Jo Cameron

Cameron was identified at the age of 66 years when she underwent trapeziectomy surgery for severe hand osteoarthritis.^[3][4][5] 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.^[3][4][5] She had also developed severe hip osteoarthritis, resulting in lopsided walking abnormality noticed by others, but also reported no pain from this.^[3][4][5] She had undergone hip replacement surgery the year before at the age of 65.^[3][5] Recovery from trapeziectomy surgery is normally very painful or "excruciating".^[3][4][5] Cameron had assured her anesthesiologist, Dr. Devjit Srivastava, that she would not need painkillers for this surgery, to which Srivastava was skeptical.^[3][1]

Extraordinarily, Cameron indeed experienced no pain during recovery and required no analgesics.^[11][3][5] 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.^[3][5] Her surprising lack of pain led to further investigations by Srivastava.^[3][5] 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.^[3][5] 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.^[3] This maneuver involves pressing hard on the inner edges of the eye sockets, which results in strong pain that shocks people awake.^[3] Cameron felt no pain from the maneuver, instead experiencing only pressure.^[3] 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.^[3][5]

Cameron subjectively reported a lifetime lack of pain, including with childbirth, broken bones, and numerous burns and cuts.^{[11][3][1][5]} She had often not noticed burns and other injuries until she smelled burning flesh or saw blood on herself.^[3][1][5] Her burns and cuts also seemed to heal quickly with less or no scarring.^[3][5] Eating Scotch bonnet chili peppers left only a "pleasant glow".^[1] 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.^[3][5] Aside from her lack of pain, Cameron was additionally described as characteristically happy, friendly, talkative, optimistic, and compassionate, as well as exceedingly affectionate and loving towards family members.^{[3][1][12][2][5]} Moreover, she was lacking in anxiety, depression, worry, fear, panic, grief, dread, and negative affect generally.^[3][1][2][5] She reported a long history of mild memory lapses and forgetfulness as well.^[2][5] Cameron also experienced characteristic severe nausea and vomiting caused by the opioid morphine that had been given to her postoperatively after hip replacement surgery.^[2][5]

Genetic testing revealed that she was heterozygous for a common hypomorphic single nucleotide polymorphism (SNP) in her FAAH gene (rs324420; C385A; C allele frequency 74%, A allele frequency 26%) that has been associated with reduced activity of the enzyme and increased anandamide levels as well as with decreased pain sensitivity, fear, and anxiety.^{[13][3][2][5]} As this polymorphism is common in the population however, it could not explain her presentation alone.^[3][5] In addition to the mutation in FAAH, Cameron showed a heterozygous microdeletions downstream of FAAH overlapping a pseudogene.^{[13][3][2][5]} This novel pseudogene was named FAAH-OUT and was considered likely to encode a long non-coding RNA (lncRNA).^[13][2][5] It was found to be expressed widely in tissues, including in the brain and the dorsal root ganglia of the spinal cord.^[5] The researchers hypothesized that the microdeletion negated the normal function of FAAH by reducing its expression.^[3][5]

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.^[13][3][5] 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.^[5] 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.^[14] Endocannabinoids like anandamide are agonists of the cannabinoid receptors, such as the CB₁ and CB₂ receptors, among others.^[12] These receptors are the same molecular targets of the phytocannabinoids, like Δ⁹-tetrahydrocannabinol (THC), that are present in cannabis.^[12]

Cameron's son was also heterozygous for the FAAH-OUT microdeletion, but did not also have the hypomorphic FAAH polymorphism, and had a lesser and only partial reduction in pain sensitivity.^[8][3][1][5] His psychological and affective characteristics were not described.^[5]

In spite of the preceding genetic and biochemical findings, it is not fully clear the extent to which Cameron's mutations in FAAH and FAAH-OUT are involved in her presentation.^[3][5] Hence, it has been stated that decreased FAAH expression remains only a possible causative factor.^[6][3][5]

A subsequent study by the team characterized the molecular basis of Cameron's FAAH-OUT-associated pain insensitivity, including changes in gene expression.^{[13][2][15][16]} They confirmed that her FAAH-OUT microdeletion reduced expression of FAAH.^[13][2][15] 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.^[2][16] Systemic FAAH inhibition has been found to increase BDNF levels in the hippocampus by approximately 25% in mice.^[2] BDNF, signaling through its receptor tropomyosin receptor kinase B (TrkB), has been highly implicated in protecting against depression and in antidepressant action.^{[17][18][19][20][2]}

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.^[3][5][10] 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][14][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 (e.g., autism spectrum 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.^{[13][9][7][22]} Results in these studies have been less than would be suggested by Cameron's case or those observed in animal models, in which the drugs are highly effective.^[13][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]

• S.M. (patient)