Who Isn’t Psyched? The Risks That Psychedelics and Marijuana Pose for Substance Induced Psychosis
On November 5th, 2024, Massachusetts voters narrowly decided against legalizing natural psychedelic substances for therapeutic use. This defeated ballot question drew parallels to a similar 2012 initiative that successfully legalized marijuana. Now, more than a decade after marijuana’s legalization, we are just beginning to see the psychological effects of long-term use, including substance-induced psychosis. Had this recent measure passed for natural psychedelics, it could have initiated a large-scale societal experiment with unpredictable mental health outcomes.
Substance-induced psychosis is a mental health condition directly triggered by the use of psychoactive substances, such as cannabis or psychedelics. Symptoms include paranoia, hallucinations, and severe delusions, often mirroring the presentation of disorders like schizophrenia. While these acute episodes of psychosis can be resolved once the substance is cleared from the body, they may also unmask underlying genetic or neurobiological vulnerabilities, leading to persistent mental health issues. As Massachusetts voters confront the decision to expand access to psychedelics, it is critical to consider these potential risks, which can be especially damaging to younger populations undergoing critical periods of brain development.
How do Psychoactive Substances Work?
Marijuana
Marijuana has demonstrated promising therapeutic effects for a variety of conditions, including epilepsy, neuropathic pain, and anxiety. The two most prominent active compounds in marijuana are cannabidiol (CBD) and delta-9 tetrahydrocannabinol (THC). CBD, a non-psychoactive compound, can be extracted from cannabis to help treat the conditions mentioned above. THC, on the other hand, is psychoactive and responsible for the mind-altering effects of the drug, namely feelings of relaxation and happiness, as well as altered time perception and impaired thinking. THC can also stimulate appetite, and has been used to help cancer patients who experience a loss of appetite after cancer treatment. When marijuana is consumed, THC enters the bloodstream either rapidly via inhalation or more slowly through ingestion. THC can then easily pass into the brain and can also accumulate in adipose (fatty) tissue throughout the body. From these adipose stores, THC can be gradually released back into the bloodstream, extending its effects. THC can be detected in adipose tissue for up to 28 days after use, and in heavy users, for as long as 77 days following the last use.
In the brain, THC interacts with the body’s endocannabinoid system, which is a complex cell signaling pathway that is involved in regulating a variety of physiological processes, including mood, memory, and appetite. THC binds very effectively to cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 receptors are present on many neurons, the signaling cells of the brain. Once THC activates CB1 receptors, it regulates the release of several key neurotransmitters (the chemical messengers of neurons) from these neurons, causing the effects we associate with marijuana use. For example, the euphoric nature of THC is believed to result from its ability to trigger an outflow of dopamine (a neurotransmitter in the brain that is responsible for pleasure and reward). The neurons that release dopamine are regulated by another neurotransmitter, GABA, which normally inhibits dopamine release. When THC binds to CB1 receptors, it blocks neurons from releasing GABA, leading to increased dopamine and the feeling of euphoria (Figure 1). That being said, this excess dopamine after THC-binding is likely also responsible for paranoia and the psychotic-like symptoms that can occur with THC use.
Psychedelics
The ballot question in MA proposed the legalization of natural psychedelic substances, specifically listing psilocybin (the psychoactive chemical contained in magic mushrooms), as well as dimethyltryptamine (DMT), mescaline, and ibogaine (iboga). Unlike THC, which impacts dopamine, these psychedelics operate through a different pathway in the brain mediated by binding to serotonin receptors (5-HT2A receptors), which are important in memory, cognition, and perception (Figure 2). When psychedelics bind to 5-HT2A receptors, they increase the activity of neurons in a way that alters perception and cognitive processes. This is a complex mechanism that not only results in heightened brain activity, but that has also been shown to promote synaptogenesis, which is the creation of new connections between neurons.
These factors have made psychedelics an appealing therapy for mental health conditions such as depression, anxiety, and addiction. Psychedelic therapy involves the controlled administration of psychedelics by a clinician, typically in conjunction with cognitive behavioral therapy, and has shown promising effects in clinical settings. However, recreational use of psychedelics can have significant risks. While it is well established that a family history of psychiatric illness puts one at a higher risk of developing psychosis after psychedelic use, several case studies have shown incidences of mania, psychosis, and paranoia developing in patients who have not had any prior personal or family history of psychiatric illness as well, thus sparking concerns for its recreational use.
Effects of Psychoactive Drugs on Brain Development
From birth through the first year of life, the primary sensory areas of the brain that respond to vision, touch, and hearing are developed. In the following five years, language and gross motor skills will undergo the majority of their development. Lastly, executive function (such as working memory, emotional-regulation, and problem solving) matures through adulthood to around the age of 30 (Figure 3).
The concerns about the recreational use of psychedelics become even more prominent when considering the unique vulnerabilities of the brain during critical periods of development. Critical periods are times of brain development that are sensitive to external stimuli. These periods are marked by substantial increases in neuroplasticity (reorganization of synaptic connections) and synaptogenesis. This allows the brain to refine its connectivity by either strengthening existing neuronal connections or pruning away inefficient connections. Most of this plasticity occurs within the first year of life; however, the last period of rewiring and development extends all the way into late adolescence, continuing until the age of 25! The introduction of psychoactive drugs during these critical periods of development can cause detrimental effects, as these substances may disrupt the neural connections being formed that are essential for higher-order function. For example, one study linked psychedelic use in adolescent populations (ages 12-17) with increased incidences of major depressive disorder. In addition, although the data is limited, a twin study has shown that psychedelic use in young adults is correlated with a higher likelihood of psychosis, particularly in individuals with a family history of psychiatric illnesses. Similarly, cannabis use in adolescence has also been correlated with a greater risk of developing major depressive disorder, as well as incidences of psychosis.
Implications for Future Use of Psychoactives
While most users of psychedelics and cannabis do not experience psychosis, the increasing availability of marijuana and the potential for broader access to psychedelics raises concerns about a possible rise in psychosis cases. Furthermore, many individuals remain unaware of the associated risks, particularly those from vulnerable populations. These populations include adolescents and young adults, whose brains are still in critical stages of development, and individuals with a predisposition to mental health disorders such as schizophrenia or anxiety.
The risks of substance-induced psychosis highlights the need for public education and harm reduction strategies. Targeted and accessible communication about the potential dangers, especially for high-risk groups, should accompany any policy changes or expanded access. Furthermore, research into the long-term effects of these substances is critical to deepen our understanding of their effects and to guide safe practices in both recreational and therapeutic contexts.
Aliya Norton is a first-year PhD student in the Harvard Program in Neuroscience and she is currently studying sensory neurons and their subtypes.
Gracyn Mose is a PhD student in the Chemical Biology program at Harvard University.
For More Information:
- To learn more about how cannabis can contribute to psychosis and schizophrenia read this review article here.