P-106 - (Poster #106) Psychedelics; an Untapped Therapeutic Niche: A Narrative Review in the Future of Cancer Pain Management

Background: Chemotherapy peripheral neuropathy (CIPN) is a prevalent and debilitating complication of cancer treatment, classified as a specific type of cancer-related pain. It arises from damage to peripheral nerves caused by certain chemotherapeutic agents, leading to symptoms such as numbness, burning pain, and loss of feeling in the extremities, often in a 'glove and stocking' distribution. CIPN tends to have a broad scope from 30-40% depending on the type and dose of chemotherapy. The prevalence of CIPN varies depending on the chemotherapeutic agent used, dosage, and treatment duration, with studies estimating up to 68% of patients experience some form of neuropathy within the first month of chemotherapy. The affected populations include a substantial proportion of cancer patients, particularly those receiving neurotoxic chemotherapeutic agents.

Purpose/Objectives: The goals of this research is to provide a narrative review of the literature on the use of classic psychedelics in the treatment of CIPN and cancer pain. It aims to highlight the potential of psychedelics in managing CIPN and cancer pain while addressing the challenges of their integration into mainstream medical practice. This review seeks to identify gaps in existing pain management strategies and highlight psychedelics as a promising alternative in oncology-related pain care.

 

Methods: This study employed a narrative review methodology to evaluate the potential role of psychedelics in managing chemotherapy-induced peripheral neuropathy (CIPN). A comprehensive literature search was conducted using electronic databases including PubMed, Scopus, PsycINFO, and Web of Science. Search terms included combinations of "psychedelics," "chemotherapy-induced peripheral neuropathy," "CIPN," "chronic pain," "neuropathic pain," "psilocybin," "LSD," "MDMA," "ayahuasca," and "neuroplasticity." Articles published between 2000 and 2025 were considered.
Inclusion criteria encompassed preclinical studies, randomized controlled trials (RCTs), observational studies, and systematic reviews addressing the use of classical psychedelics or related compounds in the context of chronic or neuropathic pain, with particular attention to cancer-related or CIPN-specific pain. Exclusion criteria included non-English articles, conference abstracts without full texts, and studies lacking relevance to pain mechanisms or therapeutic outcomes.
Data were extracted on study design, sample size, psychedelic agent used, pain outcomes, neurobiological findings, and presence or absence of adjunct psychotherapy. A qualitative synthesis was performed to identify recurring themes and mechanistic insights, particularly regarding neuroplasticity, central pain modulation, and patient-reported outcomes. Methodological quality was assessed using appropriate tools, including the Cochrane Risk of Bias tool for clinical studies and the SYRCLE tool for animal studies.

Results:  The review identified over 60 peer-reviewed studies relevant to the use of psychedelics in chronic pain, including 18 that directly investigated mechanisms of neuropathic pain modulation. While no clinical trials have yet assessed psychedelic use specifically for chemotherapy-induced peripheral neuropathy (CIPN), several lines of evidence support their potential role in pain relief and neural repair.
1. Central Modulation of Pain Perception
Multiple neuroimaging studies demonstrated that psychedelics such as psilocybin and LSD reduce activity in the default mode network (DMN), enhance thalamocortical connectivity, and modulate regions involved in pain processing, such as the anterior cingulate cortex and insula. These changes are associated with altered pain perception and increased emotional acceptance.
2. Neuroplasticity and Inflammation
Preclinical evidence suggests psychedelics promote structural neuroplasticity, including increased dendritic spine formation and synaptogenesis in cortical neurons. Animal models showed reduced neuroinflammation and pro-inflammatory cytokine expression after psychedelic administration, supporting a potential mechanism for peripheral nerve repair in CIPN.
3. Psychedelics in Chronic Pain Populations
Three clinical studies on chronic pain syndromes (e.g., cluster headaches, phantom limb pain, fibromyalgia) reported substantial subjective pain relief following psychedelic use, even at sub-hallucinogenic doses. These effects often persisted for weeks to months post-treatment and were enhanced when combined with psychotherapy.
4. Psychological and Emotional Resilience
Several studies emphasized the role of psychedelics in improving psychological flexibility, reducing fear-avoidance behavior, and facilitating emotional processing—all critical in chronic pain adaptation. This highlights the importance of integrated psychotherapeutic support alongside psychedelic treatment.
Overall, the reviewed evidence suggests that psychedelics offer a multimodal approach to pain management—targeting both biological and psychological dimensions of chronic neuropathic pain. However, there remains a lack of high-quality, controlled trials specifically addressing CIPN, highlighting the need for future translational and clinical research in oncology populations.

Conclusions/Implications for future research and/or clinical care: Chronic pain remains one of the most devastating burdens faced by cancer patients,
particularly those undergoing chemotherapy. Often, standard treatments leave patients with
debilitating and poorly managed neuropathic pain. Current analgesics including opioids come
with significant risks of tolerance, dependence and other side effects, leaving many patients
frustrated and distrustful of clinicians. This highlights the urgent need for safer and more
effective alternative.
Psychedelics offer a profound and potentially transformative hope for patients who have been
under-served by conventional therapies. The neuroplastic capabilities as well as the ability to
modulate brain connectivity provide the basis of which psychedelics may be harnessed in
pain management. However, while psychedelics alone may reduce pain perception, without
psychotherapy, their full therapeutic potential may be limited. Psychedelics could assist in the
treatment of CIPN by targeting both the biological repair mechanisms in the periphery as well
as central pain processing in the brain. In conclusion, psychedelics represent an untapped
avenue in the field of pain management, offering a novel approach to chronic pain. With
mounting evidence, this is an emerging space worth watching closely – one that could shape
the future of pain care.