From backlash to breakthrough

For “people of a certain age,” the term psychedelic may conjure all sorts of colorful cues: Jimi Hendrix jamming at Woodstock, the album cover of the Beatles’ Sgt. Pepper’s Lonely Hearts Club Band, or antihero Timothy Leary chanting “Turn on, tune in, drop out” at the peak of 1967’s so-called Summer of Love. It was an era when many young Americans, inspired by Leary himself, inhaled their first puff of marijuana, swallowed their first magic mushroom, or took their first trip on LSD.

Leary was something of an icon in the counterculture following his ouster from the Harvard Psilocybin Project (1960-63). He and his academic colleague Richard Alpert (aka Baba Ram Dass) had been experimenting with psychotropic substances on human subjects, often while under the influence themselves. They were ardent advocates for the recreational use of hallucinogens, but Harvard wasn’t having it, and neither was the federal government. The university fired the pair for scientific and ethical breaches. And in 1968, after unregulated psilocybin had infiltrated popular culture, the federal government banned the substance.

The ensuing backlash was too much for legitimate researchers. Scientific inquiry into psychotropics’ potential therapeutic benefits dried up. But the times, as someone once said, “they are a-changing.”

Rigor and responsibility

An evolving renaissance of serious scientific interest into psychedelics is gaining traction at U-M, says George A. Mashour, MD/PhD, chair of the Dept. of Anesthesiology. Researchers at the Medical School are taking a contemporary look at psychedelic drugs, as well as the psychoactive compounds in marijuana, in hopes of developing life-changing treatments for people with psychiatric disorders, chronic pain, depression, anxiety, and other medical conditions.

“Psychedelics are powerful tools to help understand the brain, and emerging clinical trial results suggest they could have therapeutic benefits,” Mashour says.

Mashour and his colleagues are not following in the footsteps of the notorious Leary, but rather Swiss chemist Albert Hofmann who first synthesized LSD-25 (lysergic acid diethylamide) in 1938 at Sandoz Laboratories. (He’d been attempting to produce a respiratory and circulatory stimulant at the time.) In 1943, Hofmann was the first to ingest the substance and his revelations sparked a surge of scientific inquiry that lasted well into the pre-Leary ‘60s.

Now that local laws governing controlled substances are easing, public attitudes toward drug usage are shifting. As of June 2023, 38 states — and the District of Columbia — have some form of legal medical and recreational marijuana, according to ProCon.org. Marijuana dispensaries offer cannabis products ranging from flower, concentrates, and tinctures to edibles, topicals, and vapes. The domestic cannabis industry is estimated to generate some $41.5 billion in sales by 2025, according to Fortune magazine. In 2019, sales totaled about $10.7 billion.

Modern times

As cannabis use becomes increasingly normalized, psychedelics are getting a second look. In 2022, Mashour founded M-PsyC, the Michigan Psychedelic Center, at Michigan Medicine to explore the scientific and clinical implications of these drugs. He encourages people to reject the “hippie” tropes popularized in the ‘60s to focus on the medicinal benefits psychedelics could offer to mainstream users.

“It is important to be mindful of the history of psychedelic use and investigation in the late 1960s ― and not to repeat the same mistakes,” Mashour says. “We should not stigmatize research on psychedelic drugs, but neither should we romanticize it. We must remain critical thinkers.”

M-PsyC’s tagline reads: “Revealing the mind, with rigor and responsibility.” Its work touches everything from Biological Chemistry, Biomedical Engineering, Neurology, and Psychiatry to Nursing, Molecular and Integrative Physiology, and the U-M Herbarium. Campus partners include the Chronic Pain & Fatigue Research Center, the School of Public Health, the College of Pharmacy, the Life Sciences Institute, and more.

Eureka!

Although M-PsyC is still in its formative stages, Mashour says researchers are “making exciting progress” in the study of psilocybin, DMT, ketamine, and nitrous oxide.

Several clinical trials provide early evidence of the anti-depressant effects of psilocybin, sometimes with a single dose and with a much more rapid onset than traditional drug therapies. Other research shows that psychedelic drugs affect an area of the brain associated with the qualitative aspects of consciousness, such as bodily sensations and imagery experiences (i.e., the aforementioned Sgt Pepper’s).

Larger-scale studies will be required to confirm these findings and illuminate safety considerations, Mashour says. But it’s going to be tough for this area of study to shake its colorful past.

“We do not conduct any study without the appropriate regulatory approvals in place, and we are committed to the highest safety and research ethics standards,” Mashour says.

Kevin Boehnke, research assistant professor in the Dept. of Anesthesiology and the Chronic Pain and Fatigue Research Center, has spearheaded numerous survey studies on psychedelics and cannabis. He is planning a small clinical trial that combines therapy and psilocybin to treat fibromyalgia, a common chronic pain condition. Participants in this trial will receive psilocybin under the guidance of therapists, and work with those therapists in the weeks before and after their psilocybin experience.

“If we proceed wisely with the study of psychedelics, then hopefully as these compounds become more widely accessible to people, we won’t end up with the huge knowledge gaps we’ve seen in the use of cannabis as a medical treatment,” Boehnke says.

“Medical” marijuana

“From a medical standpoint, I’d say medical marijuana laws that were passed in Michigan and elsewhere are just bad,” says Jonathan Morrow, MD/PhD, associate professor of psychiatry.

In 2020, more than 3 million Americans had medical cannabis cards, compared to 680,000 in 2016. More broadly, a 2022 Gallup poll reported nearly half of U.S. adults say they have tried marijuana at some point, and 68 percent think it should be legal. Though legally accessible in most states, cannabis is still classified at the federal level as a Schedule 1 controlled substance.

Medical experts disagree about the effectiveness and safety of cannabis products, which are not regulated for dosage, content, and purity in the same way as prescription drugs. Laws allow medical cannabis for pain and other ailments, but physicians lacking in formal education about the substance may be reluctant to recommend it to their patients.

“The research has not kept up with modern-day clinical practice and patient accessibility of cannabis treatments,” says Mark C. Bicket, MD/PhD, assistant professor of anesthesiology. “I find myself in a gray zone, even as a medical researcher, in terms of being able to best advise my patients.”

Heal thyself

In the absence of medical oversight and reliable scientific data, many consumers have turned to social media postings, Internet searches, and word-of-mouth to guide their decisions about how, when, and why to use cannabis. Some people contend it reduces pain while others experience unpleasant side effects or see little or no effects at all.

“The evidence about whether medical cannabis use leads to different use or lower use of other pain treatments was not clear to us,” says Bicket, who set out to learn more about people’s perceptions of cannabis.

In 2022, Bicket surveyed 1,661 adults with chronic noncancer pain who live in states with medical cannabis programs. He asked participants to report on their use of medical cannabis, as well as pharmacologic treatments (prescription opioids, prescription nonopioid analgesics, and over-the-counter analgesics) and common nonpharmacologic treatments (physical therapy, meditation, and cognitive behavioral therapy).

Bicket found that 3 in 10 persons reported using cannabis to manage their pain. Among those users, more than half said medical marijuana enabled them to lower their use of prescription opioids, as well as prescription nonopioids and OTC pain medications.

In a follow-up report, Bicket asked the survey participants about their perceptions of the relative safety and effectiveness of cannabis. Nearly half said they considered cannabis to be as effective as ― and safer than ― prescription opioids. Only 20 percent of the respondents thought prescription opioids were safe.

The same proportion of people viewed cannabis as being on par with nonopioid treatment options in terms of both safety and effectiveness.

“A person’s experience of pain is multidimensional,” Bicket says. “Cannabis affects both an individual’s emotional experience and the actual processing of pain signals.”

He emphasizes the need for more research to clarify the effectiveness and potential adverse consequences of cannabis use for chronic pain.

Raising red flags

Today’s cannabis is far more potent than it was during the late ‘60s and the “Summer of Love.”

Over the decades, growers have genetically engineered the cannabis plant to maximize its THC content, which has increased from less than 3 percent to 25 percent, or even higher. THC, or tetrahydrocannabinol, is the major psychoactive component and one of more than 100 compounds, or cannabinoids, identified in the cannabis plant.

“One of the side effects I deal with a lot is addiction and withdrawal, because cannabis is an addictive drug,” says Jonathan Morrow, MD/PhD, associate professor of psychiatry at U-M Addiction Treatment Services. “Some people are more vulnerable to addiction due to genetic and environmental factors. Other effects depend upon how individuals are using cannabis.”

People who smoke or ingest large amounts of marijuana, take it frequently, and use it for prolonged periods of time are more likely to develop addiction, says Morrow. The route of administration is also important. Smoking drugs, in general, is more addictive than using them orally as edible gummies or tinctures.

“People can get into a daily withdrawal cycle,” Morrow explains. “They will use cannabis and experience a reduction in their anxiety or get sleepy. But as the drug wears off, their body will adjust very quickly, and they will go into a withdrawal state that is the opposite of the intoxication state. Then they will end up taking cannabis to treat their withdrawal symptoms.”

To learn more about the progression of cannabis withdrawal symptoms, Michigan Medicine researchers conducted a two-year survey including 527 people in Michigan who use cannabis for chronic pain and other medical purposes. Participants were asked to report on their experiences when they abstained from using cannabis.

“More than half of the participants experienced multiple withdrawal symptoms when they went for a period of time without using cannabis,” says Lara Coughlin, PhD, a clinical psychologist and assistant professor of psychiatry. “This withdrawal syndrome can include irritability, disturbed sleep or vivid dreams, depressed mood, and reduced appetite.”

Coughlin reports that young adults, who more frequently use higher-potency cannabis products, were at increased risk for experiencing severe withdrawal symptoms when they went for a period without using cannabis.

Too young to know

Marijuana use and vaping were at their highest historic levels among younger adults aged 19-30 in 2022, according to U-M’s annual Monitoring the Future Panel Study. In addition, reports of past-year marijuana and hallucinogen use as well as marijuana and nicotine vaping significantly increased in the past five years.

“Marijuana use in the past month was reported by 29 percent of young adults (ages 19-30) and 16 percent of mid-life adults (ages 35-50),” says Megan Patrick, research professor at U-M’s Institute for Social Research (ISR). “Marijuana vaping, in particular, was reported by 12 percent of young adults in the past month.” Among those aged 19-22, marijuana use in the past month was less prevalent among college students compared to noncollege young adults.

Often teens and adults are unaware of the negative effects of marijuana, even when it is used for medical purposes.

Often teens and adults are unaware of the negative effects of marijuana, even when it is used for medical purposes.

“Cannabis is cognitively impairing, so individuals experience slowed thinking, trouble with making appropriate connections, memory problems, and slowed reactions that can persist long after they stop feeling high,” Morrow says. “People who have been using cannabis are not safe to drive, because they tend to make bad decisions and react very slowly.”

Cannabis use also can interfere with the effectiveness of treatments for psychiatric disorders, and users may require more anesthesia for surgical procedures. In some cases, heavy, sustained use of marijuana can cause cannabis hyperemesis syndrome, a withdrawal condition characterized by nausea, stomach cramps, and intractable vomiting.

“From a medical standpoint, I’d say medical marijuana laws that were passed in Michigan and elsewhere are just bad,” Morrow says. “Cannabis has been promoted for doing things that we don’t have evidence it does. We had access to THC long before it was legalized medically, but we didn’t use it, because it didn’t work very well.”

Planning for a medically safer future

As cannabis use increases and psychedelics become more commonplace, the medical community needs to expand its knowledge of these substances and how to care for the patients who use them, says clinical psychologist Coughlin.

“What we’re grappling with in the academic realm is making sure our science is keeping up with public health policy,” she says. “We should be focusing our efforts on ensuring cannabis is used in a way that minimizes harm, and making sure that individuals who do experience consequences from their use receive the care that might benefit them.”

The reluctance of some physicians to counsel patients who use or are considering using marijuana or psychedelics puts considerable burden on those patients, says Boehnke.

“It would be really helpful if people could get the support and care they need from clinical providers, especially as they are trying to understand whether these might be a safe option,” he says.

More controlled scientific studies will help physicians get a better handle on how cannabis products can be useful, and for what medical conditions, Morrow adds.

“But in order for medical doctors to administer cannabis to their patients, it will have to be manufactured in a controlled way by a reputable manufacturer so we know the exact dose in the product,” he says.

M-PsyC is committed to educating the academic community and the general public, says Mashour. On Oct. 24, the center will host the public event “The Psychedelic Renaissance.”