these cases according to the currently available data is not satisfactorily demonstrated.

It is evident that the only pathology present in all three study categories is pain, for which 4 studies had a positive outcome, 1 had a negative outcome, and 1 had an inconclusive outcome.

Among the study protocols to be trialled, pain and spasticity appear again, approved by legislation in most countries and the object of numerous studies, as well as a number of less-investigated conditions such as dementia, phobias, tic disorders and the activation of the immune system in HIV patients.

Based on the research conducted, it is, therefore, possible to stress that in spite of the growing number of recent studies on medical Cannabis , many of which have had a positive outcome while many others have had an inconclusive or negative outcome. The presumed broad spectrum action of Cannabis has led to the initiation of many trials and the preparation of many study protocols for a wide range of pathologies with the enrolment of subjects with diverse characteristics from study to study. This means that there is very little data for each pathology or symptomology.

Another important factor is that the products used are very diverse from each other; consequently, a comparison is extremely difficult to make, especially for the herbal products. All of the trials indicate the precise dosages used in terms of active molecules, but when it comes to inflorescences, or extracts derived from them, the concentration is provided only for the THC and CBD content and not for the other active molecules. Furthermore, the diverse administration routes make a comparison based on pharmacokinetics difficult for the molecules of interest.

Therefore, it is difficult to compare the studies and draw conclusions concerning the efficacy of the protocol for the single pathologies. However, for some, substantial evidence is emerging regarding their efficacy and the suitable products to ensure that. From the analysed data, it is clear that the best pain treatment is herbal Cannabis derivatives containing both THC and CBD, just as the best way to treat epilepsy is to administer CBD.

One interesting point is that for some of the pathologies approved for treatment with medical Cannabis under the current legislation, the data do not paint a definitive picture. This is true for conditions such as anxiety, ulcerative colitis, Crohn’s syndrome, and appetite enhancement.

On the other hand, the current legislation often authorises inflorescences or extracts without indicating the exact concentration of the active molecules. In parallel, many studies use different plant strains or study a small number of subjects, making it difficult to compare and consequently interpret the results. Moreover, in many studies, the Cannabis -based medicines were administered in addition to other treatments making any evaluation of their efficacy it even more complex.

5 Conclusion

Medical Cannabis is often considered as if it were a single active component, but, in fact, there are countless possible variations. Hence, it will be some time before the current list of pathologies that each product may be used for can be updated based on definitive clinical data on the efficacy of the various components. Certainly, the development of standardised industrial products will facilitate the execution of more meaningful trials compared to those that involve the administration of inflorescences or derived extracts prepared using a variety of methods and, thus, highly variable in terms of concentration of the active molecules.

The authors want moreover to put in evidence that, despite legislation authorising the use of medical Cannabis and instituting the national production centre for inflorescences more than 5 years ago, Italy is still among the states where clinical trials have not been conducted. This gap is due to legal restrictions on the approval and conduction of clinical trials in this field, and the difficulty in sourcing the raw plant material, of which there is always a shortage. The result of this is therapies using inflorescences and extracts which have never undergone specific clinical trialling.

In the end, the influence of the media, economic interests, and the demands of associations representing patients affected by these diseases and conditions, for whom Cannabis is a panacea, means that in many countries it is currently possible to use medical Cannabis even though the scientific data do not entirely support the signs of efficacy: certainly this is a special case where the consolidated procedures for the administration of any product in the medical field have been either overlooked or ignored. It is time that the regulatory agencies considered whether this is actually safeguarding the health of patients.

The analysis of the current legislation may not be exhaustive in that it refers only to public texts available online.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author Contributions

FB and PB performed the conceptualization of the work. FB, IP and LE performed the investigation and took care of the data. FB wrote the manuscript. PB coordinated the project. All authors approved the final version of the study.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

The authors would like to thank Dr Tom O Byrne for the linguistic revision of the text.

Abbreviations

ADHD, Attention-Deficit/Hyperactivity Disorder; AIDS, Acquired ImmunoDeficiency Syndrome; CBD, CannaBiDiol; COVID-19, COronaVIrus Disease 2019; FDA, Food and Drug Administration; HIV, Human Immunodeficiency Virus; NICE, National Institute for health and Care Excellence; OCD, Obsessive-Compulsive Disorder; PTSD, Post-Traumatic Stress Disorder; THC, delta-9-TetraHydroCannabinol; United States, United States of America.

1 Epidiolex ® has received approval in the European Union under the tradename Epidyolex ® .

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Keywords: medical Cannabis , clinical trials, study protocols, legislation, law

Citation: Baratta F, Pignata I, Ravetto Enri L and Brusa P (2022) Cannabis for Medical Use: Analysis of Recent Clinical Trials in View of Current Legislation. Front. Pharmacol. 13:888903. doi: 10.3389/fphar.2022.888903

Received: 03 March 2022; Accepted: 09 May 2022; Published: 25 May 2022.

Reviewed by:

Copyright © 2022 Baratta, Pignata, Ravetto Enri and Brusa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: F. Baratta, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

• Open access
• Published: 19 July 2021

Processing and extraction methods of medicinal cannabis: a narrative review

• Masoumeh Pourseyed Lazarjani 1 ,
• Owen Young 2 ,
• Lidya Kebede 1 &
• Ali Seyfoddin   ORCID: orcid.org/0000-0003-4343-9905 1  

Journal of Cannabis Research volume  3 , Article number:  32 ( 2021 ) Cite this article

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Introduction

As the cannabis industry transitions from a black market to a legal market, product development, and methods of extraction have become a focal point. To date, more than thousands of chemical constituents have been identified from the cannabis plant, all of which possess different chemical properties that require different conditions for preservation during drying and extraction. However, scientific publications that explore these areas for the cannabis plant are currently lacking.

This is a narrative review paper which focuses on critiquing drying and extraction methods of Cannabis sativa L. plant. Relevant keywords such as medicinal cannabis, extraction, solvent, cannabinoids, and terpenes have been searched in PubMed, EMBASE, MEDLINE, Google Scholar, and Cochrane Library (Wiley) databases.

To find relevant papers for this narrative review, 93 papers have been reviewed. Among them, 12 irrelevant papers were discarded. The excluded papers were either about hemp seed oil or hemp fiber and protein. Based on this review, solvent extraction is the most common method for cannabis plants. Although solventless and hydrodynamic extraction are known for their high yield and feasibility, more investigation is needed in these areas. Regarding the drying process, hang-drying is the most convenient method; however, it may be substituted by freeze-drying in the near future.

This review analyses various drying and extraction processes to guide the selection of suitable methods for various types of cannabis products and applications. This is done by outlining traditional and modern methods of drying techniques, exploring the importance of solvents for extraction, visiting solventless extraction procedures, and finally comparing conventional and alternative methods of extraction.

In conclusion, based on the current knowledge, using organic solvents is the most convenient method for medicinal cannabis extraction. However, more research is needed for some of the drying and extraction methods. Also, developing a green and sustainable cannabis extraction method should be considered for future studies.

Cannabis is a flowering plant from the Cannabaceae family and genus Cannabis . Cannabis sativa and Cannabis indica are generally well known, while subspecies Cannabis ruderalis is often overlooked due to its limited ability in producing active compounds (Gloss 2015 ). Hybrid species are variable depending on the parent plant; they can be sativa dominant, indica dominant, or balanced. Within the genus, the number of species is disputed, and the traditional nomenclature of sativa and indica may not be correct or useful in determining therapeutic potential. In any case, cannabis is dioicous, meaning it exhibits both male and female reproductive structures in separate individual plants. Female cannabis plants produce more glandular trichomes compared to the male plant. Among all the known compounds in the cannabis plant, cannabinoids and terpenes are the most active compounds with therapeutic potential which largely synthesized in those glandular trichomes. These compounds have shown to have therapeutic effects on a range of conditions such as metabolic disorders, neurodegenerative disorders, movement disorders, anorexia in HIV patients, nausea, and pain after chemotherapy in cancer patients (Namdar et al. 2018 ; Romano and Hazekamp 2013 ) (Table 1 ).

As the cannabis industry transitions from a black market to a legal market, product development, and methods of extraction have become a focal point. Traditionally, the dried cannabis flower has been a popular product for the use of smoking and vaping. However, as the industry expands, the need for cannabis products in different forms and higher potency also increases. Currently available products, medicinal or recreational, come in the forms of topicals, edibles, beverages, and vaporization cartridges. Each product type presents its own set of advantages and disadvantages allowing for customization to serve a particular purpose (Blake and Nahtigal 2019 ). For pharmaceutical and food applications, the extraction and isolation of active components and combinations of identified cannabinoids are critical steps that should be explored (Fathordoobady et al. 2019 ).

The separation of bioactive compounds has recently become rapidly sought after by the pharmaceutical and food industries. This is due to the increased understanding of the dynamic nature and potential of diverse bioactive molecules from natural sources (Azmir et al. 2013 ). To further continue scientific research on the selection, identification, and characterization of bioactive compounds, the selection of a suitable extraction process is imperative (Azmir et al. 2013 ). Failing to designate a fitting method of sample preparation can jeopardize any analytical procedure resulting in unfavorable outcomes. However, the field of extraction is often neglected and is not studied as thoroughly as other processes. This creates a gap in the literature that should be explored more extensively (Smith 2003 ). The process of extraction is commonly employed to obtain target bioactive compounds from complex plant matter, yet it can also be altered to cater for many purposes, for instance, increasing the selectivity and sensitivity of bioassays by increasing the concentration of a target compound, as well as providing a potent and reproducible sample matrix (Smith 2003 ). Valizadehderakhshan et al. ( 2021 ) compared different extraction methods for seed and trichomes in Cannabis sativa L. They also reviewed various parameters that affect cannabinoid transformation after extraction (Valizadehderakhshan et al. 2021 ).

Different methods of extraction will yield varying degrees of extract quality and composition depending on the procedure and substances used (Blake and Nahtigal 2019 ). This review focuses on various drying and extraction methods while comparing conventional and most recent methods. For example, conventional methods of extraction including Soxhlet and dynamic maceration have longer extraction time and large amounts of solvent are required to complete the extraction process (Agarwal et al. 2018 ). Recent methods including ultrasonic-assisted, microwave-assisted, supercritical fluid, and pressurized liquid extraction processes can be considered as an alternative, slightly greener, options as opposed to the conventional methods. These procedures reduce the need for synthetic and organic solvents, cut down on operational time, and produce a better quality extract with a higher yield (Azmir et al. 2013). Solventless methods such as dry sieve and water extraction are particularly known to extract entire trichomes. Hydrocarbon extraction methods can be used to avoid unwanted water and pigments such as chlorophyll. Ethanol can extract flavonoids, while carbon dioxide can be manipulated to extract different compounds depending on the conditions (Blake and Nahtigal 2019 ).

The characteristics of the product must be considered when deciding on a method. For example, depending on the application, cannabinoids can be extracted in either acidic or neutral form. The preservation of acidic cannabinoids requires extraction to be completed at room temperature (Citti et al. 2016 ). To decarboxylate acidic cannabinoids into neutral form, high temperatures are recommended for extraction, although a higher temperature may result in the loss of some terpenes and minor constituents (Fathordoobady et al. 2019 ). Therefore, the selection of an appropriate extraction procedure will benefit future stages of development by minimizing the requirements for refinements (Blake and Nahtigal 2019 ). To further understand the processes and possible outcomes, this review will explore different methods of drying and extraction procedures used for the cannabis plant.

This paper is a narrative review paper which focuses on drying, extraction, and post-extraction methods for Cannabis sativa L. plant. A combination of keywords such as medicinal cannabis, extraction, solvent, and cannabinoids have been searched in databases such as PubMed, EMBASE, MEDLINE, Google Scholar, and Cochrane Library (Wiley) from 1977 to 2021 in English.

The focus of this narrative review was on Cannabis sativa , initially where 93 papers were identified. Papers on various drying and extraction methods specifically for Cannabis sativa L. were included while those for using hemp as fiber and protein sources were excluded. Overall, 12 papers about cannabis seed oil, hemp seed oil, or hemp plant were excluded as this review focuses on the oil coming from flowers. In the end, 81 related papers about various drying, extraction, and post-harvest processes were carefully reviewed.

Influence of external factors on cannabis

External factors such as light duration, oxygen, and harvest time (floral maturity) have been shown to influence the secondary metabolite production in cannabis (Liu et al. 2015 ; Namdar et al. 2019 ). A 4-year study by Lindholst ( 2010 ) found that cannabinoid stability is affected by temperature, light, and air. Three conditions were used to store cannabis resin (hashish slabs) and extract (by the solvent): room temperature and 4 °C both with visible light exposure and darkness, and − 20 °C in darkness. The study identified that in cannabis resin, light exposure can affect the decarboxylation of THCA and the degradation of THC. This is evident as the half-life increased by 40% in darkness. However, it was observed that light was only partially influential. The resin samples that were placed at room temperature, in either light or dark settings, only exhibited little differences in the degradation of neutral THC. The dense color and structure of resin are thought to be the reason behind the reduced light sensitivity of THC. Accordingly, it is suspected that the exposure of light on resin only reaches the cannabinoids on the surface resulting in low degradation levels. This theory is further illustrated when a comparison was done between the degradation levels of both acidic and neutral THC levels in cannabis resin and cannabis extract. It was observed that both the neutral and acidic forms of THC in the cannabis extract degraded significantly more through light exposure. Furthermore, compared to resin, cannabis extract had a 10 times lower half-life (35 days for extract and 330 days for resin), while THCA decreased to nondetectable levels after 140 days. The neutral forms, in the extract, increased during this period, although THC concentrations were reduced to 1.7% after 2 years at room temperature with light exposure. It was also found that extracts stored at 4 °C showed the same pattern, but degradation was slower, while at − 20 °C all measured cannabinoids remained unchanged during the study period (Lindholst 2010 ). Danziger and Bernstein ( 2021a , b ) evaluated the effect of light on three chemovars of cannabis under four different light conditions. In this study, light as the key factor affected the profile and yield of cannabis chemovars. To be precise, using blue to red lights (1:1 and 1:4 ratios) had the highest yield compared to white LED light. In addition, CBGA as a primary cannabinoid and precursor for many cannabinoids increased by using blue light (Danziger and Bernstein 2021a ). The same authors in another study investigated the effect of architectural manipulation of the plant on the cannabinoid’s standardization. Defoliation, removing primary and secondary branches, and pruning have been considered as a part of eight various architectural manipulation treatments in different light intensities. Results showed that plant architectural modulation affects cannabinoid profile while no changes has been reported in the decarboxylation of cannabinoids (Danziger and Bernstein 2021b ). Saloner and Bernstein ( 2021 ) evaluated the effect of nitrogen supply as an environmental factor on cannabinoids and terpenes. Results showed that the concentration of THCA and CBDA decreases by increasing the amount of nitrogen 69% and 63%, respectively. Bernstein et al. ( 2019 ) evaluated the effect of common minerals on the cannabinoid profile by adding humic acid (HA), phosphor (P), nitrogen (N), and potassium (K) to the commercial treatment into irrigation solution for a high THC cannabis chemovar. Each of the supplements affected the cannabinoid concentrations differently based on the organ and its location in the plant. For example, adding NPK supplement increased 71% the amount of CBG in the flower, while it decreased the amount of CBN in the flowers and leaves by 38% and 36%, respectively (Bernstein et al. 2019 ).

For many applications, the dried version of the cannabis herb is required; however, like many plants, cannabis contains approximately 80% water. For this reason, drying is considered an essential step for product development (Hawes and Cohen 2015 ). Drying the plant not only prevents the growth of microorganisms that would otherwise rot plant tissue (based on ASTM D8196-18 which is a standard practice for determination of water activity (aw) in cannabis flower), it would also enable long term storage while maintaining potency, taste, medicinal properties, and efficacy (Hawes and Cohen 2015 ). This is done by maintaining the water activity level between 0.55 and 0.65 aw, minimizing the risk of mold or fungal infection while preserving the quality of the flower (ASTM D8196-18).

Air-drying, also known as hang-drying

Hang-drying or air-drying is considered the oldest way of drying cannabis plants after harvest (Fig.  1 ) that requires no dedicated equipment (Ross and ElSohly 1996 ). Slow-drying includes placing whole plants or separated inflorescence in a cool dark room with a temperature between 18 and 25 °C and humidity between 45 and 55%, either hung from a string or laid out on drying screens (Hawes and Cohen 2015 ). Ross and ElSohly ( 1996 ) applied four treatments for air-drying to evaluate the efficacy of each condition in producing the highest yield of cannabis products. The treatments were extracted immediately, after the flower harvest at room temperature (0.29% yield, w/v) (A), after 1 week of air-drying at room temperature (0.20% yield based on wet material, v/w) (B), after 1 week of air-drying followed by storage for 1 month at room temperature (0.16% yield based on wet material, w/v) (C), and air-drying for 1 week and stored in paper bags for 3 months at room temperature (0.13% yield based on wet material, v/w) (D). From this experiment, it was found that the yield from treatments A to D decreased from 29 to 13%, respectively (Ross and ElSohly 1996 ). Inconveniences of this method include the manual removal of leaves and buds from the stem as well as the time taken to complete the overall process. The separation is crucial as different parts dry at different rates; therefore, a lack of completing this step may result in uneven drying. Consequently, a disadvantage of removing buds from stems is the possibility of producing a product with a harsher taste. Another detriment of this method is the involvement of gravity. The water from the top part of the plant will absorb into the lower parts leading to a slower and uneven drying process. To speed up the procedure, heaters, fans, and dehumidifiers can be used. However, fast-drying can lead to a harsher taste as opposed to slow-drying which produces smoother tasting products. It is also believed that speeding up the drying process can prevent the plant from reaching peak potency in the curing phase (Hawes and Cohen 2015 ). Coffman and Gentner ( 1974 ) evaluated the effect of drying conditions on the cannabinoid profile. They stored the cannabis hang dried leaves in 65, 85, and 105 °C for 1, 4, 16, and 64 h to compare the mean percentage of total cannabinoid content. The results were shown that the percentage of total cannabinoids was decreased by increasing time and temperature. To be precise, the percentage mean weight loss of total cannabinoids increased from 7.5 to 11% in 65 °C after 1 h and 105 °C after 64 h, respectively.

Air-drying (hang-drying) of the cannabis plant

Oven-drying

A faster direct method of drying is the oven-drying approach (Mujumdar 2006 ). This method can be carried out in either a vacuum chamber, vacuum desiccator, or in a drying oven with or without air circulation (Hawes and Cohen 2015 ). To illustrate the outcomes of the process, an early study tested out four different oven conditions to compare the end products. Inflorescences were dried for 1, 4, 16, and 64 h at 65, 85, and 105 °C. After extraction with ethanol, gas chromatography showed that the yield of CBD and THC decreased as the temperature and time of drying increased. It was also observed that at temperature 105 °C, the thermal degradation of THC increased the CBN content (Coffman and Gentner 1974 ). CBN is considered a less potent psychoactive and mild analgesic; therefore, conversion of THC to CBN will decrease the therapeutic potential (Citti et al. 2016 ).

Additionally, using high temperatures and excessive drying can result in the loss of key components (Hawes and Cohen 2015 ). This statement can be the reason for the lack of information about using oven dying in the cannabis industry. This was highlighted in a study that compared the ratio of cannabinoid and by-product produced during vaporization. The cannabis material was placed in the desiccator for 5 days to dry out, while the smoke condensate and vaporized condensate trapped in the organic solvent were dried with a rotary evaporator at 40 °C. These approaches had produced intense fragrance which is indicative of the loss of terpenoids and other volatile components (Pomahacova et al. 2009 ).

Freeze-drying

Freeze-drying (also known as lyophilization) has become a popular option due to the increasing demand for high-quality medicinal cannabis. The freeze-drying method holds the cannabis plant at temperatures far below those of air or oven, while removing the water content, in the form of vapor, via sublimation in a vacuum chamber (Mujumdar 2006 ). The nascent legal cannabis industry claims that freeze-drying preserves the volatile compounds and acidic form of cannabinoids (Tambunan et al. 2001 ). It is generally agreed that the end products of freeze-drying are considered high quality compared to other methods of drying. This is due to the structural rigidity found on the surface of frozen materials where sublimation occurs, preventing the disintegration of the solid matrix and resulting in a porous, unaltered structure (Mujumdar 2006 ). When assessing the end product produced by freeze-drying, it was found that the composition is largely unaffected from that found in the plant (Tambunan et al. 2001 ). A disadvantage of freeze-drying is the cost of operation. This procedure requires an intense amount of energy to maintain such temperatures, vacuum, and long-running time (Mujumdar 2006 ).

Comparing the different drying methods, we can safely state that the approach elected will affect the yield and cannabinoid profiles in the extracts. Therefore, the selection of a drying procedure will largely alter the outcomes (Coffman and Gentner 1974 ). The process of hang-drying cannabis was found to be time-consuming as it can take several days, while the main factors that increase the rate of drying were determined to be moving air and low humidity (Ross and ElSohly 1996 ). In contrast, the oven-drying method was observed to be faster, but readily volatile compounds and neutral forms of cannabinoids decreased in extracts to almost non-detectable concentrations, affecting therapeutic potential (Coffman and Gentner 1974 ). To address this issue, freeze-drying is thought to be the preferred method. Freeze-drying enables the preservation of flavor qualities in many foods, themselves often due to the presence of volatile compounds (Tambunan et al. 2001 ).

In all the drying methods mentioned above, humidity, temperature, ventilation rate, and time are the most important parameters to be optimized. Incorrect drying conditions may cause decarboxylation of acidic cannabinoids and loss of terpenes. The presence of light, oxygen, and heat may also cause degradation in cannabinoids and terpenes and can affect the taste (Jin and Chen 2019 ).

Curing is the final post-harvest procedure that allows for the development of the maximum flavor in the cannabis plant (Vogel 2018 ). Jin et al. ( 2019 ) believed that the best temperature and humidity for curing are at 18 °C and 60% RH for 14 days. Green et al. ( 2018 ) suggested keeping the trimmed flowers in a can for up to 4 weeks in a dark cupboard while opening the lid every day for about 6 h is the best method for curing (Jin and Chen 2019 ). At temperatures between 15–21 °C and 45–55% humidity, enzymes and aerobic bacteria will be in the optimum condition to breakdown undesired sugars and degrade minerals. Curing can reduce the harsh smell and the sense of throat burning during smoking or vaping as well as increasing the shelf life by minimizing mold growth. It is also believed that curing can increase cannabis potency as the number of cannabinoids such as THC and CBN will increase by curing. Although curing is one of the most significant post-harvest stages for the cannabis plant, there are not enough academic investigations around this area.

Extraction methods

Cannabis extraction can be used to concentrate target components for product development. There are important parameters that can affect the yield of the cannabis extract such as mean particle size, size distribution, temperature, rate of agitation, and extraction time (Fathordoobady et al. 2019 ). Solventless, solvent-based, convention, and alternative methods of extraction are explored concerning cannabis extraction.

Solventless extraction

Long-established solventless methods such as dry-sieving, water extraction, and rosin press extraction lack coverage in literature due to outdated techniques and difficulty in scaling despite having simple procedures. Dry sieve extraction produces a powder-like Kief with a potency of approximately 35–50% THC. The process of dry-sieving begins by beating dried cannabis against a mesh screen and forcing the trichomes to separate and fall off. The final product can either be pressed further into hashish or mixed with dried flowers. This simple procedure is time-consuming and labor-intensive, therefore, not popular for the industrial level. Water extraction produces roughly the same potency of THC as the dry sieve method, although it also depends on the potency of the starting material. The procedure begins by placing the cannabis plant in a mesh bag immersing it in ice water and finally stirring it to knock the trichome off. The trichome is further filtered through a series of screens then allowed to settle before collecting and drying the final product, commonly known as water hash or bubble hash. Similarly, to dry sieving, this process is difficult to upscale as well as limited control of potency (Blake and Nahtigal 2019 ).

Solventless extraction exploits the fact that cannabinoids are semi-liquid and can be extracted by suitable heating and pressure. Rosin extraction uses compression and heat to obtain oils and rosin. Rosin extraction can be as simple as using a hair straightener for recreational extractions. For more commercial medicinal applications, a modified hat press is adopted. For both methods, high pressure at low temperatures is not achievable; therefore, the retention of terpenes is limited (analytical cannabis.com) (Lamy et al. 2018 ). To prevent high-temperature changes, a typical pneumatic press can be used, exerting some lower temperatures and preserving the terpenes. Pressures up to 137.8 MPa can be generated in some pneumatic presses.

Solvent-based extraction

Solvent-based extraction methods such as Soxhlet, maceration both static and dynamic, ultrasonic-assisted extraction, and microwave-assisted extraction require a solvent to complete the extraction process. A variety of solvents can be used to extract cannabinoids including ethanol, butane, propane, hexane, petroleum ether, methyl tertbutyl ether, diethyl ether, carbon dioxide (CO 2 ), and olive oil (Dussy et al. 2005 ; Lehmann and Brenneisen 1992 ; Romano and Hazekamp 2013 ; Rovetto and Aieta 2017 ). Gaseous solvents such as butane and propane can also be used for extraction purposes (Raber et al. 2015 ). Gas solvent extractions start in the gas phase at room temperature and are either cooled or pressurized into a liquid state as they run through the sample material (Rovetto and Aieta 2017 ). The extracted sample is collected, and the solvent is evaporated (Chan et al. 2017 ). The process of pressurizing these flammable and potentially explosive gases poses safety hazards (Jensen et al. 2015 ). In addition, the gases used in cannabis extractions are often industrial grade and contain impurities that end up in the cannabis extracts. Moreover, the solvents themselves may become a residue in the final extract (Raber et al. 2015 ).

The differing solubilities of individual cannabinoids and other phytochemicals are thought to be an important factor that needs to be considered when selecting a solvent. The stickiness and viscosity of cannabis oil result in binding to solvents; therefore, it is important to consider the toxicity, affinity, and temperature profile of the solvents being used (Fathordoobady et al. 2019 ). The efficiency of conventional methods of extraction is presented to be heavily dependent on the solvent of choice. Solubility, molecular affinity, mass transfer, co-solvent, toxicity, and environmental safety are major factors that should also be considered during the solvent selection process (Azmir et al. 2013 ). Commonly used solvents to extract cannabis can be divided into three groups, low molecular mass organic solvents, vegetable fats (oils), and supercritical fluids, notably supercritical carbon dioxide (Reichardt and Welton 2011 ).

Low molecular mass organic solvents

Low molecular mass organic solvents are hydrocarbon-based with limited polarity due to the presence of oxygen. Halogen substituted hydrocarbons are also included in this group.

These solvents are known for their ability to dissolve generally nonpolar compounds, following the chemistry adage: like dissolves like. Inspection of cannabinoids in Table 2 shows that they are dominated by carbon and hydrogen, making them generally nonpolar. However, the presence of alcohol and acid groups requires some polarity in extraction solvents and solvent mixtures.

Table 2 shows some of the properties of the most popular organic solvents in cannabis extraction. Notably absent from this popular group are dichloromethane and chloroform, both halogenated hydrocarbons are commonly used in analytical fat/oil extraction from plant and animal tissue. These solvents are observed to have low boiling points and high volatility, indicating their ability to be easily separated from the extract at low temperatures after the extraction process (Reichardt and Welton 2011 ).

To illustrate how different solvents can affect the yield of compounds from the source material, consider the example of phenolic extraction from grape pomace and elderberry. Phenols are nominally water soluble. The solvent combinations ethanol–water and acetone–water mixtures had a higher yield than ethyl acetate-water mixture (Vatai et al. 2009 ). In another example, isopropanol-hexane, chloroform–methanol, and hexane were used as solvents for crude fat extraction from insect, egg yolk, and krill powders in one-step organic solvent extraction. The highest fat yield was achieved with a chloroform–methanol mixture (Rose 2019 ). Thus, with a mixture of cannabinoids, terpenes, chlorophyll, carotenoids, and other fat-soluble classes in cannabis flowers, different extraction efficiencies can be confidently predicted. If seeds have matured, the fats (triacylglycerols) that comprise the energy stored in seeds will also be extractable to some extent.

Namdar et al. ( 2018 ) reported that for cannabis plant extraction, the ratio and the nature of the solvents can determine the evaporation time after extraction, which should be minimized. A mixture of polar and non-polar solvents achieved the highest yield for all the compounds in the cannabis plant (Namdar et al. 2018 ).

Vegetable fats (oils)

Vegetable oils are routinely extracted from seeds or fruits such as rapeseed, sunflower, or olive, and even brans, making them an inexpensive option. These oils are considered lipophilic due to their nonpolar characteristic, which enables selective dissolving properties. Approximately, 95 to 98% of vegetable oils consist of triglycerols whose composition is dominated by six fatty acids (Yara-Varón et al. 2017 ). Figure  2 shows the major fatty acids in different vegetable oils (Yara-Varón et al. 2017 ). Each of these has a degree of emulsifying capacity that may play a role in cannabinoid extraction. Interestingly, apart from olive oil, some specialized oils, nearly all commercial oils, are refined to eliminate the minor components. Whether this could affect cannabinoid extraction is unknown.

Vegetable oils composition by fatty acid profile, inspired by Yara-Varón et al. ( 2017 )

Olive oil is a well-known solvent in the cannabis extraction field. It is also one of the least refined oils with characteristically high oleic acid content. Terpenes can be preserved during extraction with olive oil due to their low volatile nature. Romano and Hazekamp ( 2013 ) used two different protocols with olive oil for cannabis extraction. In the first experiment, 5 g cannabis with 20 ml olive oil and 50 ml water were mixed and heated up to 60 min. In the second experiment, 10 g cannabis with 100 ml olive oil were mixed and heated for up to 120 min. The extract concentration to the solvent ratio for the first and second protocols was 5 g/20 ml and 10 g/100 ml, respectively. The high yield of terpenes obtained from using olive oil as a solvent is thought to be due to its efficient capabilities in solubilizing and limiting loss of product by protecting the compounds from evaporation (Romano and Hazekamp 2013 ).

Supercritical carbon dioxide (CO 2 )

In common with other solvents, CO 2 —which is nominally a polar gas—enters a so-called supercritical state at a defined temperature and pressure. In a supercritical state, distinct liquid and gas phases do not exist. In the case of CO 2 , the critical temperature is 31.06 °C, the critical pressure is 73.83 bar, and the critical density is 0.460 g/cm 3 (Raventós et al. 2002 ). Supercritical CO 2 behaves like a non-polar solvent, capable of extracting a broad range of non-polar solutes, cannabinoids included. In comparison, strongly polar water becomes supercritical and useful as a non-polar solvent but at a much higher temperature and pressure, 647 K and 22.1 MPa (Fig.  3 ). Therefore, CO 2 is the solvent of choice due to low critical temperature and pressure. It is also non-flammable, non-toxic, inert, renewable, easy to remove, abundant, and relatively low-cost. As an example, consider supercritical extraction of linalyl acetate from lavender oil compared with its extraction by conventional steam distillation (Reverchon et al. 1995 ). The yields for supercritical extraction were 34.7% compared with 12.1% for the conventional steam distillation. The reason proposed was that the higher temperature of steam distillation caused the undesirable hydrolysis of the linalyl acetate to linalool and acetic acid.

CO 2 pressure–temperature phase diagram, the critical temperature is 304.13 K or 31.0 °C or 87.8°F, and the critical pressure is 7.3773 MPa or 72.8 atm or 1070 psi or 73.8 bar. (Adopted from Wikimedia commons URL: https://upload.wikimedia.org/wikipedia/commons/1/13/Carbon_dioxide_pressure-temperature_phase_diagram.svg )

Thus, the low base temperature of supercritical CO 2 is probably an intrinsic advantage (Reverchon et al. 1995 ).

Conventional methods of extraction

Soxhlet extraction.

Soxhlet extraction was first proposed by Franz Ritter Von Soxhlet, a German chemist, as a method of extraction of, primarily, lipids. However, over the years, this procedure has become widely employed for various extraction purposes, commonly used for the separation of bioactive compounds from plant matter. Soxhlet is also extensively used as a model for the comparison and development of alternative methods of separation (Azmir et al. 2013 ). The process begins by placing a small amount of the dried sample in a thimble that is then transferred to a distillation flask containing a particular solvent. When the overflow level is reached by the solution, a siphon is used to aspirate the solute and unload it into the distillation flask with the extracted analyte carried along into the bulk liquid. This procedure is repeated several times until total extraction is complete (Luque de Castro and Garcı́a-Ayuso 1998 ). For cannabis extractions using the Soxhlet apparatus, Lewis-Bakker et al. ( 2019 ) compared different types of organic solvents for the procedure and found ethanol had exhibited the highest yields of cannabinoids (Lewis-Bakker et al. 2019 ). As commonly witnessed by other conventional processes, the long-running time and the large amount of solvent required are limitations that not only increase the cost of operation but also cause environmental complications (Luque de Castro and Garcı́a-Ayuso 1998 ). These drawbacks were demonstrated by a study conducted by Wianowska et al. ( 2015 ) that compared the extraction profiles of THCA and THC using the Soxhlet extraction procedure. It was clear that the long-lasting high temperature accentuated the degradation pathway from THCA to THC and finally to CBN, resulting in high levels of THC and CBN (Wianowska et al. 2015 ).

The simplicity in methodology alongside the ease of system optimization can result in high sample throughput and yield. The minimal requirement for a trained personal for process operation is also considered advantageous when compared to recently developed methods of extraction. Soxhlet methods can be manual or automatic, and the latter is less hazardous and allows multiple treatments to be examined simultaneously to optimize solvent composition, solvent to plant ratio, and extraction time (Luque de Castro and Garcı́a-Ayuso 1998 ).

Dynamic maceration (DM)

Dynamic maceration is a conventional solid-lipid extraction procedure that is based on soaking a sample in organic solvents (solvent varies depending on the polarity of the target compound) for a specific time at a specific temperature and followed by agitation (Fathordoobady et al. 2019 ). This process of separation is inexpensive and a popular method used to obtain essential oils and bioactive compounds (Azmir et al. 2013 ). Recently, the use of vegetable oils (e.g., olive oil) as maceration extraction solvents was found to be more useful for extracting higher amounts of terpenes than alcoholic solvents, notably when using extended heating time. However, vegetable oils are not volatile and are difficult to remove from extracted isolates (Romano and Hazekamp 2013 ). Alternatively, ethanol is suggested as a preferred solvent for cannabinoid extraction. A study conducted by Fathordoobady et al. ( 2019 ) demonstrated that there was no significant difference between other organic solvents (n-hexane, acetone, methanol) and ethanol when used for neutral cannabinoid recovery. However, when the recovery of acidic cannabinoids was tested, ethanol had the highest yield. The use of ethanol for maceration extraction of cannabinoids was found to produce the highest yield when used twice compared to other methods of extractions, for instance, ultrasonic-assisted extraction (UAE) or supercritical fluid extraction (SFE) (Fathordoobady et al. 2019 ).

Romano and Hazekamp ( 2013 ) compared five different solvents (naphtha, petroleum ether, ethanol, olive oil + water, and olive oil) using DM (Table 3 ). Except for naphtha, other extracts contained a small amount of THC and THCA around 5–10%. Naphtha was an exception which had 33% THC plus THCA. With ethanol as solvent, unwanted chlorophyll was extracted along with the cannabinoids. The unwanted chlorophyll not only added an unpleasant flavor and a green tinge to the end product, but it also demonstrated accounts of interference with gas chromatography–mass spectrometry analysis, hence removal is considered necessary (Ciolino et al. 2018 ). To eliminate unwanted chlorophyll, the ethanol extract can be treated with activated charcoal. However, the use of activated charcoal can result in the reduction of cannabinoid content by approximately 50%. Consequently, although yields are high with ethanol, the removal of unwanted chlorophyll with charcoal comes at the expense of cannabinoid loss. In respect of toxicity, Romano and Hazekamp ( 2013 ) found significant amounts of petroleum hydrocarbon residues in the extracts obtained with naphtha and petroleum ether, indicating that special attention must be paid to ensure safe residual concentrations (Romano and Hazekamp 2013 ).

In the same study, when compared to other solvents, the olive oil extract was shown to contain the largest number of terpenes, making it a superior crude extract. Olive oil is a cost-effective nonflammable solvent that is considered nontoxic when applied topically or consumed orally, and not through the lungs. As an added benefit, Citti et al. ( 2016 ) recognized that olive oil-based cannabis extracts maintained their cannabinoid concentration longer than ethanol-based extracts. A disadvantage associated with olive oil extracts, however, is that extracts cannot be concentrated by evaporation. This means that larger volumes of olive oil extracts need to be consumed to have the same therapeutic effects as other extracts (Romano and Hazekamp 2013 ). In another study by Hazekamp et al. ( 2009 ), hexane—the usual form of petroleum ether—was used as a solvent for the maceration method in fiber and drug varieties of cannabis. The yields of cannabinoids were discovered to be 3% and 17%, respectively. For this study, hexane was particularly used as it does not extract chlorophyll and is easily evaporated after extraction (Hazekamp et al. 2009 ).

Methods to extract chlorophyll from plants generally required acetone as the preferred solvent; however, as acetone is considered carcinogenic, it is not recommended to be used in cannabinoid extraction. Namdar et al. ( 2018 ) extracted cannabinoids with ethanol (partly polar) and hexane (non-polar), and their mixture. The highest yield was achieved with the mixture, but for cannabinoids, the polar solvent was best (Namdar et al. 2018 ). Likewise, Brighenti et al. ( 2017 ) concluded that dynamic maceration with ethanol for 45 min at ambient temperature was the best way of extracting non-psychoactive cannabinoids especially the acidic forms compared to more elaborate methods like ultrasonic-assisted extraction (UAE) (Brighenti et al. 2017 ).

Alternative methods of extraction

Ultrasonic-assisted extraction (uae).

Ultrasound technology is widely adopted in the food and chemical industry for its ability to significantly influence the rate of various processes (Chemat et al. 2008 ). The main feature that sets ultrasonic-assisted extraction (UAE) apart from other processes is the use of sound waves, commonly with frequencies between 20 to 100 kHz. This enables the penetration of solvents into a sample matrix to extract the compounds of interest. This is done during the process of cavitation. Cavitation is described as the formation, expansion, and collapse of bubbles within the solution that allows for intense mass transfer and accelerated solvent access into cell material (Azmir et al. 2013 ). The effective mixing ability of the UAE can be explained by the faster energy transfer, micro-mixing, and reduced extraction temperature (Otles 2016 ). Factors such as moisture content of a sample, particle size, milling degree, solvent, temperature, pressure, and time of sonication must be considered and manipulated to achieve efficient extractions (Azmir et al. 2013 ). A study that employed the ultrasonication method to leach and hydrolyze phenolic compounds presented evidence of low analyte decomposition during the extraction procedure when compared to other methods such as subcritical water, and microwave-assisted and solid–liquid extractions. After assessing the degradation of phenolic compounds, the decrease in decomposition was found to be due to the low energy type produced by the sonication mechanism and the short duration time. However, this was only evident when the exposure time to ultrasound was less than 10 min (Herrera et al. 2005 ).

De Vita et al. ( 2018 ) compared different methods for the extraction of commercially available hemp and medicinal cannabis to evaluate the changes in cannabinoid composition. The experimentation demonstrated the optimal conditions for the highest yield of cannabinoids using ultrasonication to be 50 min at 60 °C with ethanol as a solvent. Despite the optimal conditions, the total amounts of THC and CBD extracted were slightly lower when compared to the controls, which were obtained under reflux at 90 °C for 50 min in ethanol. Although low yield was obtained, the ultrasonication procedure had provided extracts using lower temperatures in an environmentally friendly, safe, and energy-efficient way. This study also found that ethanol extract yield was 3 to 4 times higher than olive oil extract (De Vita et al. 2020 ). To further explore the concept of solvent influence in UAE, Lewis-Bakker et al. ( 2019 ) conducted an extraction procedure with the following parameters: UAE in 80 W of ultrasonic bath power, 63 W of heating power, at 40 kHz for 5 min. A mix of ethanol, hexane, and isopropanol: hexanes (1:1) were used as solvents. The results showed that the yield for ethanol and hexane was almost the same, and isopropanol: hexanes achieved the highest yield of the extract. However, an HPLC analysis showed a reverse relationship between the extract yield and cannabinoids: the isopropanol: hexanes product had the lowest cannabinoid content, due to coextracted non-cannabinoid content. The authors also indicated that the acidic forms of cannabinoids (four shown in Fig.  2 ) were almost intact with UAE extraction compared to other methods (Lewis-Bakker et al. 2019 ). To optimize the extraction of target cannabis compounds, it is suggested to use UAE as a conditioning step for conventional extraction methods. For example, it was found that using UAE before a Soxhlet extraction improved the crude lipid yield by more than 24% without affecting the quality of extract (Fathordoobady et al. 2019 ).

Microwave-assisted extraction (MAE)

In 1980, the increasing demand for environmentally friendly and sustainable industrial processes had provoked the development of the Microwave-assisted extraction procedure (Otles 2016 ). The electromagnetic energy provided in the form of microwaves, with frequencies between 300 MHz and 300 GHz, is used to produce rapid heating following ionic conduction and dipole rotation (Azmir et al. 2013 ). This procedure directly exposes each molecule to a microwave field which is converted to kinetic energy that can break cell walls and release their contents into a liquid phase. The enhanced performance of this green extraction process can be attributed to improved solubility, efficient mass transfer, and increased surface equilibrium. These factors result in a system that uses less energy with fast processes requiring less solvent consumption but also producing a final product with high purity (Fig.  4 ) (Ani et al. 2012 ). De Vita et al. ( 2018 ) used MAE to explore time, temperature, ramping time, and solvent as variables. The study demonstrated that the extraction yield of CBD increased with increasing temperature and duration by at least 4 times when compared to the reference sample, which was prepared by ethanol reflux at 90 °C for 50 min. It was also noted that olive oil had superior properties when compared to ethanol during an MAE (De Vita et al. 2020 ).

MAE process where the flask is housed in the microwave oven (Krishnan and Rajan 2017 ). Placing the flask containing the sample in the microwave, attached to a condenser outside of microwave to capture the solution of interest compounds after distillation

Neutral phytocannabinoids have been established as important for their medicinal properties; therefore, using extraction procedures to obtain these compounds is considered essential. Methods used for the extraction of neutral cannabinoids can be explored by investigating their decarboxylation efficiencies of phytocannabinoid acids. For example, Lewis-Bakker et al. ( 2019 ) had studied the processes of different isolation methods and found MAE to be superior in terms of yielding high neutral cannabinoids. The study had found high temperature (> 130 °C) led to decarboxylation of more than 99% of acidic cannabinoids during MAE. To further promote the decarboxylation of acidic phytocannabinoids, MAE was used for 10 min at 150 °C with extracts from prior Soxhlet, UAE, and SFE extractions. However, only the isolates from the Soxhlet method had completely decarboxylated. Although prolonging the duration time to 30 min in MAE, extracts yielded 0.6% CBN. As CBN is produced from the oxidation changes of THC, this can be due to a radical-mediated or oxidation during MAE (Lewis-Bakker et al. 2019 ).

Pressurized liquid extraction (PLE)

Pressurized liquid extraction (PLE), also known as accelerated solvent extraction (ASE) (Duarte et al. 2014 ), is documented to be a highly efficient and rapid method of compound extraction. In this approach, high pressures facilitate the extraction while the high temperatures promote solubility and mass transfer to increase analyte solubility, as well as reduce solvent viscosity and surface tension (Azmir et al. 2013 ). Accordingly, altering temperature and pressure enables influence over the solubility of the compound of interest (Wianowska et al. 2015 ). This procedure also does not require a filtration step as the insoluble matrix components are contained inside the extraction cell. This feature allows for the process automation for continuous operation (Fathordoobady et al. 2019 ). Figure  5 visualizes the PLE process.

PLE process using organic solvent as extracting solvent coupled with supercritical antisolvent (SAS) precipitation process (1) heat exchanger for cooling, (2) pump, (3) heat exchanger for heating, (4) extractor, (5) T-mixer, (6) precipitation vessels, and (7) filter (Santos and Meireles 2015 )

When comparing PLE to conventional methods such as Soxhlet, features such as shorter duration, reduced solvent consumption, and decreased sample handling are observed (Rodrigues et al. 2016). To demonstrate this, Wianowska et al. ( 2015 ) compared the amount of THCA, THC, and CBN obtained from a Soxhlet and PLE process with two types of extractants, methanol, and n-hexane. Employing methanol as an extractant, the first set of results had indicated, even in high temperatures, the concentration of THC was lower than THCA using the PLE method. The Soxhlet process had contrasting results as the concentration of THC was much higher than THCA. The data obtained illustrates the influence of parameters such as time and pressure have on the end product. The high pressure applied enables the use of temperatures above the boiling point of the extractant. This increases the penetration ability of the selected solvent into the plant matrix in a short time. The high temperature used in PLE does not avoid the transformation of THCA and THC to CBN; however, the degree at which this occurs is found to be much lower than that demonstrated by the Soxhlet extraction (Wianowska et al. 2015 ).

For the extraction of cannabis constituents, Fathordoobady ( 2019 ) demonstrated that by using methanol and acetone/methanol (50:50) as solvents with PLE parameters of 1250 bar at 60 °C temperature, 17 various compounds, and three cannabinoids (Δ9-THC and its metabolites 11-nor-9-carboxy-THC and 11-hydroxy-THC) were identified from the cannabis plant (Fathordoobady et al. 2019 ).

Supercritical fluid extraction

Green approaches, such as supercritical fluid extraction (SFE), are used to displace conventional methods of pressing and organic solvent extractions. These procedures decrease environmental impacts and reduce toxic residue on products by using supercritical fluids (Aladić et al. 2015 ). The process behind SFE can be condensed into two steps: (1) the plant material of interest is solubilized in a supercritical solvent of choice, commonly CO + , to extract the desired compound. (2) Those compounds are then recovered from the solvent to produce the end product. The use of supercritical fluids is advantageous as at room temperature they are in a gaseous, allowing for recovery of extract via simple evaporation (Santos and Meireles 2015 ). The differing solubilities of different solvents allow for selective extraction, as small variations to pressure and/or temperature can allow for selectivity (Perrotin-Brunel 2011 ). The employment of low temperatures is also considered advantageous as it results in low energy consumption as well as allowing for the preservation of thermosensitive compounds, such as cannabinoids (Aladić et al. 2015 ).

Under conditions except for supercritical, CO 2 behaves as a polar compound. In instances where supercritical CO 2 is not sufficiently polar to act as a solvent, polarity modifiers, such as alcohols, water, and acids, can be used as co-solvents (Rovetto and Aieta 2017 ). However, CBD and THC are soluble in supercritical CO 2 because they are dominantly nonpolar, making this the solvent of an appropriate choice (Grijó et al. 2018 ). Rovetto and Aieta ( 2017 ) evaluated the effect of pressure and the use of ethanol as a co-solvent on cannabinoid extraction. Extractions were run at 17, 24, and 34 MPa pressure. The yields increased almost linearly to 34 MPa, 0.185 g/g of cannabis at this pressure, compared with yield from a traditional ethanol extraction of 0.132 g/g. Increased pressure can increase the solvation power but decreases the selectivity of the extraction, so a higher pressure may not be the ideal condition. Ethanol was indicated to be useful as a co-solvent: When added in pulses, it can increase the rate of supercritical CO 2 extraction of cannabinoids (Rovetto and Aieta 2017 ). Omar et al. ( 2013 ) also demonstrated that using a co-solvent can increase the yield (Omar et al. 2013 ). The optimum yield of these cannabinoids was achieved by using ethanol as co-solvent at 55 °C and 34 MPa (Fathordoobady et al. 2019 ). However, when comparing SFE with other methods of extraction, Brighenti et al. ( 2017 ) revealed that the lowest amount of CBDA, CBD, and CBG was obtained (Brighenti et al. 2017 ). Figure  6 visualizes the supercritical fluid extraction process.

Diagram of a supercritical fluid extraction (Adopted from Wikiwand.com URL: https://www.wikiwand.com/en/Supercritical_fluid_extraction# )

Hydrodynamic cannabis extraction

Hydrodynamic cannabis extraction is a recent development within the cannabis industry that can be used to produce full-spectrum cannabis extracts with high bioavailability. There have been accounts of companies, such as IASO (Incline Village, Nevada), claiming to have developed a unique extraction system that produces products with high yield and increased potency. This alternative method involves freezing fresh plant material and converting it into a nanoemulsion in water by ultrasonication. Hydrodynamic force is then used to break the cell wall and release its contents. This is followed by liquid–liquid extraction using solvents, centrifugal separation, and finally low-temperature drying. The initial step of freezing the plant matter helps preserve the volatile compounds as well as acidic cannabinoids during the following steps. Hydrodynamic extraction is claimed to exceed conventional methods mainly due to the lack of high temperatures, short contact distillation, and low organic solvent consumption (admin, n.d.). Ishida and Chapman ( 2012 ) used this technique to extract carotenoids from tomatoes and found that the extractable lycopene, other carotenoids, and accessibility of carotenoids significantly improved (Ishida and Chapman 2012 ). However, to this date, there has been no scientific publication that explores this method of extraction. Therefore, to fully understand the efficacy of this method, more research is required.

Traditionally, the dried cannabis flower was the product of choice; however, as the industry expands, the demand for various products with distinct properties also increases. Therefore, multiple factors should be considered when selecting a drying technique or an extraction method to produce a specific product. Among different drying methods for post-harvest processing, freeze-drying is considered more appropriate when compared to other methods; however, there is currently a lack of academic research and evidence to support this. Hang-drying as a traditional technique is still the most convenient way to reduce the prevalence of mold and bacteria during storage before extraction. Solventless extraction and hydrodynamic extraction are of interest due to their high yield, easy, and fast process but lack the scientific publication to promote their employment for large-scale production. According to cannabinoids’ lipophilic or hydrophobic properties, slightly polar solvents are recommended for extraction. Although for terpenes with more than 15 carbons, non-polar solvents are suggested. Soxhlet and dynamic maceration are being used as traditional methods which are time- and solvent-consuming but accurate enough to be compared with modern techniques. Among modern methods, SFE, MAE, and UAE are well recognized as feasible and convenient techniques.

In this narrative review paper, the advantages and disadvantages of various drying and extraction methods have been discussed. The best methods for industries based on the final products have been reviewed and suggested. Some gaps are found in this review paper including the lack of information and knowledge about using freeze dryer for drying plant material after harvest, hydrodynamic extraction method, and a developed green extraction technique in the cannabis research area as well as cannabis industry which needs more investigations in the future studies.

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Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

(-)-Trans-Δ 9 -tetrahydrocannabinol

(-)-Trans-Δ 9 -tetrahydrocannabinolic acid A

(-)-Trans-Δ 8 -tetrahydrocannabinol

Cannabidiol

Cannabidiolic acid

Cannabigerol

Cannabigerolic acid

Cannabichromene

Cannabichromenic acid

Endocannabinoid system

Ultrasound-assisted extraction

Microwave-assisted extraction

Dynamic maceration

High-performance liquid chromatography

Pressurized liquid extraction

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Lazarjani, M.P., Young, O., Kebede, L. et al. Processing and extraction methods of medicinal cannabis: a narrative review. J Cannabis Res 3 , 32 (2021). https://doi.org/10.1186/s42238-021-00087-9

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• v.42(3); 2017 Mar

Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting

The authors review the historical use of medicinal cannabis and discuss the agent’s pharmacology and pharmacokinetics, select evidence on medicinal uses, and the implications of evolving regulations on the acute care hospital setting.

INTRODUCTION

Medicinal cannabis, or medicinal marijuana, is a therapy that has garnered much national attention in recent years. Controversies surrounding legal, ethical, and societal implications associated with use; safe administration, packaging, and dispensing; adverse health consequences and deaths attributed to marijuana intoxication; and therapeutic indications based on limited clinical data represent some of the complexities associated with this treatment. Marijuana is currently recognized by the U.S. Drug Enforcement Agency’s (DEA’s) Comprehensive Drug Abuse Prevention and Control Act (Controlled Substances Act) of 1970 as a Schedule I controlled substance, defined as having a high potential for abuse, no currently accepted medicinal use in treatment in the United States, and a lack of accepted safety data for use of the treatment under medical supervision. 1

Cannabis is the most commonly cultivated, trafficked, and abused illicit drug worldwide; according to the World Health Organization (WHO), marijuana consumption has an annual prevalence rate of approximately 147 million individuals or nearly 2.5% of the global population. 2 In 2014, approximately 22.2 million Americans 12 years of age or older reported current cannabis use, with 8.4% of this population reporting use within the previous month. 3 , 4 General cannabis use, both for recreational and medicinal purposes, has garnered increasing acceptance across the country as evidenced by legislative actions, ballot measures, and public opinion polls; an October 2016 Gallup poll on American’s views on legalizing cannabis indicated that 60% of the population surveyed believed the substance should be legalized. 5 Further, a recent Quinnipiac University poll concluded 54% of American voters surveyed would favor the legalization of cannabis without additional constraints, while 81% of respondents favored legalization of cannabis for medicinal purposes. 6 Limited data suggest that health care providers also may consider this therapy in certain circumstances. 7 – 9 In the United States, cannabis is approved for medicinal use in 28 states, the District of Columbia, Guam, and Puerto Rico as of January 2017. 10

The use and acceptance of medicinal cannabis continues to evolve, as shown by the growing number of states now permitting use for specific medical indications. The Food and Drug Administration (FDA) has considered how it might support the scientific rigor of medicinal cannabis claims, and the review of public data regarding safety and abuse potential is ongoing. 11 , 12 The purpose of this article is to review the historical significance of the use of medicinal cannabis and to discuss its pharmacology, pharmacokinetics, and select evidence on medicinal uses, as well as to describe the implications of evolving medicinal cannabis regulations and their effects on the acute care hospital setting.

HISTORICAL SIGNIFICANCE

Cannabis is a plant-based, or botanical, product with origins tracing back to the ancient world. Evidence suggesting its use more than 5,000 years ago in what is now Romania has been described extensively. 13 There is only one direct source of evidence (Δ 6 -tetrahydrocannabinol [Δ 6 -THC] in ashes) that cannabis was first used medicinally around 400 ad . 14 In the U.S., cannabis was widely utilized as a patent medicine during the 19th and early 20th centuries, described in the United States Pharmacopoeia for the first time in 1850. Federal restriction of cannabis use and cannabis sale first occurred in 1937 with the passage of the Marihuana Tax Act. 15 , 16 Subsequent to the act of 1937, cannabis was dropped from the United States Pharmacopoeia in 1942, with legal penalties for possession increasing in 1951 and 1956 with the enactment of the Boggs and Narcotic Control Acts, respectively, and prohibition under federal law occurring with the Controlled Substances Act of 1970. 1 , 17 , 18 Beyond criminalization, these legislative actions contributed to creating limitations on research by restricting procurement of cannabis for academic purposes.

In 1996, California became the first state to permit legal access to and use of botanical cannabis for medicinal purposes under physician supervision with the enactment of the Compassionate Use Act. As previously stated, as of January 1, 2017, 28 states as well as Washington, D.C., Guam, and Puerto Rico will have enacted legislation governing medicinal cannabis sale and distribution; 21 states and the District of Columbia will have decriminalized marijuana and eliminated prohibition for possession of small amounts, while eight states, including Alaska, California, Colorado, Maine, Massachusetts, Nevada, Oregon, and Washington, as well as the District of Columbia, will have legalized use of marijuana for adult recreation. 10 , 19

THE MEDICINAL CANNABIS DEBATE

As a Schedule I controlled substance with no accepted medicinal use, high abuse potential, concerns for dependence, and lack of accepted safety for use under medical supervision—along with a national stigma surrounding the potential harms and implication of cannabis use as a gateway drug to other substances—transitioning from a vilified substance to one with therapeutic merits has been controversial. The United States Pharmacopoeia and the FDA have considered the complexities of regulating this plant-based therapy, including the numerous compounds and complex interactions between substances in this product, and how it might fit into the current regulatory framework of drugs in United States. 11 , 12 , 17

The emergence of interest in botanical medicinal cannabis is thought by many to be a collateral effect of the opioid abuse epidemic; public perception surrounding the use of medicinal cannabis suggests that this plant-based therapy is viewed as not much different than a botanical drug product or supplement used for health or relief of symptoms if disease persists. Like some herbal preparations or supplements, however, medicinal cannabis may similarly pose health risks associated with its use, including psychoactive, intoxicating, and impairing effects, which have not been completely elucidated through clinical trials. Proponents argue that there is evidence to support botanical medicinal cannabis in the treatment of a variety of conditions, particularly when symptoms are refractory to other therapies; that beneficial cannabinoids exist, as evidenced by single-entity agents derived from cannabis containing the compounds THC and cannabidiol (CBD); that cannabis is relatively safe, with few deaths reported from use; that therapy is self-titratable by the patient; and that therapy is relatively inexpensive compared with pharmaceutical agents. 20 – 22 Opponents of medicinal cannabis use argue, in part, that well-designed randomized trials to confirm benefits and harms are lacking; that it has not been subject to the rigors of the FDA approval process; that standardization in potency or quantity of pharmacologically active constituents is absent; that adverse health effects relate not only to smoking cannabis but to unmasking mental health disorders, impairing coordination, and affecting judgment; that standardization does not exist for product packaging and controls to prevent inadvertent use by minors or pets; that there is a potential for dependence, addiction, and abuse; and that costs pose a potential burden. 23 – 25

Regardless of personal views and perceptions, to deny or disregard the implications of use of this substance on patient health and the infrastructure of the health care system is irresponsible; clinicians must be aware of these implications and informed about how this therapy may influence practice in a variety of health care settings, including acute care.

PHARMACOLOGY

Endocannabinoids (eCBs) and their receptors are found throughout the human body: nervous system, internal organs, connective tissues, glands, and immune cells. The eCB system has a homeostatic role, having been characterized as “eat, sleep, relax, forget, and protect.” 26 It is known that eCBs have a role in the pathology of many disorders while also serving a protective function in certain medical conditions. 27 It has been proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent clinical eCB deficiency syndromes (CEDS). Deficiencies in eCB signaling could be also involved in the pathogenesis of depression. In human studies, eCB system deficiencies have been implicated in schizophrenia, multiple sclerosis (MS), Huntington’s disease, Parkinson’s disease, anorexia, chronic motion sickness, and failure to thrive in infants. 28

The eCB system represents a microcosm of psycho-neuroimmunology or “mind–body” medicine. The eCB system consists of receptors, endogenous ligands, and ligand metabolic enzymes. A variety of physiological processes occur when cannabinoid receptors are stimulated. Cannabinoid receptor type 1 (CB 1 ) is the most abundant G-protein–coupled receptor. It is expressed in the central nervous system, with particularly dense expression in (ranked in order): the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala. CB 1 is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, connective and musculoskeletal tissues, and the gonads. CB 2 is principally associated with cells governing immune function, although it may also be expressed in the central nervous system.

The most well-known eCB ligands are N-arachidonyl-ethanolamide (anandamide or AEA) and sn-2-arachidonoyl-glycerol (2-AG). AEA and 2-AG are released upon demand from cell membrane phospholipid precursors. This “classic” eCB system has expanded with the discovery of secondary receptors, ligands, and ligand metabolic enzymes. For example, AEA, 2-AG, N-arachidonoyl glycine (NAGly), and the phytocannabinoids Δ 9 -THC and CBD may also serve, to different extents, as ligands at GPR55, GPR18, GPR119, and several transient receptor potential ion channels (e.g., TRPV1, TRPV2, TRPA1, TRPM8) that have actions similar to capsaicin. 28 The effects of AEA and 2-AG can be enhanced by “entourage compounds” that inhibit their hydrolysis via substrate competition, and thereby prolong their action through synergy and augmentation. Entourage compounds include N-palmitylethanolamide (PEA), N-oleoylethanolamide (SEA), and cis-9-octadecenoamide (OEA or oleamide) and may represent a novel route for molecular regulation of endogenous cannabinoid activity. 29

Additional noncannabinoid targets are also linked to cannabis. G-protein–coupled receptors provide noncompetitive inhibition at mu and delta opioid receptors as well as norepinephrine, dopamine, and serotonin. Ligand-gated ion channels create allosteric antagonism at serotonin and nicotinic receptors, and enhance activation of glycine receptors. Inhibition of calcium, potassium, and sodium channels by noncompetitive antagonism occurs at nonspecific ion channels and activation of PPARα and PPARγ at the peroxisome proliferator-activated receptors is influenced by AEA. 30

THC is known to be the major psychoactive component of cannabis mediated by activation of the CB 1 receptors in the central nervous system; however, this very mechanism limits its use due to untoward adverse effects. It is now accepted that other phytocannabinoids with weak or no psychoactivity have promise as therapeutic agents in humans. The cannabinoid that has sparked the most interest as a nonpsychoactive component is CBD. 31 Unlike THC, CBD elicits its pharmacological effects without exerting any significant intrinsic activity on CB 1 and CB 2 receptors. Several activities give CBD a high potential for therapeutic use, including antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective effects. CBD in combination with THC has received regulatory approvals in several European countries and is under study in registered trials with the FDA. And, some states have passed legislation to allow for the use of majority CBD preparations of cannabis for certain pathological conditions, despite lack of standardization of CBD content and optimal route of administration for effect. 32 Specific applications of CBD have recently emerged in pain (chronic and neuropathic), diabetes, cancer, and neurodegenerative diseases, such as Huntington’s disease. Animal studies indicate that a high dose of CBD inhibits the effects of lower doses of THC. Moreover, clinical studies suggest that oral or oromucosal CBD may prolong and/or intensify the effects of THC. Finally, preliminary clinical trials suggest that high-dose oral CBD (150–600 mg per day) may exert a therapeutic effect for epilepsy, insomnia, and social anxiety disorder. Nonetheless, such doses of CBD have also been shown to cause sedation. 33

PHARMACOKINETICS AND ADMINISTRATION

The three most common methods of administration are inhalation via smoking, inhalation via vaporization, and ingestion of edible products. The method of administration can impact the onset, intensity, and duration of psychoactive effects; effects on organ systems; and the addictive potential and negative consequences associated with use. 34

Cannabinoid pharmacokinetic research has been challenging; low analyte concentrations, rapid and extensive metabolism, and physicochemical characteristics hinder the separation of compounds of interest from biological matrices and from each other. The net effect is lower drug recovery due to adsorption of compounds of interest to multiple surfaces. 35 The primary psychoactive constituent of marijuana—Δ 9 -THC—is rapidly transferred from lungs to blood during smoking. In a randomized controlled trial conducted by Huestis and colleagues, THC was detected in plasma immediately after the first inhalation of marijuana smoke, attesting to the efficient absorption of THC from the lungs. THC levels rose rapidly and peaked prior to the end of smoking. 36 Although smoking is the most common cannabis administration route, the use of vaporization is increasing rapidly. Vaporization provides effects similar to smoking while reducing exposure to the byproducts of combustion and possible carcinogens and decreasing adverse respiratory syndromes. THC is highly lipophilic, distributing rapidly to highly perfused tissues and later to fat. 37 A trial of 11 healthy subjects administered Δ 9 -THC intravenously, by smoking, and by mouth demonstrated that plasma profiles of THC after smoking and intravenous injection were similar, whereas plasma levels after oral doses were low and irregular, indicating slow and erratic absorption. The time courses of plasma concentrations and clinical “high” were of the same order for intravenous injection and smoking, with prompt onset and steady decline over a four-hour period. After oral THC, the onset of clinical effects was slower and lasted longer, but effects occurred at much lower plasma concentrations than they did after the other two methods of administration. 38

Cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops, and aerosols have been used in only a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Inhalation of THC causes a maximum plasma concentration within minutes and psychotropic effects within seconds to a few minutes. These effects reach their maximum after 15 to 30 minutes and taper off within two to three hours. Following oral ingestion, psychotropic effects manifest within 30 to 90 minutes, reach their maximum effect after two to three hours, and last for about four to 12 hours, depending on the dose. 39

Within the shifting legal landscape of medical cannabis, different methods of cannabis administration have important public health implications. A survey using data from Qualtrics and Facebook showed that individuals in states with medical cannabis laws had a significantly higher likelihood of ever having used the substance with a history of vaporizing marijuana (odds ratio [OR], 2.04; 99% confidence interval [CI], 1.62–2.58) and a history of oral administration of edible marijuana (OR, 1.78; 99% CI, 1.39–2.26) than those in states without such laws. Longer duration of medical cannabis status and higher dispensary density were also significantly associated with use of vaporized and edible forms of marijuana. Medical cannabis laws are related to state-level patterns of utilization of alternative methods of cannabis administration. 34

DRUG INTERACTIONS

Metabolic and pharmacodynamic interactions may exist between medical cannabis and other pharmaceuticals. Quantification of the in vitro metabolism of exogenous cannabinoids, including THC, CBD, and cannabinol (CBN), indicates hepatic cytochrome 450 (CYP450) isoenzymes 2C9 and 3A4 play a significant role in the primary metabolism of THC and CBN, whereas 2C19 and 3A4 and may be responsible for metabolism of CBD. 40 Limited clinical trials quantifying the effect of the exogenous cannabinoids on the metabolism of other medications exist; however, drug interaction data may be gleaned from the prescribing information from cannabinoid-derived pharmaceutical products such as Sativex (GW Pharmaceuticals, United Kingdom) and dronabinol (Marinol, AbbVie [United States]). 41 , 42 Concomitant administration of ketoconazole with oromucosal cannabis extract containing THC and CBD resulted in an increase in the maximum serum concentration and area under the curve for both THC and CBD by 1.2-fold to 1.8-fold and twofold, respectively; coadministration of rifampin is associated with a reduction in THC and CBD levels. 40 , 41 In clinical trials, dronabinol use was not associated with clinically significant drug interactions, although additive pharmacodynamic effects are possible when it is coadministered with other agents having similar physiological effects (e.g., sedatives, alcohol, and antihistamines may increase sedation; tricyclic antidepressants, stimulants, and sympathomimetics may increase tachycardia). 41 Additionally, smoking cannabis may increase theophylline metabolism, as is also seen after smoking tobacco. 40 , 42

ADVERSE EFFECTS

Much of what is known about the adverse effects of medicinal cannabis comes from studies of recreational users of marijuana. 43 Short-term use of cannabis has led to impaired short-term memory; impaired motor coordination; altered judgment; and paranoia or psychosis at high doses. 44 Long-term or heavy use of cannabis, especially in individuals who begin using as adolescents, has lead to addiction; altered brain development; cognitive impairment; poor educational outcomes (e.g., dropping out of school); and diminished life satisfaction. 45 Long-term or heavy use of cannabis is also associated with chronic bronchitis and an increased risk of chronic psychosis-related health disorders, including schizophrenia and variants of depression, in persons with a predisposition to such disorders. 46 – 48 Vascular conditions, including myocardial infarction, stroke, and transient ischemic attack, have also been associated with cannabis use. 49 – 51 The use of cannabis for management of symptoms in neurodegenerative diseases, such as Parkinson’s, Alzheimer’s, and MS, has provided data related to impaired cognition in these individuals. 52 , 53

A systematic review of published trials on the use of medical cannabinoids over a 40-year period was conducted to quantify adverse effects of this therapy. 54 A total of 31 studies evaluating the use of medicinal cannabis, including 23 randomized controlled trials and eight observational studies, was included. In the randomized trials, the median duration of cannabinoid exposure was two weeks, with a range between eight hours and 12 months. Of patients assigned to active treatment in these trials, a total of 4,779 adverse effects were reported; 96.6% (4,615) of these were not deemed by authors to be serious. The most common serious adverse effects included relapsing MS (9.1%; 15 events), vomiting (9.8%; 16 events), and urinary tract infections (9.1%; 15 events). No significant differences in the rates of serious adverse events between individuals receiving medical cannabis and controls were identified (relative risk, 1.04; 95% CI, 0.78–1.39). The most commonly reported non-serious adverse event was dizziness, with an occurrence rate of 15.5% (714 events) among people exposed to cannabinoids. 54

Other negative adverse effects reported with acute cannabis use include hyperemesis syndrome, impaired coordination and performance, anxiety, suicidal ideations or tendencies, and psychotic symptoms, whereas chronic effects may include mood disturbances, exacerbation of psychotic disorders, cannabis use disorders, withdrawal syndrome, and neurocognitive impairments, as well as cardiovascular and respiratory conditions. 52 Long-term studies evaluating adverse effects of chronic medicinal cannabis use are needed to conclusively evaluate the risks when used for an extended period of time.

MEDICINAL USES

Cannabis and cannabinoid agents are widely used to alleviate symptoms or treat disease, but their efficacy for specific indications is not well established. For chronic pain, the analgesic effect remains unclear. A systematic review of randomized controlled trials was conducted examining cannabinoids in the treatment of chronic noncancer pain, including smoked cannabis, oromucosal extracts of cannabis-based medicine, nabilone, dronabinol, and a novel THC analogue. 55 Pain conditions included neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain. Fifteen of the 18 included trials demonstrated a significant analgesic effect of cannabinoids compared with placebo. Cannabinoid use was generally well tolerated; adverse effects most commonly reported were mild to moderate in severity. Overall, evidence suggests that cannabinoids are safe and moderately effective in neuropathic pain with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis. 55

While there is not enough evidence to suggest routine use of medicinal cannabis for alleviating chemotherapy-related nausea and vomiting by national or international cancer societies, therapeutic agents based on THC (e.g., dronabinol) have been approved for use as an antiemetic in the United States for a number of years. Only recently has the efficacy and safety of cannabis-based medicines in managing nausea and vomiting due to chemotherapy been evaluated. In a review of 23 randomized, controlled trials, patients who received cannabis-based products experienced less nausea and vomiting than subjects who received placebo. 56 The proportion of people experiencing nausea and vomiting who received cannabis-based products was similar to those receiving conventional antiemetics. Subjects using cannabis-based products experienced side effects such as “feeling high,” dizziness, sedation, and dysphoria and dropped out of the studies at a higher rate due to adverse effects compared with participants receiving either placebo or conventional antiemetics. In crossover trials in which patients received cannabis-based products and conventional antiemetics, patients preferred the cannabis-based medicines. Cannabis-based medications may be useful for treating chemotherapy-induced nausea and vomiting that responds poorly to conventional antiemetics. However, the trials produced low to moderate quality evidence and reflected chemotherapy agents and antiemetics that were available in the 1980s and 1990s.

With regard to the management of neurological disorders, including epilepsy and MS, a Cochrane review of four clinical trials that included 48 epileptic patients using CBD as an adjunct treatment to other antiepileptic medications concluded that there were no serious adverse effects associated with CBD use but that no reliable conclusions on the efficacy and safety of the therapy can be drawn from this limited evidence. 57 The American Academy of Neurology (AAN) has issued a Summary of Systematic Reviews for Clinicians that indicates oral cannabis extract is effective for reducing patient-reported spasticity scores and central pain or painful spasms when used for MS. 58 THC is probably effective for reducing patient-reported spasticity scores but is likely ineffective for reducing objective measures of spasticity at 15 weeks, the AAN found; there is limited evidence to support the use of cannabis extracts for treatment of Huntington’s disease, levodopa-induced dyskinesias in patients with Parkinson’s disease, or reducing tic severity in Tourette’s. 58

In older patients, medical cannabinoids have shown no efficacy on dyskinesia, breathlessness, and chemotherapy-induced nausea and vomiting. Some evidence has shown that THC might be useful in treatment of anorexia and behavioral symptoms in patients with dementia. The most common adverse events reported during cannabinoid treatment in older adults were sedation-like symptoms. 59

Despite limited clinical evidence, a number of medical conditions and associated symptoms have been approved by state legislatures as qualifying conditions for medicinal cannabis use. Table 1 contains a summary of medicinal cannabis indications by state, including select disease states and qualifying debilitating medical conditions or symptoms. 10 , 60 , 61 The most common conditions accepted by states that allow medicinal cannabis relate to relief of the symptoms of cancer, glaucoma, human immunodeficiency virus/acquired immunodeficiency syndrome, and MS. A total of 28 states, the District of Columbia, Guam, and Puerto Rico now allow comprehensive public medical marijuana and cannabis programs. 10 The National Conference of State Legislatures uses the following criteria to determine if a program is comprehensive:

Medicinal Cannabis Indications for Use by State 10 , 60 , 61

1 = State law additionally covers any condition where treatment with medical cannabis would be beneficial, according to the patient’s physician

2 = State law covers any severe condition refractory to other medical treatment

3 = Additional restrictions on the use for this indication exist in this state

4 = State law requires providers to certify the existence of a qualifying disease and symptom

HIV/AIDS = human immunodeficiency virus/acquired immunodeficiency syndrome

Table adapted with permission from the Marijuana Policy Project; 60 table is not all-encompassing and other medical conditions for use may exist. The reader should refer to individual state laws regarding medicinal cannabis for specific details of approved conditions for use. In addition, states may permit the addition of approved indications; list is subject to change.

• Protection from criminal penalties for using marijuana for a medical purpose;
• Access to marijuana through home cultivation, dispensaries, or some other system that is likely to be implemented;
• Allows a variety of strains, including more than those labeled as “low THC;” and
• Allows either smoking or vaporization of some kind of marijuana products, plant material, or extract.

Some of the most common policy questions regarding medical cannabis now include how to regulate its recommendation and indications for use; dispensing, including quality and standardization of cultivars or strains, labeling, packaging, and role of the pharmacist or health care professional in education or administration; and registration of approved patients and providers.

REGULATORY IMPLICATIONS OF MEDICINAL CANNABIS

The regulation of cannabis therapy is complex and unique; possession, cultivation, and distribution of this substance, regardless of purpose, remain illegal at the federal level, while states that permit medicinal cannabis use have established individual laws and restrictions on the sale of cannabis for medical purposes. In a 2013 U.S. Department of Justice memorandum to all U.S. attorneys, Deputy Attorney General James M. Cole noted that despite the enactment of state laws authorizing marijuana production and sale having a regulatory structure that is counter to the usual joint efforts of federal authorities working together with local jurisdictions, prosecution of individuals cultivating and distributing marijuana to seriously ill individuals for medicinal purpose has not been identified as a federal priority. 62

There are, however, other regulatory implications to consider based on the federal restriction of cannabis. Physicians cannot legally “prescribe” medicinal cannabis therapy, given its Schedule I classification, but rather in accordance with state laws may certify or recommend patients for treatment. Medical cannabis expenses are not reimbursable through government medical assistance programs or private health insurers. As previously described, the Schedule I listing of cannabis according to federal law and DEA regulations has led to difficulties in access for research purposes; nonpractitioner researchers can register with the DEA more easily to study substances in Schedules II–V compared with Schedule I substances. 63 Beyond issues related to procurement of the substance for research purposes, other limitations in cannabis research also exist. For example, the Center for Medicinal Cannabis Research at the University of California–San Diego had access to funding, marijuana at different THC levels, and approval for a number of clinical research trials, and yet failed to recruit an adequate number of patients to conduct five major trials, which were subsequently canceled. 64 Unforeseen factors, including the prohibition of driving during the clinical trials, deterred patients from trial enrollment. The limited availability of clinical research to support or refute therapeutic claims and indications for use of cannabis for medicinal purposes has frequently left both state legislative authorities and clinicians to rely on anecdotal evidence, which has not been subjected to the same rigors of peer review and scrutiny as well-conducted, randomized trials, to validate the safety and efficacy of medicinal cannabis therapy. Furthermore, although individual single-entity pharmaceutical medications, such as dronabinol, have been isolated, evaluated, and approved for use by the FDA, a plant cannot be patented and mass produced by a corporate entity. 65 Despite this limitation, some corporations, including GW Pharmaceuticals, are mass producing cannabis plants and extracting complex mixtures or single cannabinoids for clinical trials. 65 The complex pharmacology related to the numerous substances and interactions among chemicals in the cannabis plant coupled with environmental variables in cultivation further complicate regulation, standardization, purity, and potency as a botanical drug product.

RELEVANCE TO HOSPITAL PRACTITIONERS

Although the public has largely accepted medicinal cannabis therapy as having a benefit when used under a provider’s supervision, the implications of the use of this substance when patients transition into the acute care setting are additionally complex and multifaceted. The Schedule I designation of cannabis causes hospitals and other care settings that receive federal funding, either through Medicare reimbursement or other federal grants or programs, to pause to consider the potential for loss of these funds should the federal government intercede and take action if patients are permitted to use this therapy on campus. Similarly, licensed practitioners registered to certify patients for state medicinal cannabis programs may have comparable concerns regarding jeopardizing their federal DEA registrations and ability to prescribe other controlled substances as well as jeopardizing Medicare reimbursements. In 2009, U.S. Attorney General Eric Holder recommended that enforcement of federal marijuana laws not be a priority in states that have enacted medicinal cannabis programs and are enforcing the rules and regulations of such a program; despite this, concerns persist.

The argument for or against the use of medicinal cannabis in the acute care setting encompasses both legal and ethical considerations, with the argument against use perhaps seeming obvious on its surface. States adopting medical cannabis laws may advise patients to utilize the therapy only in their own residence and not to transport the substances unless absolutely necessary. 66 Further, many acute care institutions have policies prohibiting smoking on facility grounds, thus restricting the smoking of cannabis, regardless of purpose or indication. Of note, several Canadian hospitals, including Montreal’s Jewish General Hospital and Quebec’s Centre Hospitalier Universitaire de Sherbrooke, have permitted inpatient cannabis use via vaporization; the pharmacy departments of the respective institutions control and dispense cannabis much like opioids for pain. Canada has adopted national regulations to control and standardize dried cannabis for medical use. 67 , 68 There are complicated logistics for self-administration of medicinal cannabis by the patient or caregiver; in particular, many hospitals have policies on self-administration of medicines that permit patients to use their own medications only after identification and labeling by pharmacy personnel. The argument can be made that an herb- or plant-based entity cannot be identified by pharmacy personnel as is commonly done for traditional medicines, although medicinal cannabis dispensed through state programs must be labeled in accordance with state laws. Dispensing and storage concerns, including an evaluation of where and how this product should be stored (e.g., within the pharmacy department and treated as a controlled substance, by security personnel, or with the patient); who should administer it, and implications or violations of federal law by those administering treatment; what pharmaceutical preparations should be permitted (e.g., smoked, vaporized, edible); and how it should be charted in the medical record represent other logistical concerns. Inpatient use of medicinal cannabis also carries implications for nursing and medical staff members. The therapy cannot be prescribed, and states may require physicians authorizing patient use to be registered with local programs. In a transition into the acute care setting from the community setting, a different clinician who is not registered could be responsible for the patient’s care; that clinician would be restricted in ordering continuation of therapy.

Despite the complexities in the logistics of continuing medicinal cannabis in the acute care setting, proponents of palliative care and continuity of care argue that prohibiting medicinal cannabis use disrupts treatment of chronic and debilitating medical conditions. Patients have been denied this therapy during acute care hospitalizations for reasons stated above. 69 Permission to use medicinal cannabis in the acute care setting may be dependent on state legislation and restrictions imposed by such laws. Legislation in Minnesota, as one example, has been amended to permit hospitals as facilities that can dispense and control cannabis use; similar legislative actions protecting nurses from criminal, civil, or disciplinary action when administering medical cannabis to qualified patients have been enacted in Connecticut and Maine. 70 – 73 Proposed legislation to remove restrictions on the certification of patients to receive medicinal cannabis by doctors at the Department of Veterans Affairs was struck down in June; prohibitions continue on the use of this therapy even in facilities located in states permitting medicinal cannabis use. 74

Despite lingering controversy, use of botanical cannabis for medicinal purposes represents the revival of a plant with historical significance reemerging in present day health care. Legislation governing use of medicinal cannabis continues to evolve rapidly, necessitating that pharmacists and other clinicians keep abreast of new or changing state regulations and institutional implications. Ultimately, as the medicinal cannabis landscape continues to evolve, hospitals, acute care facilities, clinics, hospices, and long-term care centers need to consider the implications, address logistical concerns, and explore the feasibility of permitting patient access to this treatment. Whether national policy—particularly with a new presidential administration—will offer some clarity or further complicate regulation of this treatment remains to be seen.

Disclosures: The authors report no commercial or financial interests in regard to this article.

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Title: hallucination-free assessing the reliability of leading ai legal research tools.

Abstract: Legal practice has witnessed a sharp rise in products incorporating artificial intelligence (AI). Such tools are designed to assist with a wide range of core legal tasks, from search and summarization of caselaw to document drafting. But the large language models used in these tools are prone to "hallucinate," or make up false information, making their use risky in high-stakes domains. Recently, certain legal research providers have touted methods such as retrieval-augmented generation (RAG) as "eliminating" (Casetext, 2023) or "avoid[ing]" hallucinations (Thomson Reuters, 2023), or guaranteeing "hallucination-free" legal citations (LexisNexis, 2023). Because of the closed nature of these systems, systematically assessing these claims is challenging. In this article, we design and report on the first preregistered empirical evaluation of AI-driven legal research tools. We demonstrate that the providers' claims are overstated. While hallucinations are reduced relative to general-purpose chatbots (GPT-4), we find that the AI research tools made by LexisNexis (Lexis+ AI) and Thomson Reuters (Westlaw AI-Assisted Research and Ask Practical Law AI) each hallucinate between 17% and 33% of the time. We also document substantial differences between systems in responsiveness and accuracy. Our article makes four key contributions. It is the first to assess and report the performance of RAG-based proprietary legal AI tools. Second, it introduces a comprehensive, preregistered dataset for identifying and understanding vulnerabilities in these systems. Third, it proposes a clear typology for differentiating between hallucinations and accurate legal responses. Last, it provides evidence to inform the responsibilities of legal professionals in supervising and verifying AI outputs, which remains a central open question for the responsible integration of AI into law.

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The state of AI in early 2024: Gen AI adoption spikes and starts to generate value

If 2023 was the year the world discovered generative AI (gen AI) , 2024 is the year organizations truly began using—and deriving business value from—this new technology. In the latest McKinsey Global Survey  on AI, 65 percent of respondents report that their organizations are regularly using gen AI, nearly double the percentage from our previous survey just ten months ago. Respondents’ expectations for gen AI’s impact remain as high as they were last year , with three-quarters predicting that gen AI will lead to significant or disruptive change in their industries in the years ahead.

About the authors

This article is a collaborative effort by Alex Singla , Alexander Sukharevsky , Lareina Yee , and Michael Chui , with Bryce Hall , representing views from QuantumBlack, AI by McKinsey, and McKinsey Digital.

Organizations are already seeing material benefits from gen AI use, reporting both cost decreases and revenue jumps in the business units deploying the technology. The survey also provides insights into the kinds of risks presented by gen AI—most notably, inaccuracy—as well as the emerging practices of top performers to mitigate those challenges and capture value.

AI adoption surges

Interest in generative AI has also brightened the spotlight on a broader set of AI capabilities. For the past six years, AI adoption by respondents’ organizations has hovered at about 50 percent. This year, the survey finds that adoption has jumped to 72 percent (Exhibit 1). And the interest is truly global in scope. Our 2023 survey found that AI adoption did not reach 66 percent in any region; however, this year more than two-thirds of respondents in nearly every region say their organizations are using AI. 1 Organizations based in Central and South America are the exception, with 58 percent of respondents working for organizations based in Central and South America reporting AI adoption. Looking by industry, the biggest increase in adoption can be found in professional services. 2 Includes respondents working for organizations focused on human resources, legal services, management consulting, market research, R&D, tax preparation, and training.

Also, responses suggest that companies are now using AI in more parts of the business. Half of respondents say their organizations have adopted AI in two or more business functions, up from less than a third of respondents in 2023 (Exhibit 2).

Gen AI adoption is most common in the functions where it can create the most value

Most respondents now report that their organizations—and they as individuals—are using gen AI. Sixty-five percent of respondents say their organizations are regularly using gen AI in at least one business function, up from one-third last year. The average organization using gen AI is doing so in two functions, most often in marketing and sales and in product and service development—two functions in which previous research  determined that gen AI adoption could generate the most value 3 “ The economic potential of generative AI: The next productivity frontier ,” McKinsey, June 14, 2023. —as well as in IT (Exhibit 3). The biggest increase from 2023 is found in marketing and sales, where reported adoption has more than doubled. Yet across functions, only two use cases, both within marketing and sales, are reported by 15 percent or more of respondents.

Gen AI also is weaving its way into respondents’ personal lives. Compared with 2023, respondents are much more likely to be using gen AI at work and even more likely to be using gen AI both at work and in their personal lives (Exhibit 4). The survey finds upticks in gen AI use across all regions, with the largest increases in Asia–Pacific and Greater China. Respondents at the highest seniority levels, meanwhile, show larger jumps in the use of gen Al tools for work and outside of work compared with their midlevel-management peers. Looking at specific industries, respondents working in energy and materials and in professional services report the largest increase in gen AI use.

Investments in gen AI and analytical AI are beginning to create value

The latest survey also shows how different industries are budgeting for gen AI. Responses suggest that, in many industries, organizations are about equally as likely to be investing more than 5 percent of their digital budgets in gen AI as they are in nongenerative, analytical-AI solutions (Exhibit 5). Yet in most industries, larger shares of respondents report that their organizations spend more than 20 percent on analytical AI than on gen AI. Looking ahead, most respondents—67 percent—expect their organizations to invest more in AI over the next three years.

Where are those investments paying off? For the first time, our latest survey explored the value created by gen AI use by business function. The function in which the largest share of respondents report seeing cost decreases is human resources. Respondents most commonly report meaningful revenue increases (of more than 5 percent) in supply chain and inventory management (Exhibit 6). For analytical AI, respondents most often report seeing cost benefits in service operations—in line with what we found last year —as well as meaningful revenue increases from AI use in marketing and sales.

Inaccuracy: The most recognized and experienced risk of gen AI use

As businesses begin to see the benefits of gen AI, they’re also recognizing the diverse risks associated with the technology. These can range from data management risks such as data privacy, bias, or intellectual property (IP) infringement to model management risks, which tend to focus on inaccurate output or lack of explainability. A third big risk category is security and incorrect use.

Respondents to the latest survey are more likely than they were last year to say their organizations consider inaccuracy and IP infringement to be relevant to their use of gen AI, and about half continue to view cybersecurity as a risk (Exhibit 7).

Conversely, respondents are less likely than they were last year to say their organizations consider workforce and labor displacement to be relevant risks and are not increasing efforts to mitigate them.

In fact, inaccuracy— which can affect use cases across the gen AI value chain , ranging from customer journeys and summarization to coding and creative content—is the only risk that respondents are significantly more likely than last year to say their organizations are actively working to mitigate.

Some organizations have already experienced negative consequences from the use of gen AI, with 44 percent of respondents saying their organizations have experienced at least one consequence (Exhibit 8). Respondents most often report inaccuracy as a risk that has affected their organizations, followed by cybersecurity and explainability.

Our previous research has found that there are several elements of governance that can help in scaling gen AI use responsibly, yet few respondents report having these risk-related practices in place. 4 “ Implementing generative AI with speed and safety ,” McKinsey Quarterly , March 13, 2024. For example, just 18 percent say their organizations have an enterprise-wide council or board with the authority to make decisions involving responsible AI governance, and only one-third say gen AI risk awareness and risk mitigation controls are required skill sets for technical talent.

Bringing gen AI capabilities to bear

The latest survey also sought to understand how, and how quickly, organizations are deploying these new gen AI tools. We have found three archetypes for implementing gen AI solutions : takers use off-the-shelf, publicly available solutions; shapers customize those tools with proprietary data and systems; and makers develop their own foundation models from scratch. 5 “ Technology’s generational moment with generative AI: A CIO and CTO guide ,” McKinsey, July 11, 2023. Across most industries, the survey results suggest that organizations are finding off-the-shelf offerings applicable to their business needs—though many are pursuing opportunities to customize models or even develop their own (Exhibit 9). About half of reported gen AI uses within respondents’ business functions are utilizing off-the-shelf, publicly available models or tools, with little or no customization. Respondents in energy and materials, technology, and media and telecommunications are more likely to report significant customization or tuning of publicly available models or developing their own proprietary models to address specific business needs.

Respondents most often report that their organizations required one to four months from the start of a project to put gen AI into production, though the time it takes varies by business function (Exhibit 10). It also depends upon the approach for acquiring those capabilities. Not surprisingly, reported uses of highly customized or proprietary models are 1.5 times more likely than off-the-shelf, publicly available models to take five months or more to implement.

Gen AI high performers are excelling despite facing challenges

Gen AI is a new technology, and organizations are still early in the journey of pursuing its opportunities and scaling it across functions. So it’s little surprise that only a small subset of respondents (46 out of 876) report that a meaningful share of their organizations’ EBIT can be attributed to their deployment of gen AI. Still, these gen AI leaders are worth examining closely. These, after all, are the early movers, who already attribute more than 10 percent of their organizations’ EBIT to their use of gen AI. Forty-two percent of these high performers say more than 20 percent of their EBIT is attributable to their use of nongenerative, analytical AI, and they span industries and regions—though most are at organizations with less than $1 billion in annual revenue. The AI-related practices at these organizations can offer guidance to those looking to create value from gen AI adoption at their own organizations.

To start, gen AI high performers are using gen AI in more business functions—an average of three functions, while others average two. They, like other organizations, are most likely to use gen AI in marketing and sales and product or service development, but they’re much more likely than others to use gen AI solutions in risk, legal, and compliance; in strategy and corporate finance; and in supply chain and inventory management. They’re more than three times as likely as others to be using gen AI in activities ranging from processing of accounting documents and risk assessment to R&D testing and pricing and promotions. While, overall, about half of reported gen AI applications within business functions are utilizing publicly available models or tools, gen AI high performers are less likely to use those off-the-shelf options than to either implement significantly customized versions of those tools or to develop their own proprietary foundation models.

What else are these high performers doing differently? For one thing, they are paying more attention to gen-AI-related risks. Perhaps because they are further along on their journeys, they are more likely than others to say their organizations have experienced every negative consequence from gen AI we asked about, from cybersecurity and personal privacy to explainability and IP infringement. Given that, they are more likely than others to report that their organizations consider those risks, as well as regulatory compliance, environmental impacts, and political stability, to be relevant to their gen AI use, and they say they take steps to mitigate more risks than others do.

Gen AI high performers are also much more likely to say their organizations follow a set of risk-related best practices (Exhibit 11). For example, they are nearly twice as likely as others to involve the legal function and embed risk reviews early on in the development of gen AI solutions—that is, to “ shift left .” They’re also much more likely than others to employ a wide range of other best practices, from strategy-related practices to those related to scaling.

In addition to experiencing the risks of gen AI adoption, high performers have encountered other challenges that can serve as warnings to others (Exhibit 12). Seventy percent say they have experienced difficulties with data, including defining processes for data governance, developing the ability to quickly integrate data into AI models, and an insufficient amount of training data, highlighting the essential role that data play in capturing value. High performers are also more likely than others to report experiencing challenges with their operating models, such as implementing agile ways of working and effective sprint performance management.

About the research

The online survey was in the field from February 22 to March 5, 2024, and garnered responses from 1,363 participants representing the full range of regions, industries, company sizes, functional specialties, and tenures. Of those respondents, 981 said their organizations had adopted AI in at least one business function, and 878 said their organizations were regularly using gen AI in at least one function. To adjust for differences in response rates, the data are weighted by the contribution of each respondent’s nation to global GDP.

Alex Singla and Alexander Sukharevsky  are global coleaders of QuantumBlack, AI by McKinsey, and senior partners in McKinsey’s Chicago and London offices, respectively; Lareina Yee  is a senior partner in the Bay Area office, where Michael Chui , a McKinsey Global Institute partner, is a partner; and Bryce Hall  is an associate partner in the Washington, DC, office.

They wish to thank Kaitlin Noe, Larry Kanter, Mallika Jhamb, and Shinjini Srivastava for their contributions to this work.

This article was edited by Heather Hanselman, a senior editor in McKinsey’s Atlanta office.

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