Researchers have re-opened a line of inquiry into the potential therapeutic applications of the classical psychedelic compound LSD, but is LSD addictive?
The renewed interest in psychedelic compounds, particularly for the treatment of certain mental health disorders, has many people wondering about how they compare to current treatments in terms of both efficacy and side effects.
Ketamine, psilocybin, and MDMA (also called “ecstasy”) are just some of the mind-altering drugs undergoing extensive scientific investigation for their healing potential, having shown early promise in the treatment of anxiety, depression, post-traumatic stress disorder, and a variety of addictions.
However, the semisynthetic psychedelic compound lysergic acid diethylamide (LSD), or, acid, as it is colloquially known, had been psychedelic therapists’ principal psychoactive ally throughout the 50s and 60s — the “golden age” of psychedelic research — and was largely hailed as a breakthrough for psychiatry.
During this period, more than 40,000 patients were treated with LSD-assisted therapy for a variety of chronic pain and mental health conditions, including cancer pain, anxiety, depression, and alcohol addiction, and over 1000 scientific papers were published indicating the treatment’s healing potential.
That said, primitive research designs often led to unreliable outcomes, and it was difficult to determine whether LSD had any real therapeutic value.
Unfortunately, LSD research and therapy went dormant when sensationalist media reporting associated the drug with the youth-led counterculture movement and condemned it as a threat to both well-being and culture, culminating in its eventual prohibition in 1968. In 1970, LSD was placed in Schedule I of the Controlled Substances Act where it is classified as having a high potential for abuse.
But is there any evidence to support LSD’s restrictive classification as a schedule I substance?
When determining if psychedelic compounds such as LSD are addictive, it’s important to first understand their activity in the human brain — and it turns out they don't produce their effects like drugs of abuse.
Addictive substances like alcohol, nicotine, cocaine, amphetamines, and opioids directly or indirectly stimulate dopaminergic neurons, elevating extracellular concentrations of dopamine in the brain and producing transient feelings of pleasure.
The euphoria and excitement produced by the persistent release of dopamine as a consequence of chronic consumption implant drug cues into the amygdala — an integrative brain region involved in emotional processes and motivation — and recruit several additional brain regions in the obsessive craving for these habit-forming substances.
This series of processes can very quickly lead to addiction as users attempt to chase a high and/or numb physical or emotional pain. During periods of abstinence, the addicted user’s brain is primed to re-engage in drug use when triggered by single use of the drug, environmental cue-induced craving, withdrawal, or stress — even in the face of negative health or social consequences. The compulsive drive to engage in drug use is aided by drug-induced deficits in impulse control and decision-making.
In contrast, a large population study of 130,000 adults published in the Journal of Psychopharmacology in 2015 concluded that the use of LSD is not linked to any mental health problems, including addiction. According to the study’s authors, “psychedelics are not known to harm the brain or other body organs or to cause addiction or compulsive use.”
This is because so-called “classical psychedelics” — including LSD, psilocybin, mescaline, and DMT — primarily interact with the serotonin neurotransmitter system, not the dopamine system. Specifically, psychedelics like LSD exert their psychoactive effects via activation of the 5-HT2A serotonin receptor, a mechanism that is not associated with the kind of pleasurable reinforcing effects observed with drugs of abuse. In general, the use of psychedelics does not promote redosing, which suggests a low potential for abuse.
The overall lack of activity with dopamine receptors has led researchers to conclude that addiction to classic psychedelics, including LSD, is highly unlikely for the majority of people. LSD has not shown any dependence liability since recreational use and research began in the 1940s, and psychedelic compounds in general simply don’t induce cravings the way other drugs do.
Furthermore, the intensity, long duration of action, and unpredictability of the LSD experience, which can be significantly challenging, likely causes recreational users to limit their frequency of use.
The natural progression of addiction centers on tolerance, wherein a user needs more and more of their drug to experience its full effects. With addictive drugs like cocaine, tolerance builds up gradually and slowly, making it more conducive to daily use and its users more susceptible to addiction and unpleasant effects.
Contrastingly, users of psychedelic drugs like LSD tend to rapidly develop tolerance, making it extremely difficult to produce any compelling effects after a few days of repeated usage.
A 2016 review by renowned pharmacologist and medicinal chemist David Nichols found that “daily administration of LSD leads essentially to complete loss of sensitivity to the effects of the drug by day 4.” Nichols, considered one of the world’s top experts on the pharmacology of psychedelics, surmises that there is zero incentive to continue habitual use of LSD if it fails to produce psychoactive effects.
As yet, scientists are not entirely certain as to why LSD tolerance develops so quickly, however, repeated administration has been shown to downregulate 5-HT2A receptors in the brain, meaning there are fewer binding partners for LSD to produce its characteristic effects. Also, repeated LSD administration has been shown to reduce the binding affinity of glutamate — the brain’s most abundant neurotransmitter — and the responsiveness of glutamate receptors in the cortex of LSD-tolerant rats, which may further explain the rapidity of LSD tolerance.
It is widely known that increased tolerance to addictive drugs can lead to life-threatening overdoses. According to Nichols, approximately 31 million people have ever taken LSD in the United States, with not a single documented death due to LSD at recreational doses. Although a few LSD-related fatalities have occurred, these are typically a consequence of engaging in dangerous activities while intoxicated.
Interestingly, because all classical psychedelics exert their effects via activation of the same serotonin receptor, cross-tolerance occurs, meaning if someone consumes psilocybin today, the effects of taking LSD or mescaline tomorrow will be significantly diminished.
Before prohibition, LSD was touted as a potential cure for alcohol-use disorder.
In fact, Alcoholics Anonymous co-founder Bill Wilson became an ardent supporter of the use of LSD-assisted therapy to treat alcohol addiction after participating in a supervised trip as part of a controlled experiment in 1956. Wilson believed that the spiritual implications of an LSD-induced mystical-type experience could help people to overcome addiction, but this hypothesis was dismissed by his counterparts and he left the organization two years later.
A recent meta-analysis of six randomized controlled clinical trials conducted between 1966 and 1970 provided support for Wilson’s intuition regarding the anti-addictive potential of LSD, finding that a single dose had a significant beneficial effect on alcohol misuse.
Meanwhile, LSD’s psychedelic cousin psilocybin has shown tremendous efficacy for smoking addiction in combination with cognitive behavioral therapy. An open-label pilot study published in 2014 found that 2-3 psilocybin-assisted therapy sessions could produce substantially higher abstinence rates than currently available treatments. 12 months after psilocybin treatment, 67% of participants remained smoking abstinent.
As a reward for their seminal research, the Johns Hopkins researchers that conducted this study recently received a $4 million grant funded by the National Institutes of Health to conduct a three-year, multi-site, double-blind, randomized controlled trial on the effects of psilocybin-assisted therapy on smoking addiction.
Great strides have been made in psychedelic research in recent years, with psilocybin- and MDMA-assisted therapy becoming recognized as breakthrough mental health treatments deserving of expedited clinical evaluation. And now, having been unnecessarily shunned from scientific research for 50-odd years, LSD is getting back in on the act.
A recent randomized, double-blind, placebo-controlled phase II study showed that 2 high doses of LSD administered in a clinical context can significantly reduce anxiety scores for up to 3 months. A question that has naturally emerged as clinical research continues to gather pace and psychedelic medicines expand into the public consciousness is how safe their clinical use may be once integrated into mainstream medicine.
Many people consider psychedelics to have a similar potential for abuse and harm as substances like alcohol, tobacco, cocaine, and opioids, but, the truth is, that psychedelics are among the safest of all recreational substances. Classical psychedelics like LSD are physiologically very safe and nonaddictive, particularly when dosages are moderate and consumed in controlled environments.
Not only is LSD nonaddictive, but we may also see LSD-facilitated interventions integrated into future addiction treatment — a welcome addition, especially for those who may have been disappointed by traditional addiction treatments.
Importantly, although dissociative anesthetics like ketamine and phencyclidine (PCP) and entactogens like MDMA are often referred to as psychedelics, they are distinct from classical psychedelics and have an entirely different mechanism of action that may promote addiction or compulsive use.
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