LSD & Psilocybin: Pain Relief Reimagined

This article is a type of research paper called a narrative review. A narrative review provides an overall summary on the current research to date on a topic, while allowing the author(s) a degree of subjective interpretation in their writing.

Contrast this to a systematic review. A systematic review will usually focus on a narrow question interpreted under a specific context. They aim to distill down a single reality based on available evidence. A subjective review, on the other hand, operates under the assumption that reality is subjective and constantly changing. A systematic review seeks an answer to a narrow question; a narrative review offers…well, a bit more of a narrative. A narrative review can offer a succinct explanation of research to date on a subject, but brings the author’s subjective interpretation into play – for example, they may critique past policy or practice, and offer suggestions for changes to be made moving forward based on the evidence presented in the review.

Both narrative reviews and systematic reviews play important roles in the world of scientific research. From my perspective, I look for systematic reviews when trying to answer a specific question about a specific treatment for a specific patient population. I turn to a narrative review when I’d like more subjective insight from the author(s) about where science and medicine may go next.

The article, “LSD and psilocybin for chronic nociplastic pain: A narrative review of the literature supporting the use of classic psychedelic agents in chronic pain”, published in the South African Medical Journal in November 2023. It explores research on LSD and psilocybin use for treating chronic pain, focusing on research prior to the War on Drugs and recent studies during the “psychedelic renaissance”.

 

Chronic Pain: Background

Chronic pain was estimated to affect ~20% of the U.S. population (1 out of every 5 persons) in 2021. The International Association for the Study of Pain (IASP) updated a new definition for pain in 2020, describing it as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.” Incorporating emotional experience and the notion of potential (rather than realized) tissue damage is important, for reasons we’ll discuss a bit later in this article.

The term “nociplastic pain” refers to chronic pain caused by changes to processing of emotional and sensory stimuli in our central and peripheral nervous systems. This differentiates nociplastic pain from neuropathic (nerve) pain and nociceptive pain (pain caused by actual, noxious damage, such as placing your hand into a burning flame). Boiled down, nociplasic pain is caused by either increased transmission or lowered inhibition of painful stimuli within our central nervous system (CNS). According to IASP, nociplastic pain happens “despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain”. This is pain with no clear cause.

Despite the development of dozens of pain relievers, including opioid medications (which typically bring a host of side effects and risks that, ultimately, may actually worsen patient quality of life), and the incorporation of additional treatment modalities such as physical therapy and cognitive behavioral therapy (CBT), chronic pain often eludes satisfactory treatment.

The authors of this paper propose that, “management of the chronic pain experience must focus not only on the mechanisms of nociception on a receptor level, but move beyond physiology to incorporate the experiential aspect of pain as an ‘embodied’ experience within a specific psychosocial ‘embedded’ environment.”

The paper focuses on LSD (“acid”) and psilocybin (“magic mushrooms”, “shrooms”) as these classic psychedelics both act on 5-HT_1A (“serotonin 1A”) receptors, which play a role in transmitting pain stimuli, and on 5-HT_2A (“serotonin 2A”) receptors, which can both boost mood and regulate neuroplastic changes which occur due to chronic pain.

 

Neuroplastic Changes with Nociplastic Pain

Classic psychedelics target neuroplastic changes that occur with chronic nociplastic pain. With chronic nociplastic pain, nociceptive neurons (cells that sense and transmit pain) in the CNS experience increased responsiveness to pain signaling, a process called sensitization.

Think of sensitization like this: let’s assume the threshold amount of money required to convince you to jump into a pool of freezing water is $100. If you experience chronic financial problems, your threshold may be lowered to $90, $75, maybe even $50. You are increasing your responsiveness despite the lowering of the monetary reward. It’s not a perfect analogy, but I’m on a plane coming back from vacation so work with me here. With chronic pain, the threshold signal required to signal to your brain “you are in pain” becomes lower and lower. And, again, these signals may occur despite no apparent tissue damage or sensory detection of damage.

Psychedelics target neuroplastic changes that occur with chronic nociplastic pain. One such change is an increased emotional response to pain, along with a drop in the ability to accurately sense interoceptive processing – in other words, the pain is perceived to be worse than what is actually occurring.

Nerve fibers which run throughout your body end in an area called the dorsal spinal horn (DSH). Here, information on nociception, temperature, and a host of other functions help paint a picture of what your senses perceive and what is occurring within your body. This “interoceptive map” plays a role in generating pain.

Within the DSH there is a section called the insular cortex (IC). The posterior portion of the insula is involved in sensory processing, while the anterior portion is involved with our emotions and the limbic system. In chronic nociplastic pain, activity shifts from the posterior to the anterior portion of the insula. This leads to an increased emotional response to pain, and it’s believed that LSD and psilocybin can help alleviate these changes by acting on 5-HT_2A receptors within the IC – dampening the emotional response to pain and helping your body more accurately sense pain signals (or lack thereof).

Recent research has uncovered a strong overlap between major depressive disorder (MDD) and chronic pain. The neurotransmitter serotonin (5-HT) is involved in both mood and pain, showing a potential shared cause and treatment solution for both conditions.

First, we need to review a brain area called the default mode network (DMN). Our current understanding paints the DMN as overlapping several connected brain regions and acting as a central coordinator. The DMN activates during rest when we’re focused internally, and not when we are engaged in a specific cognitive task. In this state, the DMN turns up the “watchfulness” factor. According to the internal mentation hypothesis, it is during this state in which our mind wanders and begins simulating alternative futures based on your specific past experiences.

Imaging studies in people with both MDD and chronic nociplastic pain show a sustained increase in activity in the DMN, with a corresponding decrease in functional connectivity to other parts of the brain. This increased DMN activity creates an excessive internal focus, leading to depressive rumination – negative thought patterns that can continue on loop. And because there is decreased functional connectivity to other regions of the brain, there is a drop in the brain’s ability to receive feedback from sensory regions. So, the brain struggles to connect with the sensors that can detect actual tissue damage or other problems which truly cause “pain”, and instead relies on past experience – which, in someone with chronic pain, means that the brain anticipates there is pain whether or not a noxious cause actually exists.

Where do psilocybin and LSD come into focus?

The DMN contains many 5-HT_2A receptors. Psilocybin and LSD bind and activate these receptors, and current research suggests when psilocybin and LSD do so, it can “reset” brain regions within the DMN. This helps the brain better process the whole picture of sensory and cognitive inputs, rather than relying on assumptions based on past experience due to internal rumination caused by an overactive DMN.

This suggests that psilocybin and LSD may be better suited to treat the root cause of pain. This stands in stark contrast to opioid pain relievers, which alter the subjective perception of pain by reducing neuronal activity in the somatosensory cortex, but do not solve root causes of pain.

We must also understand the descending noxious inhibitory pathway to appreciate the potential mechanisms behind psilocybin and LSD’s potential as pain relievers. This pathway exists in the central nervous system, and serves to not only sense pain, but potentially inhibit it as well. Serotonin and norepinephrine receptors are found throughout this pathway, and these receptors play a role in neurotransmission within the DSH.

We want to focus specifically on 5HT-_1A and 5HT-_2A receptors found throughout the pathway. These receptors appear to have a role in decreasing chronic pain perception and transmission. Activation of the 5HT-_1A receptor increases inhibition of pain perception, and both receptor types promote analgesia upon agonism by psilocybin or LSD. The 5HT-_1A receptor also plays a role in the development of MDD, meaning psilocybin or LSD could simultaneously treat MDD and chronic pain.

 

LSD/Psilocybin Research on Treating Chronic Pain

Prior to the “War on Drugs”, LSD was marketed by the pharmaceutical company Sandox as “Delysid” for psychotherapy research. Over 1,000 research papers published between 1949 and 1966 revealed potential for treating drug dependency (now called substance use disorder) and alcohol addiction (alcohol use disorder).

Between 1964 and 1977, several small studies evaluated LSD’s potential for treating chronic pain:

• Kast and Collins found LSD superior to the opioids dihydromorphine and pethidine in patients experiencing severe pain related to cancer and gangrene.
• Another study by Kast found that a single 100 ug LSD dose decreased pain intensity for three weeks.
• Pahnke, et al (1967) studied the uses of LSD in patients with terminal metastatic cancer and depression. They found patients who received LSD reported improvements in anxiety, mood, and pain. Another study on metastatic cancer patients by Grof et al (1973) utilized psychosocial support plus LSD and showed improvements in preoccupation with pain, pain severity, and reported physical suffering.
• Fanciullacci et al (1977) studied LSD in seven patients with phantom limb pain (the perception of pain in a limb which is no longer there, which can plague combat veterans and others who receive an amputation). Participants received an LSD dose of 25 μg per day for 1 week, which was then increased to 50 μg per day for an additional two weeks (both doses too low to produce hallucinations). Two participants reported a resolution of their pain symptoms, and others reported a decreased need for pain relievers.

These studies were small and had methodology issues, but showed that LSD, used in a clinical setting, had minimal potential risk for causing physical dependence, withdrawal, or addiction. The movement to list LSD as a Schedule I substance with a “no accepted medical use and a high risk for abuse and misuse” was, frankly, fraudulent.

Research on LSD, psilocybin, and other psychedelics ended with the enforcement of the Controlled Substances Act. Thanks to the efforts of dedicated scientists and medical researchers, the “psychedelic renaissance” has brought attention back to the therapeutic potential of these substances. Studies show a wide range of potential uses, including: MDD, depression associated with terminal cancer, obsessive compulsive disorder (OCD), alcohol use disorder, smoking cessation, anxiety disorders, cluster headaches, and chronic pain. Similar to early research from the 1940s – 1960s, recent studies reveal a strong safety profile for classic psychedelics used in clinical settings. We will continue monitoring and reporting on recent developments using psilocybin, LSD, and potentially other psychedelics in treating chronic pain and depression, given the potential for these agents to treat both combinations with fewer side effects compared to current treatments.