1287:
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.
1417:
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.
1358:
FAAH-knockout mice have enhanced levels of AEA and display a CB1 receptor-mediated hypoalgesic phenotype . 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
1286:
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
1466:
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
1416:
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
1128:
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
282:
left only a "pleasant glow". 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. Aside from her lack of pain, Cameron was additionally described as characteristically happy, friendly, talkative,
242:
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. Srivastava remained slightly skeptical until
Cameron allowed him to perform a normally very painful maneuver used by
645:. However, clinical trials of FAAH inhibitors in the treatment of pain, anxiety, and depression have so far been unsuccessful or disappointing. Results in these studies have been less than would be suggested by Cameron's case or those observed in
255:. This maneuver involves pressing hard on the inner edges of the eye sockets, which results in strong pain that shocks people awake. Cameron felt no pain from the maneuver, instead experiencing only pressure. At that point, Srivastava developed a
1184:
A molecular genetic study associating a FAAH gene polymorphism with pain sensitivity and a recent case report of a woman with pain insensitivity who had a heterozygous microdeletion downstream from the 3' end of FAAH also tie in FAAH with
1467:
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.
238:(acetaminophen; Tylenol) was administered, but this medication was routinely given to all patients by the nurses. Her surprising lack of pain led to further investigations by Srivastava. Review of her
550:
microdeletion reduced expression of FAAH. In addition, they found alterations that might help to explain her positive mood and low anxiety levels, for instance a dramatic increase in
211:. 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. She had also developed severe
274:
and cuts. She had often not noticed burns and other injuries until she smelled burning flesh or saw blood on herself. Her burns and cuts also seemed to heal quickly with less or no
1803:
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?".
1756:"Effects of Antidepressant Medication on Brain-derived Neurotrophic Factor Concentration and Neuroplasticity in Depression: A Review of Preclinical and Clinical Studies"
1032:
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).
768:
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).
1719:
Castrén E, Rantamäki T (April 2010). "The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity".
463:
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
649:, in which the drugs are highly effective. Potential reasons for these discrepancies include species differences between animals and humans, lack of
524:
polymorphism, and had a lesser and only partial reduction in pain sensitivity. His psychological and affective characteristics were not described.
219:
surgery the year before at the age of 65. Recovery from trapeziectomy surgery is normally very painful or "excrutiating". Cameron had assured her
1956:
932:
259:
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.
1601:
1246:
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).
1534:
Tripathi RK (February 2020). "A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents".
535:
are involved in her presentation. Hence, it has been stated that decreased FAAH expression remains only a possible causative factor.
215:
osteoarthritis, resulting in lopsided walking abnormality noticed by others, but also reported no pain from this. She had undergone
1670:"Neuroplasticity and the Biological Role of Brain Derived Neurotrophic Factor in the Pathophysiology and Management of Depression"
347:
1299:
1845:"The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses"
642:
527:
In spite of the preceding genetic and biochemical findings, it is not fully clear the extent to which
Cameron's mutations in
1946:
1941:
634:
1034:"Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity"
433:. The researchers hypothesized that the microdeletion negated the normal function of FAAH by reducing its expression.
551:
1318:"Identifying FAAH Inhibitors as New Therapeutic Options for the Treatment of Chronic Pain through Drug Repurposing"
111:
626:
363:
570:
1204:
Santoso AD, De Ridder D (February 2023). "Fatty Acid Amide
Hydrolase: An Integrative Clinical Perspective".
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448:(PEA) levels were elevated by approximately 3-fold relative to several controls. Conversely, levels of
134:
73:
1248:"Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years"
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is common in the population however, it could not explain her presentation alone. In addition to the
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1090:"The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics"
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1921:
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Campos RM, Aguiar AF, Paes-Colli Y, Trindade PM, Ferreira BK, de Melo Reis RA, Sampaio LS (2021).
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1986:
1976:
1376:"Cannabinoid Therapeutics in Chronic Neuropathic Pain: From Animal Research to Human Treatment"
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frequency 74%, A allele frequency 26%) that has been associated with reduced activity of the
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617:. FAAH inhibitors are under development for various medical uses and several have reached
8:
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1629:"Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action"
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Chakrapani S, Eskander N, De Los Santos LA, Omisore BA, Mostafa JA (November 2020).
456:(MAGL) rather than by FAAH, were largely unchanged relative to controls. Studies of
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Extraordinarily, Cameron indeed experienced no pain during recovery and required no
1971:
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188:) for treatment of pain and psychiatric disorders has been encouraged by her case.
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amides which are degraded by FAAH were unusually elevated in this individual.112
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452:(2-AG), another endocannabinoid mainly metabolized by a different enzyme called
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A subsequent study by the team characterized the molecular basis of
Cameron's
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Measurement of circulating endocannabinoid levels revealed that anandamide (
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Hill MN, Haney M, Hillard CJ, Karhson DS, Vecchiarelli HA (November 2023).
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that had been given to her postoperatively after hip replacement surgery.
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1146:"The endocannabinoid system - current implications for drug development"
440:-arachidonoylethanolamine; AEA) levels were increased by 1.7-fold while
1732:
1602:"Study reveals unique molecular machinery of woman who can't feel pain"
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Cameron subjectively reported a lifetime lack of pain, including with
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1922:
Profile: The Far Out
Initiative - Astral Codex Ten (Scott Alexander)
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1435:
166:. Cameron has high levels of anandamide and other endocannabinoids.
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Zanfirescu A, Nitulescu G, Mihai DP, Nitulescu GM (December 2021).
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by approximately 25% in mice. BDNF, signaling through its receptor
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715:"At 71, She's Never Felt Pain or Anxiety. Now Scientists Know Why"
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770:"Molecular basis of FAAH-OUT-associated human pain insensitivity"
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933:"Scientists find genetic mutation that makes woman feel no pain"
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and loving towards family members. Moreover, she was lacking in
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Ahmed M, Boileau I, Le Foll B, Carvalho AF, Kloiber S (2022).
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Fatty-acid amide hydrolase 1 § FAAH-OUT microdeletion
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573:(TrkB), has been highly implicated in protecting against
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1496:"Out of the dark: the emerging roles of lncRNAs in pain"
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as well. Cameron also experienced characteristic severe
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in these animals. Endocannabinoids like anandamide are
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optimistic, and compassionate, as well as exceedingly
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542:-associated pain insensitivity, including changes in
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microdeletion, but did not also have the hypomorphic
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for this surgery, to which
Srivastava was skeptical.
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1573:"Rare genetic mutation allows woman to feel no pain"
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in 2019 and was subsequently featured widely in the
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1754:Esalatmanesh S, Kashani L, Akhondzadeh S (2023).
417:(lncRNA). It was found to be expressed widely in
223:, Dr. Devjit Srivastava, that she would not need
16:Patient with little to no pain or negative affect
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641:) and has also been studied in the treatment of
589:Cameron's case has helped encourage interest in
247:on patients who are having difficulty regaining
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315:generally. She reported a long history of mild
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565:has been found to increase BDNF levels in the
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497:, among others. These receptors are the same
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1436:"The Chemistry of Cannabis and Cannabinoids"
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516:Cameron's son was also heterozygous for the
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1494:Habib AM, Cox JJ, Okorokov AL (June 2024).
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1359:and activity, lead to similar results .
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196:Cameron was identified at the age of 66
1957:Congenital disorders of nervous system
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413:and was considered likely to encode a
234:. Her pain ratings were 0/10 and only
1627:Castrén E, Monteggia LM (July 2021).
635:pervasive child development disorders
629:clinical trials for the treatment of
341:
889:
1298:: CS1 maint: PMC embargo expired (
13:
1434:Duggan, Peter J. (18 March 2021).
409:. This novel pseudogene was named
79:Tooltip fatty acid amide hydrolase
14:
1998:
1915:
713:Murphy, Heather (28 March 2019).
552:brain-derived neurotrophic factor
405:downstream of FAAH overlapping a
385:levels as well as with decreased
401:, Cameron showed a heterozygous
1440:Australian Journal of Chemistry
1646:10.1016/j.biopsych.2021.05.008
890:Levy, Ariel (3 January 2020).
364:single nucleotide polymorphism
1:
1817:10.1080/17460441.2020.1751118
931:Sample, Ian (28 March 2019).
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571:tropomyosin receptor kinase B
389:, fear, and anxiety. As this
169:She was first presented as a
114:and experiences little to no
1548:10.1016/j.ejmech.2019.111953
7:
1947:21st-century Scottish women
1942:20th-century Scottish women
1264:10.1124/pharmrev.122.000600
1106:10.1590/1516-4446-2021-1926
668:
509:(THC), that are present in
280:Scotch bonnet chili peppers
10:
2003:
591:pharmaceutical development
585:Pharmaceutical development
546:. They confirmed that her
345:
135:fatty acid amide hydrolase
1861:10.1017/S0033291723002465
1772:10.18502/ajmb.v15i3.12921
1760:Avicenna J Med Biotechnol
1509:10.1016/j.tig.2024.04.009
1393:10.3389/fphys.2021.785176
1050:10.1016/j.bja.2019.02.019
639:autism spectrum disorders
200:years when she underwent
56:
48:
40:
28:
21:
1206:Cannabis Cannabinoid Res
1805:Expert Opin Drug Discov
1322:Pharmaceuticals (Basel)
1144:Fowler CJ (July 2021).
454:monoacylglycerol lipase
892:"A World Without Pain"
665:, and various others.
663:clinical trial designs
657:, differences between
558:derived from Cameron.
507:Δ-tetrahydrocannabinol
355:revealed that she was
137:(FAAH) and one in the
102:years), also known as
1218:10.1089/can.2021.0237
786:10.1093/brain/awad098
607:psychiatric disorders
601:for the treatment of
554:(BDNF) expression in
480:cannabinoid receptors
450:2-arachidonylglycerol
446:palmitoylethanolamide
192:Clinical presentation
98:(born 1948; age 75–76
1687:10.7759/cureus.11396
625:, which has reached
373:(rs324420; C385A; C
182:pharmaceutical drugs
118:or other aspects of
659:preclinical studies
651:predictive validity
427:dorsal root ganglia
421:, including in the
415:long non-coding RNA
204:surgery for severe
1899:. 20 December 2022
1733:10.1002/dneu.20758
1335:10.3390/ph15010038
1162:10.1111/joim.13229
719:The New York Times
643:anxious depression
442:oleoylethanolamide
342:Genetic evaluation
66:pain insensitivity
1855:(15): 7006–7024.
1094:Braz J Psychiatry
631:anxiety disorders
503:phytocannabinoids
499:molecular targets
257:research protocol
245:anesthesiologists
180:. Development of
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270:, and numerous
217:hip replacement
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186:FAAH inhibitors
120:negative affect
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361:hypomorphic
236:paracetamol
225:painkillers
174:case report
104:Patient PFS
44:Patient PFS
1931:Categories
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681:References
611:depression
575:depression
472:phenotypes
469:anxiolytic
444:(OEA) and
407:pseudogene
383:anandamide
346:See also:
293:depression
264:childbirth
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232:analgesics
164:anandamide
156:metabolism
148:expression
139:pseudogene
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560:Systemic
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329:vomiting
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