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Jo Cameron
Born1948 (age 75–76 years)[1]
Known forFamous patient with pain insensitivity and low negative affect associated with FAAHTooltip fatty acid amide hydrolase-related mutations and elevated endocannabinoid levels[2][3][4]

Jo Cameron (born 1948; age 75–76 years), also known as Patient PFS, is a Scottish woman who feels no pain and experiences little to no anxiety or other aspects of negative affect.[5][2][1][3][6][4] She has two mutations, one in the gene encoding fatty acid amide hydrolase (FAAH) and one in the pseudogene FAAH-OUT, which are thought to be responsible for her condition.[5][6][2][4] FAAH is an enzyme involved in the metabolism of endocannabinoids like anandamide.[7][8][9][2][4] Cameron has high levels of anandamide and other endocannabinoids.[5][2][4] She was first presented as a published case report in 2019 and was subsequently featured widely in the mainstream media.[2][1][3][4]

Clinical presentation

Cameron was identified at the age of 66 years when she underwent trapeziectomy surgery for severe hand osteoarthritis.[2][3][4] This condition had led to deformity of her thumbs such that she could not hold a pen properly, although Cameron reported experiencing no pain from it.[2][3][4] She had also developed severe hip osteoarthritis, resulting in lopsided walking abnormality noticed by others, but also reported no pain from this.[2][3][4] She had undergone hip replacement surgery the year before at the age of 65.[2][4] Recovery from trapeziectomy surgery is normally very painful or "excrutiating".[2][3][4] Cameron had assured her anesthesiologist, Dr. Devjit Srivastava, that she would not need painkillers for this surgery, to which Srivastava was skeptical.[2][1]

Extraordinarily, Cameron indeed experienced no pain during recovery and required no analgesics.[10][2][4] Her pain ratings were 0/10 and only paracetamol (acetaminophen; Tylenol) was administered, but this medication was routinely given to all patients by the nurses.[2][4] Her surprising lack of pain led to further investigations by Srivastava.[2][4] Review of her medical chart showed that she had also reported little to no pain with hip replacement, for which her pain scores were 0/10 or 1/10 once on the postoperative evening.[2][4] Srivastava remained slightly skeptical until Cameron allowed him to perform a normally very painful maneuver used by anesthesiologists on patients who are having difficulty regaining consciousness following sedation.[2] This maneuver involves pressing hard on the inner edges of the eye sockets, which results in strong pain that shocks people awake.[2] Cameron felt no pain from the maneuver, instead experiencing only pressure.[2] At that point, Srivastava developed a research protocol involving a team of highly regarded scientists from around the world in an attempt to figure out what was responsible for her lack of pain.[2][4]

Cameron subjectively reported a lifetime lack of pain, including with childbirth, broken bones, and numerous burns and cuts.[10][2][1][4] She had often not noticed burns and other injuries until she smelled burning flesh or saw blood on herself.[2][1][4] Her burns and cuts also seemed to heal quickly with less scarring than normal.[2][4] Eating Scotch bonnet chili peppers left only a "pleasant glow".[1] Cameron was additionally described as characteristically happy, friendly, talkative, optimistic, and compassionate, as well as exceedingly affectionate and loving towards family members.[2][1][11][6][4] Moreover, she was lacking in anxiety, depression, worry, fear, panic, grief, dread, and negative affect generally.[2][1][6][4] She reported a long history of mild memory lapses and forgetfulness as well.[6][4] Attempts by researchers to induce pain, including burning her, sticking her with pins, and pinching her with tweezers until she bled, resulted in no pain.[2][4]

Genetic evaluation

See also: Fatty-acid amide hydrolase 1 § FAAH-OUT microdeletion

Genetic testing revealed a common single nucleotide polymorphism (SNP) in her FAAH gene that has been associated with reduced activity of the enzyme and increased anandamide levels, as well as decreased pain sensitivity, fear, and anxiety.[12][2][6][4] As this polymorphism is common in the population however, it could not explain her presentation alone.[2][4] In addition to the mutation in FAAH, Cameron showed a microdeletion downstream of FAAH overlapping a pseudogene.[12][2][6][4] This novel pseudogene was named FAAH-OUT and was considered likely to encode a long non-coding RNA (lncRNA).[12][6][4] It was found to be expressed widely in tissues, including in the brain and the dorsal root ganglia of the spinal cord.[4] The researchers hypothesized that the microdeletion negated the normal function of FAAH by reducing its expression.[2][4]

Measurement of circulating endocannabinoid levels revealed that anandamide (N-arachidonoylethanolamine; AEA) levels were increased by 1.7-fold while oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels were elevated by approximately 3-fold relative to several controls.[12][2][4] Conversely, levels of 2-arachidonylglycerol (2-AG), another endocannabinoid mainly metabolized by a different enzyme called monoacylglycerol lipase (MAGL) rather than by FAAH, were largely unchanged relative to controls.[4] Studies of FAAH knockout mice have found that brain levels of anandamide and other endocannabinoids are increased by 10- to 15-fold in several regions and this correlated well with analgesic and anxiolytic phenotypes in these animals.[13] Endocannabinoids like anandamide are agonists of the cannabinoid receptors, such as the CB1 receptor among others.[11] These receptors are the same molecular targets of the phytocannabinoids, like Δ9-tetrahydrocannabinol (THC), that are present in the recreational drug cannabis.[11]

Cameron's son also carried the FAAH-OUT microdeletion, but did not also have the FAAH reduced-function polymorphism and had a lesser and only a partial reduction in pain sensitivity.[8][2][1][4]

In spite of the preceding genetic findings, it is not fully clear the extent to which Cameron's mutations in FAAH and FAAH-OUT are involved in her presentation.[2][4] Hence, it has been stated that decreased FAAH expression remains only a possible causative factor.[5][2][4]

A subsequent study by the team characterized the molecular basis of Cameron's FAAH-OUT-associated pain insensitivity, including changes in gene expression.[12][6][14][15] They confirmed that her FAAH-OUT microdeletion reduced expression of FAAH.[12][6][14] In addition, they found alterations that might help to explain her positive mood and low anxiety levels, for instance a dramatic increase in brain-derived neurotrophic factor (BDNF) expression in fibroblasts derived from Cameron.[6][15] Systemic FAAH inhibition has been found to increase BDNF levels in the hippocampus by approximately 25% in mice.[6] BDNF, signaling through its receptor tropomyosin receptor kinase B (TrkB), has been highly implicated in protecting against depression and in antidepressant action.[16][17][18][19][6]

Pharmaceutical development

Cameron's case has helped encourage interest in pharmaceutical development and repurposing of FAAH inhibitors for the treatment of pain and psychiatric disorders like depression and anxiety.[2][4][20] FAAH inhibitors are under development for various medical uses and several have reached clinical trials, but none have reached the market as of 2023.[8][13][21][22] The most advanced drug candidate is JNJ-42165279, which has reached phase 2 clinical trials for the treatment of anxiety disorders and pervasive child development disorders and has also been studied in the treatment of anxious depression.[22][23] However, clinical trials of FAAH inhibitors in the treatment of pain, anxiety, and depression have so far been unsuccessful or disappointing.[12][9][7][22] Results in these studies have been less than Cameron's case or those suggested by animal models, in which the drugs are highly effective.[12][8][9] Potential reasons for these discrepancies include species differences between animals and humans, lack of predictive validity of animal models, differences between preclinical studies and clinical trial designs, and various others.[9]

See also

References

  1. ^ a b c d e f g h i j Murphy, Heather (28 March 2019). "At 71, She's Never Felt Pain or Anxiety. Now Scientists Know Why". The New York Times. Retrieved 3 August 2024.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai Levy, Ariel (3 January 2020). "A World Without Pain". The New Yorker. Retrieved 2 August 2024.
  3. ^ a b c d e f g Sample, Ian (28 March 2019). "Scientists find genetic mutation that makes woman feel no pain". the Guardian. Retrieved 3 August 2024.
  4. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai Habib AM, Okorokov AL, Hill MN, Bras JT, Lee MC, Li S, Gossage SJ, van Drimmelen M, Morena M, Houlden H, Ramirez JD, Bennett DL, Srivastava D, Cox JJ (August 2019). "Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity". Br J Anaesth. 123 (2): e249–e253. doi:10.1016/j.bja.2019.02.019. PMC 6676009. PMID 30929760.
  5. ^ a b c d Ahmed M, Boileau I, Le Foll B, Carvalho AF, Kloiber S (2022). "The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics". Braz J Psychiatry. 44 (1): 81–93. doi:10.1590/1516-4446-2021-1926. PMC 8827369. PMID 34468550. Finally, in the remarkable case report of a patient presenting with pain insensitivity and low fear and anxiety, the C385A polymorphism together with a microdeletion linked to decreased FAAH expression was detected as a possible causal factor. In addition, blood levels of AEA and other fatty-acid amides which are degraded by FAAH were unusually elevated in this individual.112
  6. ^ a b c d e f g h i j k l m Mikaeili H, Habib AM, Yeung CW, Santana-Varela S, Luiz AP, Panteleeva K, Zuberi S, Athanasiou-Fragkouli A, Houlden H, Wood JN, Okorokov AL, Cox JJ (September 2023). "Molecular basis of FAAH-OUT-associated human pain insensitivity". Brain. 146 (9): 3851–3865. doi:10.1093/brain/awad098. PMC 10473560. PMID 37222214.
  7. ^ a b Fowler CJ (July 2021). "The endocannabinoid system - current implications for drug development". J Intern Med. 290 (1): 2–26. doi:10.1111/joim.13229. PMC 8358957. PMID 33348434. A molecular genetic study associating a FAAH gene polymorphism with pain sensitivity [135] and a recent case report of a woman with pain insensitivity who had a heterozygous microdeletion downstream from the 3' end of FAAH [136] also tie in FAAH with pain.
  8. ^ a b c d Santoso AD, De Ridder D (February 2023). "Fatty Acid Amide Hydrolase: An Integrative Clinical Perspective". Cannabis Cannabinoid Res. 8 (1): 56–76. doi:10.1089/can.2021.0237. PMID 35900294.
  9. ^ a b c d Maccarrone M, Di Marzo V, Gertsch J, Grether U, Howlett AC, Hua T, Makriyannis A, Piomelli D, Ueda N, van der Stelt M (September 2023). "Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years". Pharmacol Rev. 75 (5): 885–958. doi:10.1124/pharmrev.122.000600. PMID 37164640. There is strong preclinical evidence indicating that eCBs are critical regulators of pain sensation (for review, see Finn et al., 2021). The analgesic phenotype of individuals carrying loss-of-function FAAH mutations (C385A, faah-out) supports this conclusion (Habib et al., 2019), but the results of clinical trials have been disappointing (Huggins et al., 2012; Wagenlehner et al., 2017). Possible explanations for this discrepancy include species-specific differences, selection of inadequate clinical pain conditions, inconsistencies between preclinical and clinical study design, and lack of predictive validity of current animal models.
  10. ^ a b Campos RM, Aguiar AF, Paes-Colli Y, Trindade PM, Ferreira BK, de Melo Reis RA, Sampaio LS (2021). "Cannabinoid Therapeutics in Chronic Neuropathic Pain: From Animal Research to Human Treatment". Front Physiol. 12: 785176. doi:10.3389/fphys.2021.785176. PMC 8669747. PMID 34916962. Clinical evidence for the role of the eCS in pain management was reported based on a serendipitous case of a Scottish patient (Habib et al., 2019). Authors described the clinical data from a woman submitted to orthopedic surgery, a procedure recognized for being associated with severe pain, with no need for analgesics. The same patient also had a long clinical history of cuts and burns without any sensation of pain. Genetic investigation revealed a deletion in the gene responsible for FAAH transcription, which led to reduced degradation and higher levels of AEA in peripheral blood and probably other organs.
  11. ^ a b c Duggan, Peter J. (18 March 2021). "The Chemistry of Cannabis and Cannabinoids". Australian Journal of Chemistry. 74 (6): 369–387. doi:10.1071/CH21006. ISSN 0004-9425. The inhibition of these enzymes allows the corresponding endocannabinoids to accumulate, increasing their agonistic effects on cannabinoid receptors. This appears to be supported by the interesting case of a woman with reduced expression and activity of FAAH in her central nervous system (CNS), and consequent high circulating levels of anandamide and other endocannabinoids, who was found to have remarkable pain insensitivity, a highly optimistic outlook, and very low anxiety and depression scores.[96]
  12. ^ a b c d e f g h Habib AM, Cox JJ, Okorokov AL (June 2024). "Out of the dark: the emerging roles of lncRNAs in pain". Trends Genet. doi:10.1016/j.tig.2024.04.009. PMID 38926010.
  13. ^ a b Tripathi RK (February 2020). "A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents". Eur J Med Chem. 188: 111953. doi:10.1016/j.ejmech.2019.111953. PMID 31945644.
  14. ^ a b "Rare genetic mutation allows woman to feel no pain". BBC Home. 24 May 2023. Retrieved 3 August 2024.
  15. ^ a b "Study reveals unique molecular machinery of woman who can't feel pain". UCL News. 24 May 2023. Retrieved 3 August 2024.
  16. ^ Castrén E, Monteggia LM (July 2021). "Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action". Biol Psychiatry. 90 (2): 128–136. doi:10.1016/j.biopsych.2021.05.008. PMID 34053675.
  17. ^ Chakrapani S, Eskander N, De Los Santos LA, Omisore BA, Mostafa JA (November 2020). "Neuroplasticity and the Biological Role of Brain Derived Neurotrophic Factor in the Pathophysiology and Management of Depression". Cureus. 12 (11): e11396. doi:10.7759/cureus.11396. PMC 7725195. PMID 33312794.
  18. ^ Castrén E, Rantamäki T (April 2010). "The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity". Dev Neurobiol. 70 (5): 289–297. doi:10.1002/dneu.20758. PMID 20186711.
  19. ^ Esalatmanesh S, Kashani L, Akhondzadeh S (2023). "Effects of Antidepressant Medication on Brain-derived Neurotrophic Factor Concentration and Neuroplasticity in Depression: A Review of Preclinical and Clinical Studies". Avicenna J Med Biotechnol. 15 (3): 129–138. doi:10.18502/ajmb.v15i3.12921. PMC 10634295. PMID 37538241.
  20. ^ Zanfirescu A, Nitulescu G, Mihai DP, Nitulescu GM (December 2021). "Identifying FAAH Inhibitors as New Therapeutic Options for the Treatment of Chronic Pain through Drug Repurposing". Pharmaceuticals (Basel). 15 (1): 38. doi:10.3390/ph15010038. PMC 8781999. PMID 35056095. FAAH-knockout mice have enhanced levels of AEA and display a CB1 receptor-mediated hypoalgesic phenotype [14]. In humans, a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, or a common functional single-nucleotide polymorphism in FAAH conferring reduced enzymatic expression and activity, lead to similar results [15].
  21. ^ Fazio D, Criscuolo E, Piccoli A, Barboni B, Fezza F, Maccarrone M (July 2020). "Advances in the discovery of fatty acid amide hydrolase inhibitors: what does the future hold?". Expert Opin Drug Discov. 15 (7): 765–778. doi:10.1080/17460441.2020.1751118. PMID 32292082.
  22. ^ a b c Hill MN, Haney M, Hillard CJ, Karhson DS, Vecchiarelli HA (November 2023). "The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses". Psychol Med. 53 (15): 7006–7024. doi:10.1017/S0033291723002465. PMC 10719691. PMID 37671673.
  23. ^ "JNJ 42165279". AdisInsight. 20 December 2022. Retrieved 3 August 2024.
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