06/21/22

Gambling with Cannabis and Psychosis

Biological evidence supports a causal link between marijuana and psychosis. Additionally, this seems to be dose-dependent—with higher potency marijuana, there is an increased likelihood of a psychotic disorder. What is not clear, however, is whether at a population level patterns of cannabis use influence the levels of psychotic disorder. A new study published in The Lancet Psychiatry reported there is a strong link between high-potency marijuana and psychosis. “The odds of psychotic disorder among daily cannabis users were 3·2 times higher than for never users, whereas the odds among users of high potency cannabis were 1·6 times higher than for never users.”

If an individual began using marijuana before the age of fifteen, the odds were slightly increased, but not independent of the frequency of use or the potency of cannabis used. Compared with individuals who never used marijuana, those who used high-potency marijuana daily had four-times higher odds of psychosis. People who were using high-potency marijuana doubled their risk of psychotic disorder. “Our results show that in areas where daily use and use of high potency cannabis are more prevalent in the general population, there is an excess of cases of psychotic disorder.” The researchers estimated that 20% of the new cases of psychotic disorder could have been prevented if the daily use of cannabis had been arrested.

The study drew its data on first-episode psychosis cases from 17 areas in England, France, the Netherlands, Italy, Spain and Brazil. The novelty of this study was its multicenter structure and the availability of incidence rates for all the sites. The use of high-potency cannabis was a strong predictor of psychotic disorder in Amsterdam, London, and Paris where it was widely available. In the Netherlands the THC content can reach as high as 67%. See the chart below.

In conclusion, our findings confirm previous evidence of the harmful effect on mental health of daily use of cannabis, especially of highpotency types. Importantly, they indicate for the first time how cannabis use affects the incidence of psychotic disorder. Therefore, it is of public health importance to acknowledge alongside the potential medicinal properties of some cannabis constituents the potential adverse effects that are associated with daily cannabis use, especially of highpotency varieties.

Susan Gage, a psychologist and epidemiologist at the University of Liverpool, wrote a commentary on the study. Commenting for NPR, she said: “What this paper has done that’s really nice is they look at rates of psychosis and cannabis use in lots of different places where underlying rates of psychosis are different.” With regard to the finding that cities with more easily available high-THC marijuana have a higher rate of new diagnoses of psychosis, she said: “That’s a really interesting finding, and that’s not something anyone has done before.”

However, there are some who seek to minimize the findings. In “Psychosis is the last marijuana side effect you should be worried about,” on the Popular Science website, Kat Eschner not-so-subtly dismissed the findings as “an ableist morality fable,” comparing it to the film, Reefer Madness. For more on the film Reefer Madness, see “Remembering Reefer Madness.” She acknowledged that for a specific population of marijuana users, there was a link, but “overemphasizing the connection poses its own problems.” She quoted a University of York mental health and addiction researcher, Ian Hamilton, who pointed out the connection between cannabis and psychosis has been known for a long time and said: “I think we have to be careful we don’t exaggerate the risk.” But that was not all Hamilton had to say on the matter.

Hamilton published his own research into the association of cannabis and psychosis, in the journal Addiction. The University of York press release on his study indicated that while the population level risk of developing psychosis was low, and those vulnerable to developing serious mental health problems is relatively rare. But for individuals who already have schizophrenia, marijuana can make their symptoms worse. He said: “The research was clear that the more high potency cannabis used, the higher the risk of developing mental health problems, even if they are relatively low in number. For those who already had schizophrenia cannabis exacerbated the symptoms.”

Professor Robin Murray, a Scottish psychiatrist and Professor of Psychiatric Research at King’s College, London, “cautioned that cannabis is not as safe as was once thought.” In an editorial for the British Journal of Psychiatry, he said 10 of 13 longitudinal studies showed cannabis users are “at significant increased risk of subsequently developing psychotic symptoms or schizophrenia-like psychotic illness.” The remaining three studies showed a trend in the same direction. “A recent meta-analysis reported that the odds ratio for developing psychotic symptoms or a psychotic disorder in individuals who had used cannabis over non-users reached 3.9 (95% CI 2.84–5.34) among the heaviest users.”

He noted where most forms of cannabis in the 1960s and 1970s contained less than 4% of THC and an equal proportion of CBD (which ameliorates the psychoactive properties of THC). But these have been displaced by stronger varieties, which range in THC potency from 16% up to 90% as wax “dabs.” Then there is the rise of synthetic cannabinoids. “In contrast to THC which is a partial agonist at the cannabinoid CB1 receptor, most synthetic cannabinoids are full agonists and consequently more powerful.” He noted how “the USA and Canada have embarked on a major pharmaceutical experiment with the brains of their youth.” He suggested that the UK “wait and see the outcome of the experiment.”

Researchers at Radbound University published the results of a large-scale genetic study in Nature Neuroscience. “The researchers found that people with schizophrenia are also more likely to use cannabis.” There were 35 different genes associated with cannabis use, particularly with the gene CADM2. This gene was already associated with risky behavior, personality and alcohol use. They found a genetic overlap between cannabis and the risk of schizophrenia, which was no big surprise as other studies have shown the association of cannabis use and schizophrenia. However, they also showed a causal connection.

The researchers used an analysis technique called “Mendelian randomisation” to show a causal relationship between schizophrenia and an increased risk of cannabis use. This may indicate that people with schizophrenia use cannabis as a form of self-medication. However, the researchers cannot exclude a reverse cause-and-effect relationship, meaning that cannabis use could contribute to the risk of schizophrenia.

It seems that adolescents are at a greater risk of experiencing symptoms like hallucinations, paranoia and anxiety with marijuana use. Levy and Weitzman published a research letter in JAMA Pediatrics. They found that of 146 teen marijuana users, 40 (27%) reported hallucinations and 49 (34%) said they experience paranoia or anxiety. “Compared to youth who said they had only tried marijuana once or twice, adolescents who used it every month were more than three times more likely to experience hallucinations, paranoia or anxiety.” One in four reported symptoms of depression.

Adolescents with symptoms of depression were more than three times more likely to experience paranoia and anxiety. And they were 51% more likely to report hallucinations than teens without depression. Sharon Levy, one of the researchers said:

We don’t know if the greater exposure to marijuana over time made the brain more susceptible to psychotic symptoms, whether kids who experienced psychotic symptoms became more likely to continue to use marijuana or if some third factor, such as depression, made kids both more likely to use marijuana heavily and also more susceptible to psychotic symptoms triggered by marijuana. . . . Regardless of which of these explanations is most accurate, there is clearly an interaction between marijuana use and brain function.

A study published in The Journal of Child Psychology and Psychiatry found that increased use of cannabis between 13 and 16 was associated with a higher likelihood of having psychotic-like experiences (PLEs). The lead author of the study said: “Our findings confirm that becoming a more regular marijuana user during adolescence is, indeed, associated with a risk of psychotic symptoms.” Going from occasional use to weekly or daily use increased an adolescent’s risk of PLEs by 159%. Also see: “Psychosis and Adolescent Marijuana Use.”

It seems clear that as a society we are moving towards increased use and availability of marijuana. And where recreational marijuana has been legalized, there appears to be more potent forms of marijuana and an increasing incidence of psychosis. While a 1:20,000 risk of developing symptoms of psychosis is negligible, it won’t remain that rare as people play the odds with marijuana and psychosis.

This article was originally posted on 5/21/2019.

12/21/21

The Risks of Legalizing Marijuana in PA

Attempts to legalize recreational marijuana in PA with Senate Bill 350, the “Adult-Use Cannabis Act,” failed. But efforts to do so have not stopped. In September of 2021, State Representatives Jake Wheatley and Dan Frankel sponsored H.B. 2050, which would legalize adult-use recreational marijuana. Not to be outdone, State Senators Dan Laughlin and Sharif Street introduced Senate Bill 473 to legalize recreational marijuana in October of 2021. Laughlin and Street believe their bi-partisan bill has the best chance of ultimately legalizing recreational marijuana in Pennsylvania, and could generate between $400 million and $1 billion of new tax revenue. But what are the risks of such legislative action?

Larry Weigand, who was running for sheriff in Delaware County, said he understood that social views on marijuana use have changed and polls report most Pennsylvanians support legalization. “But the social views of intoxication and driving under the influence have not; to the contrary, they have become more stringent.” He thought the legislature needs to be considerate of both sides of the issues, considering all who would be affected, “including the non-users of marijuana and law enforcement.”

Negative Consequences in Colorado

Consider the negative consequences of legalization in Colorado reported in The New York Times, “Reefer Madness or Pot Paradise?” Legalization coincided with a 20 percent rise in violent crime rates in Colorado, while marijuana-related arrests fell by half. Although low-level marijuana charges dropped, racial discrepancies in drug arrests persisted. African-Americans were still being arrested on marijuana charges almost twice as often. One of the state legislators who endorsed the Colorado ballot measure that legalized recreational marijuana said: “You don’t see drug-addled people roaming the streets, but we haven’t created a utopia.”

Since recreational sales began in 2014, more people in Colorado are going to emergency rooms for marijuana-related problems. Hospitals report higher rates of mental health cases associated with marijuana. An emergency room physician and researcher with the University of Colorado Hospital, Andrew Monte, analyzed hospital data that showed more people were arriving at ERs for marijuana-related reasons. He said, “There’s a disconnect between what was proposed as a completely safe drug.”

Other researchers in “Marijuana and acute health care contacts in Colorado” reported that marijuana-related ER patients were five times as likely to have a mental-health issue as those with other cases. “As more states legalize marijuana, it is important to address public education and youth prevention, and understand the impact on mental health disorders.” The most frequent primary diagnosis of ER visits with marijuana-related billing codes compared to those without marijuana-related billing codes was for mental illness.

Among primary diagnosis categories, mental illness was more prevalent in ED visits and hospitalizations with marijuana-related billing codes. Examination of the role marijuana plays in mental health driven healthcare encounters is critical given the relationship between drug use disorders and mental health disorders. While it is unclear whether this finding is reflective of changes due to a legal market, it clearly prioritizes the consequences of marijuana use within a mental health population as a priority area for further research.

Psychosis and Marijuana

While political rhetoric in favor of legalization is calling for the end of marijuana “prohibition,” scientific research is forming a consensus that THC, the psychoactive cannabinoid in marijuana, induces psychotic symptoms. A research article published in The Lancet Psychiatry, “Psychiatric symptoms caused by cannabis constituents,” included additional evidence for that consensus. The authors readily acknowledged that cannabis was one of the most widely used psychoactive substances worldwide, with 6-7% of Europeans and 15.3% of Americans using it each year. Decriminalization and legalization trends were happening globally, with Canada, Uruguay and a growing number of US state permitting the sale and recreational use of marijuana. However,

Given the projected increase in rates of cannabis use, the increasing potency of cannabis and cannabis-based products, and the burgeoning interest in the therapeutic potential of cannabinoids, it is timely to assess the psychiatric effects of cannabis constituents.

The researchers demonstrated that THC induced significant increases of symptoms as they were reported on psychiatric scales, the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS). Positive symptoms included delusions and hallucinations; negative symptoms included blunted affect and amotivation; and general symptoms included depression and anxiety. Effect sizes were greater for positive symptoms than negative symptoms, but not for general symptoms. This finding suggested that THC induced positive symptoms like psychosis to a greater extent than negative symptoms.

Speaking with Healio Psychiatry in “THC linked to psychiatric symptoms with large effect sizes,” Oliver Howes, one of the co-authors, said: “These findings highlight a potential risk of taking THC-containing cannabis products, and, importantly, show that THC can lead to short-term psychotic symptoms even in people with no history of mental illness or other risk factors.” While there has been previous evidence for the association of positive psychiatric symptoms and marijuana, Howes said he was surprised that THC induced other psychiatric symptoms like social withdrawal.

In conclusion, these findings demonstrate that the acute administration of THC induces positive, negative, and general psychiatric symptoms with large effect sizes. By contrast, CBD does not induce psychiatric symptoms, and there is inconclusive evidence that it moderates the induction of psychiatric symptoms by THC. These effects are larger with intravenous administration than with inhaled administration, and tobacco smokers have less severe positive symptoms. These findings highlight the acute risks of cannabis use, which are highly relevant as medical, societal, and political interest in cannabinoids continues to grow.

In a related editorial published in the same issue of The Lancet Psychiatry, “THC: harmful even in low doses?”, Carsten Hjorthøj, and Christine Merrild Posselt said there was a growing scientific consensus that marijuana does have a causal role in the development of psychosis. And they thought the association seems to be bidirectional. “In some people, cannabis leads to incident psychosis, whereas in other people, psychosis leads to incident cannabis use.” However, they noted this consensus was not reflected in mainstream public discourses, “which have a major effect on the political agenda to decriminalize cannabis.”

Referring to “Psychiatric symptoms caused by cannabis constituents,” Hjorthøj and Posselt said finding large effect sizes for general psychiatric symptoms, even with low doses of THC, was “extremely important and worrying.”

Moreover, the authors failed to find any clear evidence that concurrent administration of cannabidiol (CBD) reduced these symptoms. Indeed, such an ameliorating effect was observed in only one of four included studies. This finding is notable because CBD in particular is being touted as a potential wonder drug with antipsychotic, anxiolytic, and other properties. . . As Hindley and colleagues have clearly demonstrated, there are at least transient psychiatric symptoms associated with even relatively low doses of THC. Of course, this result should not be extrapolated as meaning that single doses of THC will eventually lead to schizophrenia or other severe disorders. However, it might be prudent to extrapolate and paraphrase the words of Moore and colleagues from their 2007 meta-analysis to apply to both recreational and medicinal use of THC-containing cannabis: “there is sufficient evidence to warn people that using THC could increase their risk of developing psychiatric symptoms or even a psychotic illness”.

So, pointing to the potential for increased tax revenue, the opportunity for new jobs in the marijuana industry, and all the other supposed benefits of ending the so-called ‘prohibition’ of recreational marijuana is not enough. Pennsylvania also needs to consider the risks to its citizens if it legalizes recreational marijuana. And one of them is people who use cannabis increase their risk of experiencing psychosis and other psychiatric symptoms.

There are several other articles on the risk of psychosis with marijuana on this website, and the concerns for Pennsylvania if recreational marijuana is legalized in the Commonwealth. Here are a few: “Cannabis and Psychosis: More Reality Than Satire,” “Telling the Truth About Marijuana and Psychosis,” “The Business of Legalizing Marijuana in PA,” and “Should Pennsylvania Go ‘Full Colorado’ with Marijuana?” Part 1 and Part 2.

07/29/16

Be Careful of Where You’re Going

On July 9, 2015 eight Senators sent a letter to the Department of Health and Human Services (HHS), Office of National Drug Control Policy (ONDCP), and the Drug Enforcement Administration (DEA) asking for information on their efforts to facilitate scientific research into the benefits of medical marijuana. The Senators asked for answers to a series of questions, stating that relevant federal agencies had to play a leadership role in coordinating and facilitating research into medical marijuana. This began a process culminating in the administrators of the three agencies sending a detailed reply to their questions in an April 4, 2016 response … 26 pages long. And so speculation began that the DEA would decide whether or not to change the controlled substance status of marijuana “in the first half of 2016.”

This was part of the inquiry made by the Senators’ letter, in noting the need to remove “extraneous regulatory barriers for researchers who wish to perform scientific studies on the sue of marijuana for various diseases.” They pointed to the need of the federal government to make a concerted effort to understand how marijuana works and what the appropriate doses and methods of treatment are, “like any prescribed medicine.” Within Appendix C of the HHS, ONDCP, DEA response, was the following graphic and text delineating the process to schedule or re-schedule any drug.

The Controlled Substance Act requires eight factors as part of its scientific review: 1) the actual or relative potential for abuse; 2) the scientific evidence of its pharmacological effect; 3) the state of current scientific knowledge regarding the substance; 4) the history and current pattern of abuse; 5) the scope, duration and significance of abuse; 6) the risk to the public health; 7) the psychic or physiological dependence liability; and 8) the immediate precursor of a substance already controlled.

Writing for the Huffington Post in April 2016, Matt Ferner noted the FDA completed its review of the medical evidence of the safety and effectiveness of marijuana, and forwarded it to the DEA. But the FDA recommendations are still not public. In the Washington Post, Christopher Ingraham interviewed John Hudak of the Brookings Institution, who said the small amount of researchers currently working with marijuana is not due to the government turning down applications to do the research. Rather, it is a function of the application process itself. “People just aren’t applying because of all the headaches involved. . . . It’s a huge disincentive for the academic community.”

The bureaucratic hurdles also mean that colleges and universities are often hesitant to fund marijuana research for fear of running afoul of complex federal regulations. One ongoing study on the use of marijuana to treat veterans with PTSD has been struggling to get off the ground for more than five years, for instance.

There was an unconfirmed rumor by an “anonymous” DEA attorney that the DEA planned to reschedule marijuana as a Schedule II controlled substance and make medical marijuana legal with a doctor’s prescription in all 50 states. This is simply not true. Rescheduling would merely make it easier to get permission to do research with marijuana, not make it legal for doctors in all 50 states to prescribe marijuana. If that were the case, why can’t doctors prescribe cocaine legally? It is a Schedule II Controlled Subtance. Writing for The Fix, McCarton Ackerman noted the skepticism about the validity of the source.

In response to the rumors, DEA staff coordinator Russ Baer would not confirm the rumored rescheduling by August 1st in an interview with aNewDomain. Baer pointed out the complexity of what is referred to as “medical marijuana.” While THC and CBD are the two main cannabinoids, there are an estimated 480 compounds in cannabis. “What is under-reported right now is how complex the marijuana plant is.”

Baer said the DEA wants to remove the roadblocks to further research into the effectiveness of medical marijuana. However, he said the DEA doesn’t support decisions made on anecdotal evidence.

We want there to be research on marijuana and its component parts, there needs to be (more) studies about both the benefits and the adverse effects about marijuana. . . . We want to know more about cannabis— we need rigorous scientific research — the DEA stands behind the scientific process.

He added that safe medical cannabis requires rigorous peer-reviewed studies. He singled out current research into the benefits of cannabinol (CBD). “We are told by NIDA, also, that there are medical studies out there also preliminarily indicate CBD is beneficial.” But the opioid crisis has captured most of the DEA’s attention. “Marijuana is important, but our efforts are mainly focused on the nation’s growing opioid crisis. . . . We’re focusing on fentanyl, fentanyl compounds and on preventing the deaths caused by opioid addiction.”

A June 24th article by Kate O’Keeffe for the Wall Street Journal said Baer didn’t expect an answer by June 30th, but the agency was in the final stages of deciding whether to reschedule marijuana. He added that a decision is expected sometime soon.

On July 13, 2016 Dr. Douglas Throckmorton of the FDA appeared before the Judiciary Subcommittee on Crime and Terrorism. In his written statement to the committee, he reiterated its standing 2006 recommendation that marijuana remain as a Schedule I controlled substance because of a high potential for abuse; no currently-accepted medical use; and that it lacks accepted safety for use under medical supervision. However, “DEA is currently in the process of evaluating a number of other Citizen Petitions regarding the scheduling of marijuana.”

He noted there are three drugs approved for human use that contain active ingredients present in or similar to those in botanical marijuana: Marinol Capsules, Syndros and Cesamet Capsules. These products have undergone the FDA’s approval process and have been determined to be safe and effective for their respective indications. The future of medical marijuana lies in “classical drug development.”

If there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives. Isolated cannabinoids will provide more reliable effects than crude plant mixtures. Therefore, the purpose of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug but rather to serve as a first step toward the development of nonsmoked rapid-onset cannabinoid delivery systems.

Throckmorton pointed to three Fast Track designations for Savitex (April 2014), Epidiolex (June 2014) and a CBD formulation of Insys Therapeutics to treat Dravet syndrome (February 2015). All three are drugs derived from marijuana. He said the FDA is working with researchers who are conducting studies on the development of potential new drugs derived from marijuana.

FDA encourages and supports medical research into the safety and effectiveness of marijuana products through adequate and well-controlled clinical trials conducted under an IND [Investigational New Drug] and consistent with DEA requirements for research on Schedule I substances. FDA has provided scientific advice to representatives from several states considering support for medical research of marijuana and its derivatives, including CBD, to help ensure that their research is rigorous and appropriate.

Another date floated on the rumor pond for a DEA decision on rescheduling marijuana was August 1st, which is fast approaching. Will there be an answer? Who knows? According to Russ Baer, the DEA is not bound to give its answer within some artificially determined timeframe. So I suggest those anxious for an announcement by the DEA (senators and marijuana activists alike) apply a mash up of a famous Yogi-ism here: “Marijuana ain’t re-scheduled till it’s rescheduled.” Perhaps the DEA is just trying to be careful in its decision making process about the rescheduling. Yogi Berra has some further words of wisdom to apply there: “You’ve got to be very careful if you don’t know where you are going, because you might not get there.”

08/3/15

Is the Cart Before the Horse?

Senators Dianne Feinstein and Charles Grassley wrote a brief article for Time that highlighted the effectiveness of CBD oil, a product derived from cannabis, in treating the debilitating seizures of a little girl. Her father, an ER doctor, said it took just 36 hours to see profound changes. However, CBD (cannabidiol) oil is not approved by the FDA; and there is no guarantee that the formulation of each batch will be the same. A one-month supply can cost up to $2,500; and the girl’s parents are forced to pay $100 per bottle if they want to verify the contents. “Simply put, we need to know more about CBD, and the only way to gain that knowledge is to remove barriers to research.”

The Time article has a 16-minute video linked, which reviews the issue in more detail and mentions some of the problems with the current state of regulation and research into medical marijuana. I’ve written several other articles on the legalization of marijuana and have a concern that the current practice of state-by-state approval is creating greater problems for the legitimate use of medicinal cannabis products; problems that must be addressed by federal action. The potential for CBD products should be fast tracked to confirm their medicinal use.

Currently, medical marijuana products are typically high in THC, the psychoactive cannabinoid in marijuana, and low in CBD. Compared to CBD, THC has limited medical benefits. But it is the only “therapeutic” agent in the vast majority of medical marijuana products. It seems this crucial and basic understanding of medical marijuana is not widely known or understood. It may be that many “medical” marijuana users don’t care. But it begs the following question—is the current process of state-by-state approval just a “smoke screen?” Is what is actually happening with medical marijuana just the first stage of national legalization of recreational marijuana use?

There is real, legitimate potential for the use of cannabis-based medicines. But they should pass through the same FDA gauntlet that other medicines have, even though the process itself in not perfect. It was put in place because of past abuses and the resulting dangers to public consumers from other so-called miracle cures. Let’s not ignore the past and repeat its mistakes.

The June 23/30 2015 issue of JAMA, The Journal of the American Medical Association, contained several articles related to medical marijuana. Three of them are reviewed below. They address both the potential benefits and consequences with medical marijuana. One article raises the concern embodied in the title of this article: are we putting the cart before the horse in rushing to approve medical marijuana without taking the time to scientifically assess its pros and cons?

Vandrey et al. in a JAMA research letter reported on edible cannabis products that they purchased from three randomly selected dispensaries in three cities: Los Angeles, San Francisco, and Seattle. Of the 75 different products purchased from 47 different brands, only 17% were accurately labeled with respect to their THC content. Twenty-three percent were underlabeled (contained more THC than claimed on the label); and 60% were overlabeled (contained less THC than claimed on the label). Some of the overlabled products contained negligible amounts of THC.

The non-THC content of tested products was generally low. Forty-four products (59%) contained detectable levels of CBD. But only 13 had their CBD content labeled. Four products were overlabeled and nine were underlabeled.

Whiting et al. did a systematic review and meta-analysis, “Cannabinoids for Medical Use,” of randomized clinical trials of cannabinoids for various conditions: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity from multiple sclerosis or paraplegia, depression anxiety disorder, sleep disorder, psychosis, glaucoma or Tourette syndrome. They used a methodology designed to reduce the risk of publication bias in their analyses.

The study concluded there was moderate-quality evidence for the use of cannabinoids (smoked THC and nabiximols) to treat chronic pain and spasticity. There was low-quality evidence to support using cannabinoids for nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders and Tourette syndrome. There was very low quality evidence for improvement in anxiety as assessed by a public speaking test. There was some evidence that cannabinoids (mainly nabiximols) were associated with an improvement in sleep. There was no evidence showing that cannabinoids helped in the treatment of depression or glaucoma.

Cannabinoids were also found to be associated with increased risk of short-term adverse events such as: dizziness, dry mouth, nausea, fatigue, drowsiness, euphoria, vomiting, disorientation, confusion, loss of balance and hallucination. The two studies that assessed the association between psychosis and cannabis found no difference in mental health outcomes, but they were judged to be at high risk of bias. There were no identified studies of long-term adverse events of cannabinoids, even when the searches were extended to lower levels of evidence than established in the initial methodology.

Doctors D”Souza and Ranganathan wrote an editorial for the same issue of JAMA, “Medical Marijuana: Is the Cart Before the Horse?” They raised the same concern Whitling et al. found, namely that for most of the indications that qualify by state law for medical marijuana, the supporting evidence for its use is of poor quality. “For most qualifying conditions, approval has relied on low-quality scientific evidence, anecdotal reports, individual testimonials, legislative initiatives, and public opinion.” So state and federal governments should support and encourage research so that high quality research on medical marijuana can be done for the conditions for which the existing evidence is insufficient or of poor quality.

They also noted how there are inconsistencies from state to state in how conditions are qualified for medical marijuana use. One example noted was that posttraumatic stress disorder was approved as a qualifying condition in some, but not all states. Unlike most FDA-approved drugs, marijuana has over 400 compounds; and there isn’t a uniform composition of the cannabis preparations. “Given the variable composition, patients will have to experiment with different strains and doses to achieve the desired effects,” a process known as titrating. The patient is looking for the personal Goldilocks dose—not too high and not too low.

While the acute adverse effects are known, the effects of repeated exposure, as would occur with medical marijuana needs further study. The risk of addiction, and a smaller risk of psychotic disorder were discussed. The interaction of marijuana with other drugs concurrently prescribed needs further study. They suggested that medical marijuana be added to monitoring databases along with opioids and benzodiazepines, so doctors would have a more complete understanding of the medication profile of their patients.

The human endocannabinoid system is involved in a variety of physiological processes such as appetite, pain-sensation, mood and memory. And there are two known cannabinoid receptors, CB1 and CB2. THC is a direct “fit” with the CB1 receptor, while another cannabinoid, cannabinol fits with CB2. The receptors are predominantly found in the brain (CB1) and the immune system (CB2). Cannabidiol (CBD) does not directly fit with either receptor, but has powerful indirect effects that are still being studied. See this graphic representation of the human endocannabinoid system.

“Emerging evidence suggests that the endocannabinoid system is critical in brain development and maturation processes, especially during adolescence and early adulthood.” This ongoing development of the system during adolescence then raises questions on what age exposure to medical marijuana is justifiable. Brain development continues until the age of 25. “Changes in the endocannabinoid system have been linked to affective, behavioral, cognitive and neurochemical consequences that last into adulthood.”

In conclusion, if the states’ initiative to legalize medical marijuana is merely a veiled step toward allowing access to recreational marijuana, then the medical community should be left out of the process, and instead marijuana should be decriminalized. Conversely, if the goal is to make marijuana available for medical purposes, then it is unclear why the approval process should be different from that used for other medications. Evidence justifying marijuana use for various medical conditions will require the conduct of adequately powered, doubleblind, randomized, placebo/active controlled clinical trials to test its short- and long-term efficacy and safety. The federal government and states should support medical marijuana research. Since medical marijuana is not a life-saving intervention, it may be prudent to wait before widely adopting its use until high-quality evidence is available to guide the development of a rational approval process. Perhaps it is time to place the horse back in front of the cart.

04/27/15

Quantifying Impaired Drivers

The CDC statistics on alcohol-impaired driving are stunning. Every day almost 30 people die in the US in motor vehicle accidents. That’s about one person every 51 minutes. In 2012, 10,322 people died in alcohol-impaired accidents, 31% of all traffic-related deaths in the US. Looking at the most at risk drivers with BAC levels of 0.08 or higher involved in fatal crashes in 2012, 32% were between 21 and 24; 27% were between 25 and 34; 24% were between 35 and 44. Half of the children under the age of 14 killed in alcohol-impaired driving accidents were riding in the vehicle with the alcohol-impaired driver.

Two new studies on impaired driving were released by the National Highway Traffic Safety Administration (NHTSA). The Roadside Survey of Alcohol and Drug Use by Drivers (RSADU) found that since 2007, the last time the survey was done, the number of drivers with alcohol in their system declined by about 30 percent. Since the first survey in 1973, alcohol use among survey participants has decreased by almost 80 percent. In 2014, about 8.3 percent had some measurable amount of alcohol in their system; 1.5 percent of weekend nighttime drivers were .08 or higher on breathalyzer tests. You can download copies of the two surveys and summaries of the results at the above link.

Figure 1 of the report showed a decline in each of three breath alcohol concentration (BrAC) categories since 1973. Individuals who tested at .08 and above, the legal limit in all states, dropped from 7.5 percent in 1973 to 1.5 percent in 2013-2014. This was an 80 percent drop in the percentage of alcohol-impaired drivers on the road on weekend nights. Results, which are no surprise, show that more people are driving with alcohol in their system on weekend nights (Friday and Saturday) than during the daylight on Fridays. “During weekday daytime hours (Friday), only 1.1 percent of drivers were alcohol positive, while at weekend nighttime hours (Friday and Saturday), 8.3 percent of drivers were alcohol positive.” Weekday drivers above the .08 BrAC level were quite low, at .04 percent. See the chart below taken from the NHTSA report.

NHSTA administrator Mark Rosekind said that the survey results showed how “a focused effort and cooperation among the federal government, states and communities, law enforcement, safety advocates and industry can make an enormous difference.” Nevertheless, there is no victory as long as one person dies in an alcohol-related crash. He then said that the survey raised questions about drug use and highway safety.

The RSADU survey found that 22.5 percent of weekend nighttime drivers tested positive for some drug in oral fluid and/or blood test. This was almost identical to the Friday daytime rate (22.4 percent). When illegal drugs versus legal medication were distinguished, there was a clear difference. More individuals tested positive for illegal drugs on weekend nighttime than Friday daytime (15.2% versus 12.1%, respectively). There was actually a decrease with legal medications from 10.3% during daylight, to 7.3% on weekend nighttime.

The drug with the largest increase in weekend nighttime use was THC. In 2007, 8.6 percent of weekend nighttime drivers tested positive for THC. In 2013-2014, 12.6 percent of weekend nighttime drivers tested positive for THC; a 48 percent increase. The report noted how changes in state policy on marijuana use, now legal in many states for medical use and a growing number of states for recreational use, may have contributed to the increase in marijuana use by drivers.

Further caution interpreting the survey results is needed because drug presence does not necessarily imply driving impairment. “For many drug substances, drug presence can be detected after impairment that might affect driving has passed.” One example is with marijuana. THC can be detected in blood and urine samples several weeks after heavy users have last used marijuana. So there is some indication that reported percentages of impaired drivers from marijuana were high.

Although the attempt to survey impaired drivers is noble and needed, I’m not sure I am all that encouraged by the reported drop in the percentages of alcohol-impaired drivers. Neither am I alarmed at the reported increase with THC positive drivers. And here’s why—I believe all the results are under reporting the true percentages. This is simple common sense. The survey was COMPLETELY VOLUNTARY. You cannot assume that individuals who stopped for the survey were a representative sample of all the impaired drivers on the road at that time! Here is a summary of the methodology given within the executive summary of the National Roadside Survey:

The National Roadside Survey collected information from volunteer drivers at 300 research checkpoints across the Nation. The survey methods were reviewed and approved by an Institutional Review Board and all data was completely anonymous. Drivers were free to pass by the research site or pull in to find out details of the survey. A small fee (up to $60) was offered to compensate drivers for their time. About 85 percent of drivers who pulled into the research site chose to provide breath samples, more than 70 percent provided oral fluid, and over 40 percent chose to provide blood samples.

Although 85.2 percent of the eligible drivers who entered the data collection site to get information on the survey participated, how many just passed by? Additionally, only 42.2 percent provided blood samples.

The second survey, the “Drug and Alcohol Crash Risk” study, assessed whether crash-involved drivers in Virginia Beach over a 20-month time period had drugs in their system at the time of the crash. THC was the most frequently used drug, by 7.6 percent of the crash-involved drivers. However, 6.1 percent of the control group drivers also tested positive for THC. Overall, 16 percent of the crash-involved drivers and 14.4 percent of the control drivers tested positive for drugs. When the data looked at illegal versus legal drugs, 10.4 percent of the crash-involved drivers used an illegal drug, while 8.8 percent of the control group used an illegal drug. See the table below taken from the “Drug and Alcohol Crash Risk” study.

Again, should be used when interpreting the results of the survey as indicating impairment. In some cases, “drug presence can be detected for a period of days or weeks after ingestion.” The discussion indicated its results were consistent with previous research, including the NHTSA’s 2007 Roadside Survey (RSADU). Driver impairment from both alcohol and other drugs is a serious safety concern. However, drugs other than alcohol have a less-certain impact on driving impairment. This is primarily due to the lack of reliable research into quantifying the driving impairment of substances other than alcohol.

Understanding the effects of other drugs on driving is considerably more complicated than is the case for alcohol impairment. This stems from the fact that there are many potentially impairing drugs and the relationship between dosage levels and driving impairment is complex and uncertain in many cases.

Particularly with the recent legalization of marijuana in several states and the growing acceptance of medical marijuana, more studies into the driving impairment from marijuana need to be done.

Faith Seeking Understanding

Charles Sigler, D.Phil.

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