From ... in Psychology Herbalism — Aug 10, 2021

Psychedelics and Cannabis Therapeutics

Although it may not be obvious during these Trump-rattled times, we’re in the midst of a psychedelic revival.

There is more interest than ever before in experimenting with LSD, magic mushrooms, ayahuasca, ketamine, and other psychedelic drugs. This renaissance is happening without all the fanfare of the day-glo Sixties, when lysergic acid diethylamide (LSD) escaped from the laboratory and assumed the lead role in an improbable Sorcerer’s Apprentice tale.

The phrase “stranger than fiction” doesn’t do justice to the real-world trajectory of LSD, a once-secret weapon of the Central Intelligence Agency (CIA) and the U.S. army, which shape-shifted into a potent counterculture catalyst and dazzled the minds of artists, scientists, inventors, healers, and many others. While LSD never achieved the social popularity of cannabis, the two substances were linked during the social tumult loosely known as “the Sixties.” Almost everyone who tried LSD back in the day also smoked marijuana.

These mood-altering drugs were like a one-two punch that wobbled the American psyche.

The ensuing backlash was fierce and efforts to integrate cannabis and LSD into the mainstream were frustrated for decades. Under federal law both are still officially Schedule I substances, a category reserved for dangerous drugs with no medical value. It’s taken a while, but psychedelic advocates are regaining the momentum. To win social acceptance, they’ve adopted the successful strategy that marijuana proponents have pursued – emphasize the medical aspect, produce some solid science, and show that psychedelics can cure deep psychological wounds when administered under the watchful eye of a trained health professional. Today’s psychedelic champions are careful to distance themselves from the memory of 1960s, even as they carry on its legacy. Whereas Sixties radicals celebrated LSD as a chemical capable of subverting the established order, psychedelics are now being promoted as a remedy for traumatized soldiers. In what way is LSD therapeutic? And how, if at all, does this relate to medical cannabis? To answer these questions, it’s helpful to survey the various groups of people that got involved with LSD before it became illegal in the United States in the mid-1960s.

These groups, representing disparate segments of society, all had different ideas about LSD and how it could be used to advance their specific agendas.

The scientific pioneers who began experimenting with LSD in the late 1940s and early 1950s saw it as a powerful instrument for studying how the mind works, a long-awaited chemical key for unlocking the mysteries of brain chemistry and mental illness. A boon for neuroscience, this exciting new research tool gave rise to novel theories about the biochemical basis of schizophrenia and possible remedies for this perplexing malady. Very early on, LSD was also embraced – albeit secretly – by the CIA as a “potential new agent for unconventional warfare.” This is how LSD was described in once-classified CIA documents in the 1950s. At a time when society at large knew precious little about LSD, American spy chiefs viewed this odorless, colorless, and tasteless compound as the key to revolutionizing the cloak-and-dagger trade, a means of affording U.S. intelligence a decisive advantage over its Cold War rivals.

The U.S. military also had big ideas about LSD. U.S. Army strategists were high on the prospect of deploying LSD as a psychochemical weapon – spray a cloud of “madness gas” over a city and you could incapacitate a large population without killing anyone. Or so they fantasized. LSD raised the possibility of a new kind of battle weapon that would supposedly usher in an era of “war without death.” By the late 1950s, a growing number of psychiatrists and other physicians were touting LSD as a healing agent that could expedite the process of psychotherapy. LSD had an uncanny ability to make the unconscious conscious, to illuminate long-hidden sources of stress and neurotic behavior by bringing to the surface whatever might be lurking in the depths of the mind. Hence the word “psychedelic,” which literally means “mind manifesting.” Taking LSD does not guarentee that a person’s consciousness will automatically be “expanded” or that one will neceessarily have a religioius experience or live a spiritual life thereafter. But the overpowering immediacy and experiential density of LSD can be conducive to deep insight and healing. Dr. Albert Hoffman, the Swiss chemist who discovered LSD, described it as “medicine for the soul,” a tool to help us become who we are supposed to be. During the 1960s, the therapeutic potential of LSD was projected onto a broad social landscape. Acid was trumpeted by Timothy Leary and his counterculture acolytes as a cure-all for a sick society, a species-catalyst capable of catapulting humanity to the next evolutionary level. This utopian vision seems worlds apart from the covert use of LSD as an espionage weapon, yet both share a common theme. With the benefit of hindsight, we can look back and see that every group that got involved with LSD became very enthusiastic about the grandiose possibilities conjured by the drug.

They all viewed it as the key to the big breakthrough. In each case, the encounter with LSD triggered an envisioning of new possibilities. Whether or not these different possibilities would ever be actualized is another matter, but the opening, the awakened sense of potential, was real. In essence, LSD and other psychedelic drugs are best understood as potentiators of possibility – for good or ill. Magic mushrooms, ayahuasca, peyote, rue, iboga ... these vision-inducing flora and fungi are revered as “plant teachers” by native cultures. Cannabis is also a plant teacher, of sorts. But is cannabis a psychedelic drug, a hallucinogen, like magic mushrooms or LSD? Yes and no. A lot depends on dosage. LSD is much stronger than smoked cannabis, which doesn’t generally threaten to overwhelm the cognitive mechanism as psychedelic drugs sometimes do. Cannabis and LSD both slow down the passage of time and intensify the present moment. But LSD triggers a departure from normal waking consciousness so preternaturally vivid that a few puffs of weed seem tame by comparison. Ingesting cannabis can have a far more profound effect than smoking it. Swallowing a chunk of hashish (concentrated cannabis resin) or consuming too much of a cannabis-infused edible can cause intense LSD-like hallucinations. Dr. Harris Isbell, for many years a CIA contract employee, conducted a scientific study to compare the effects of LSD and tetrahydrocannabinol (THC), the main psychoactive component of cannabis. After giving both compounds to inmates at the federal narcotics hospital in Lexington, Kentucky, Isbell concluded in a 1969 report that a high dose of pure THC could cause hallucinations similar to lysergic acid. LSD, like cannabis, was well regarded among physicians and scientists for its medicinal potential before it became associated with recreational abuse. During the 1950s, high-dose psychedelic therapy showed promise as a treatment for alcoholism. Researchers theorized that an LSD-induced peak experience could lead to a profound, long-lasting change in the way alcoholics and other addicts viewed themselves and the world. More recently, psilocybin (the magic mushroom compound) has shown favorable results for both smoking cessation and clinical depression. In a 2017 paper in Nature, medical scientists at Imperial College in London reported that patients with treatment-resistant depression experienced significant benefits that persisted after two psilocybin sessions and some psychological counseling. In 2018, the U.S. Food and Drug Administration (FDA) took the unusual step of designating an experimental psilocybin-based compound as a breakthrough treatment for depression in order to fast-track the drug development and review process. Ayahuasca (the powerful hallucinogen brewed by rainforest shamans in South America) and MDMA (“ecstasy”) have also shown therapeutic benefits in cases of substance abuse and treatment-resistant depression. So has ketamine, an FDA-approved “dissociative anesthetic,” which is administered as an off-label remedy for patients who don’t respond to conventional anti-depressants. Whereas moderate doses of ketamine can banish suicidal thoughts and send one’s darkest moods into remission, high doses can induce a full-blown psychedelic experience. “Special K” acquired a reputation as a party drug many years before scientists discovered that cannabinoid receptors in the brain and the peripheral nervous system mediate ketamine’s painkilling and antidepressant effects. Ketamine also inhibits NMDA, a glutamate receptor, and this triggers the production of a chemical known as “brain-derived neurotrophic factor” (BDNF). Described as “fertilizer for the brain,” BDNF stimulates the growth of new brain cells, a process referred to as “neurogenesis.” New neurons are continually forming in at least two regions of the adult mammalian brain – the sub-ventricular zone of the lateral ventricle and the sub-granular layer of the hippocampal dentate gyrus. BDNF also stimulates “synaptogenesis,” the formation of new connections between brain cells, which facilitates neuroplasticity, the brain’s ability to adapt to stress and injury and new experiences. Ketamine, psilocybin and LSD are neurogenic compounds that promote neuroplasticity and new neural connections. Scientists recognize that the anti-depressant effect of psychedelic drugs is contingent upon enhanced neurogenesis. Cannabis, it turns out, is another neurogenic substance that spurs the creation of new brain cells – unlike alcohol exposure, which “disrupts adult neurogenesis” in animal models. In 2005, researchers at the University of Saskatchewan found that THC increases neurogenesis by activating CB1 cannabinoid receptors in the hippocampus, the locus of short-term, long-term, and spatial memory. And cannabidiol (CBD), a nonintoxicating cannabis component, can reduce anxiety and depression by stimulating neurogenesis in the hippocampus, according to a 2013 Brazilian study in the International Journal of Neuropsychopharmacology. THC and CBD promote neurogenesis and other health benefits by mimicking and augmenting the activity of endogenous cannabinoid compounds produced in our own brains.

These endogenous signaling molecules are part of the endocannabinoid system, which plays a key role in regulating adult neurogenesis and BDNF expression on a cellular level. Endocannabinoids and plant cannabinoids activate the same cannabinoid receptors that densely populate the brain’s neurogenic zones. Scientists are exploring various ways that THC and CBD interact with the serotonin (5-HT) system. CBD, for example, binds to three serotonin receptor subtypes, including 5-HT2a. Aberrant 5-HT2a signaling has been linked to headaches, mood disorders, and hallucinations.

The 5-HT2a receptor is also a key mediator of the psychedelic experience. LSD and several other psychedelic compounds bind to 5-HT2a, and this is thought to be responsible for producing many of LSD’s signature effects. LSD and CBD are both mighty molecules. But CBD is positively un-psychedelic – it’s about the least hallucinogenic substance imaginable. CBD seems to act as a weak 5-HT2a antagonist, which means that it binds to the receptor and partially blocks it. Psychedelics do the opposite – they activate this receptor in a big way. LSD is a super-potent 5-HT2a agonist; it has a much stronger binding affinity for the 5-HT2a receptor than serotonin itself. THC – unlike LSD and CBD – doesn’t bind directly to 5-HT2a. But THC participates in crosstalk between the endocannabinoid and serotonin systems through a process known as “dimerization.” THC activates cannabinoid receptors – and these receptors can link up and combine with serotonin receptors to form novel signaling complexes called “heterodimers.” Receptor dimers are a relatively new and controversial area of neuroscience and researchers have barely scratched the surface of understanding these curious protein conjugates. Preclinical studies indicate that conjoined CB1 cannabinoid receptors and 5-HT2a serotonin receptors facilitate the painkilling and the neuroprotective effects of THC, as well as the cognitive deficits caused by THC’s impact on short-term memory. A 2015 report by a team of European scientists observed that CB1/5-HT2a heterodimers are “expressed and functionally active in specific brain areas involved in memory impairment.” Are these conjoined receptors also implicated in the neurobiological underpinnings of hallucinations that may follow the ingestion of a high dose of THC? Is this why the oral consumption of hashish resin or a well-endowed cannabis edible can trigger kaleidoscopic, LSD-like visions? Several studies suggest that cannabis use promotes 5-HT2a receptor signaling. In 2013, for example, scientists at the University of Kansas found that cannabinoid compounds can upregulate and enhance serotonin 5-HT2a activity in the prefrontal cortex. Even more intriguing, the molecular pathway that links 5-HT2a and CB1 cannabinoid receptors appears to be a two-way street. In 2006, David Nichols and his team at Purdue University reported that 5-HT2a receptor activation leads to the formation and release of endocannabinoids.

The interaction between 5-HT2a receptors and the endocannabinoid system is fundamental to the neurogenic and antidepressant properties of psychedelic drugs. What about microdosing psychedelics? If a high dose of THC can produce effects that are similar to a full-blown psychedelic experience, then microdosing LSD is more akin to taking CBD. According to favorable anecdotal accounts, microdosing magic mushrooms and LSD can help with anxiety, depression, and substance abuse disorders.

The same has been said for CBD, which confers therapeutic effects through multiple molecular channels. One of the ways CBD relieves anxiety is by binding to another serotonin receptor, 5-HT1a. Scientists have identified this receptor as a major target of CBD, more so than 5-HT2a.

There’s also a growing body of evidence that CBD has significant anti-addictive potential, a recurring therapeutic attribute of psychedelic compounds. Preclinical research suggests that CBD may have remedial properties for opioid, cocaine, tobacco, and methamphetamine addiction. CBD also protects against neurodegeneration caused by binge-drinking. A 2017 study in the journal Addiction Biology suggested that CBD can aid in addiction recovery due to its effects on memory. CBD was found to blunt cue-induced cravings that make recovery from addiction very difficult.

The importance of forgetting should not be underestimated in mental health, particularly when it involves disrupting an association with a drug-related cue on a visceral level – one of the many gifts of CBD. Plant cannabinoids like CBD and THC are biphasic compounds, meaning high and low doses convey opposite effects: low doses tend to stimulate, high doses tend to sedate. LSD is also a biphasic compound, as evidenced by the distinctly different effects of macrodosing and microdosing psychedelics – as different as a high dose of THC and a nonintoxicating dose of CBD.

There’s a saying in neuroscience: “Neurons that fire together, wire together.” Brain habits get stuck. Psychedelics may indeed open the doors of perception. But even more fundamental is how these substances thrust open windows of enhanced neuroplasticity by stimulating the creation of new brain cells and synaptic connections. Science has proven that this is what psychedelics do. A full-blown LSD experience might last from 8 to 12 hours, but the adaptive changes in the brain triggered by the drug can last much longer. New neural connections may lead to new perspectives.

The phrase “high on LSD” implies rising above the ordinary and getting a long-range, overarching view, a big-picture satori – what was once unimagined suddenly becomes saturated with possibility. LSD has a propensity for catalyzing intensely meaningful moments of vision, those seminal light bulb moments, the explosive epiphanies, which alter mental constructs and transform how we look at things. But integrating those insights and applying them in daily life is easier said than done. Broadening our horizons doesn’t necessarily change our immediate circumstances. Whether microdosing or chasing the ultimate high, psychedelics are not a quick fix. But they can deliver a neurogenic spark that resets brain circuits in people who are depressed or in a problem-solving rut or who just want some unsupervised awe and wonder. And this reset can resonate well into the future. Originally published by Project CBD at “PSYCHEDELICS & CANNABIS THERAPEUTICS“. Reprinted with permission. co-founder and director of Project CBD and the author of several books, including Smoke Signals: A Social History of Marijuana–Medical, Recreational and Scientific, which received the American Botanical Council’s James A. Duke Award for Excellence in Botanical Literature. Named by High Times as one of the 100 most influential people in cannabis, he is the 2016 winner of the Emerald Cup’s Lifetime Achievement Award. Lee is also co-founder of the media watch group FAIR (Fairness & Accuracy In Reporting) and the author of Acid Dreams: The Complete Social History of LSD–The CIA, the Sixties and Beyond.

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