Most people know rapamycin as a longevity drug and a drug to stop organ transplant rejection. But scientists are uncovering a hidden side to it, one that could help people reconnect socially, overcome emotional barriers, and escape the grip of rigid or isolating behaviors.
Research shows that overactivation of the mTOR pathway in the brain can contribute to fatigue, autism spectrum disorders, PTSD, addiction, and other conditions that make it harder to engage with others. Rapamycin, which quiets this pathway, is showing remarkable results across multiple studies.
In patients with chronic fatigue syndrome, low-dose rapamycin reduced exhaustion, brain fog, and post-exertional crashes. Freed from constant energy drain, many could return to conversations, hobbies, and social activities they had been missing for years.
Animal studies in autism models reveal that rapamycin can boost social interest and reduce repetitive, isolating behaviors. In some cases, it restored social preference even in adulthood, suggesting the brain remains more adaptable than once thought.
Rapamycin also shows promise for easing the emotional weight of traumatic memories and weakening the triggers that drive drug cravings. By disrupting these harmful memory links, it may help people feel safer in social spaces or break free from environments tied to past harm.
Taken together, these findings suggest that rapamycinâs impact may go far beyond lifespan. It could give people their connections back, to friends, to family, and to the world around them.
The future of this research is still unfolding, but one thing is clear: the real promise of rapamycin may not just be adding years to life, but adding life back to those years.
Sources:
Low Dose Rapamycin Alleviates Clinical Symptoms of Fatigue and PEM in ME/CFS Patients via Improvement of Autophagy
- mTOR activation is associated with chronic inflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
- Previous studies have shown that sustained mTOR activation can cause chronic muscle fatigue by inhibiting ATG13-mediated autophagy.
- Low-dose rapamycin (6 mg/week) was administered, and core ME/CFS symptoms were assessed on days 30 (T1), 60 (T2), and 90 (T3)
- Plasma levels of autophagy metabolites, such as pSer258-ATG13 and BECLIN-1, were measured and correlated with clinical outcomes, specifically Multidimensional Fatigue Inventory (MFI).
- Rapamycin (6 mg/week) was tolerated without any serious adverse events.
- Of the 40 patients, 29 (72.5%) showed strong recovery in post-exertional malaise, fatigue, and orthostatic intolerance, along with improvements in MFI fatigue domains and SF-36 aspects.
- High levels of BECLIN-1 were detected in T3.
- Plasma pSer258-ATG13 levels were strongly downregulated at T1.
- Spearmanâs correlation analysis indicated an association between autophagy impairment and reduced activity.
- Low-dose rapamycin effectively reduced PEM and other key symptoms in patients with ME/CFS, as measured by BAS, SSS, MFI, and SF-36.
- Evaluations of different fatigue parameters of BAS, BSL, MFI and SF-36 revealed a significant restoration of health deficits, such as general fatigue, reduced motivation, physical fatigue, mental fatigue, reduced activity, disturbed sleep, post exertional malaise, social functioning and emotional health.
- The effect of rapamycin on the overall metabolism of sugars, lipids, and cholesterol was monitored in all patients during each milestone. However, no significant differences were observed.
Significance: Chronic fatigue symptoms leave people drained of energy and unable to participate in small talk and other social interactions outside of what is purely necessary for them to get by to the minimal degree in day-to-day life. Alleviation of CFS like symptoms frees people up to be more socially switched on.
Low dose rapamycin (6/mg week) addressed multiple parameters of physical and mental health which can facilitate more pro-social behaviour.
Rapamycin improves social and stereotypic behavior abnormalities induced by pre-mitotic neuronal subset specific Pten deletion
Mutations to the phosphatase and tensin homolog gene (PTEN) on chromosome 10 results in hyperactivation of the mTOR pathway, as well as seizures, intellectual disabilities and autistic behaviours.
Rapamycin, an inhibitor of mTOR, can reverse the epileptic phenotype of neural subset specific Pten knockout (NS-Pten KO) mice
Male and female NS-Pten KO and wildtype (WT) mice were assigned as controls or administered 10 mg/kg of rapamycin for 2 weeks followed by behavioural testing.
Rapamycin improved social behaviour in both genotypes and stereotypic behaviours in NS-Pten KO mice.
Rapamycin treatment resulted in a reduction of several measures of activity in the open field test in both genotypes
Rapamycin did not reverse the reduced anxiety behaviour in KO mice.
These data show the potential clinical use of mTOR inhibitors by showing its administration can reduce the production of autistic-like behaviours in NS-Pten KO mice.
PTEN is a suppressor of the mTOR pathway, important in mediating cell growth and migration during neurodevelopment.14 Loss of function mutations to PTEN in both humans and rodent models have been associated with ASD and neurological features commonly found comorbid in individuals with ASD, such as macrocephaly and epilepsy.
KO mice spent more time performing stereotypies compared with WT mice, as did males when compared with females. Treatment with rapamycin induced an overall reduction in stereotypy time.
Rapamycin treated mice showed more social preference compared to the control mouse. KO mice spent less time in the chamber with the novel mouse compared with WT mice. Mice administered rapamycin spending more time in the chamber with the novel mouse than control mice.
Rapamycin treated mice showed less contextual fear memory compared to control. This might indicate an alleviation of PTSD from rapamycin.
Rapamycin induced an initial suppression of general activity in the open field, corrected stereotypies and increased sociability.
- Iâm unsure of âsuppression of general activity in the open fieldâ is a good thing.
- The open field part of the study indicates rapamycin may increase anxiety like behaviour, but none of the other tests indicate this.
Significance: Certain mutations that cause hyperactivation of the mTOR pathway also can lead to autistic behaviours and intellectual disabilities. mTOR inhibition is shown to alleviate some of these behavioural disorders.
While rapamycin didnât improve all aspects of anxiety in this study it did help alleviate excessive stereotypy, and increase the preference for socialization.
Rapamycin also reduced contextual fear memory. If this translates to humans, it could help alleviate PTSD in social contexts to allow people to overcome past negative experiences and not let it shape their perception of future social interactions.
Rapamycin improves sociability in the BTBR T+Itpr3tf/J mouse model of autism spectrum disorders
- Overactivation of the mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of syndromic forms of autism spectrum disorders (ASDs), such as tuberous sclerosis complex, neurofibromatosis 1, and fragile X syndrome.
- Administration of mTORC1 (mTOR complex 1) inhibitors (e.g. rapamycin) in syndromic mouse models of ASDs improved behaviour, cognition, and neuropathology.
- Rapamycin, an inhibitor of the mTORC1 complex significantly increased the amount of time the BTBR mouse spent engaged in active exploration (sniffing) of the enclosed ICR stimulus mouse
- Consistent with this prosocial effect of rapamycin on the BTBR mouse strain observed in session II, it significantly increased the numbers of discrete episodes of social approach and anogenital sniffing made by BTBR mice when they were allowed to interact freely with the ICR stimulus mouse in session III
- Interestingly, although the BTBR mouse displays impaired sociability on several objective outcome measures, this mouse strain did not manifest more intensive stereotypic behaviours (i.e., rearing and self-grooming) during its free interaction with the ICR stimulus mouse in session III
- These latter data on stereotypic behaviours in session III suggest that the symptom domains of impaired sociability and stereotypic behaviours may be dissociable and mediated by different neural circuits
- Rapamycin did not worsen stereotypic behaviours in the BTBR mouse, supporting development of anti-mTOR pharmacotherapeutic strategies for ASD; an ideal medication for ASDs should not worsen stereotypic behaviours while improving sociability and vice versa.
Significance: Rapamycin is shown to improve behaviour, cognition and neuropathology. It increased the number of episodes of social approach.
Rapamycin did not worsen stereotypic behaviour compared to control, even though it benefited their sociability in other areas.
Systemic Inhibition of Mammalian Target of Rapamycin Inhibits Fear Memory Reconsolidation
- Systemic rapamycin, in conjunction with therapeutic traumatic memory reactivation, can decrease the emotional strength of an established traumatic memory.
- This finding not only establishes mTOR regulation of protein translation in the reconsolidation phase of traumatic memory, but also implicates a novel, FDA-approved drug treatment for patients suffering from acquired anxiety disorders such as PTSD and specific phobia.
- The effect of rapamycin is similar to, although stronger than, that of anisomycin, a drug that empirically defines reconsolidation.
Significance: Rapamycin and other mTOR inhibitor drugs may show promise as treatments for PTSD and phobias. This may translate to improved social behaviour if the impaired behaviour is linked to fear due to previous negative social interactions.
Rapamycin prevents drug seeking via disrupting reconsolidation of reward memory in rats
https://academic.oup.com/ijnp/article/17/1/127/825914
- The maladaptive drug memory developed between the drug-rewarding effect and environmental cues contributes to difficulty in preventing drug relapse.
- Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) kinase, has been proved to be involved in various memory consolidation.
- Using a conditioned place preference (CPP) procedure, we examined the effects of systemically administered rapamycin on reconsolidation of drug memory in rats. We found that systemically administered rapamycin (0.1 or 10 mg/kg, i.p.) after re-exposure to drug-paired environment, dose dependently decreased the expression of CPP 1 d later, and the effect lasted for up to 14 d and could not be reversed by a priming injection of morphine.
- These results indicated that systemic administration of rapamycin after memory reactivation can persistently inhibit the drug seeking behaviour via disruption of morphine memory reconsolidation in rats.
- Additionally, the effect of rapamycin on memory reconsolidation was reproduced in cocaine CPP and alcohol CPP.
- Furthermore, rapamycin did not induce conditioned place aversion and had no effect on locomotor activity and anxiety behaviour.
- Systemically administered rapamycin, in conjunction with therapeutic traumatic memory reactivation, can decrease the emotional strength of an established traumatic memory.
- In heroin addicts, a study also indicated that a single dose of rapamycin significantly reduced the craving, but not anxiety induced by drug-related cues
Significance: Rapamycin help disassociate a location with drug addictive tendencies. Often when someone abuses drugs in a certain location, that location is a constant reminder of drug use. This is worst in a persons own home. The ability to uncouple location and thought is powerful and useful way of reducing the likelihood of drug relapse.
This may indicate not just the ability to uncouple location with drug abuse memory, but perhaps other negative associations with location. It might be useful to mentally recover after an assault or home invasion.
Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity
https://www.biorxiv.org/content/10.1101/2024.07.08.602602v1.full
- Our findings suggest that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction, including neuronal excitability, altered gene expression in multiple cell types, sensory functional network connectivity, and modulation of information flow.
- We demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD behaviours in adult animals without requiring long-term physical alterations to the brain.
- Large-fold increases in several pro- inflammatory cytokines were observed in blood samples from MIR offspring compared to controls in both young and old adults in G-CSF, IFN-g, IL-6, MCP-1, MIG, KC, M-CSF, GM-CSF and there were also smaller but significant increases in IL-9, IL-1beta, TNF-alpha, VEGF, IP-10, and LIF
- The largest increases in pro- inflammatory cytokines in the young adult MIR mice were in IFN-g, MCP-1, and IL-6 and in old adult mice were M-CSF, MCP-1, and G-CSF
- Acute 2-hour treatment with the mTOR inhibitor rapamycin had negligible effects on blood cytokines in adult MIR and control offspring
- Increased microglia in the brain in response to this chronic state could be one mechanism driving abnormal mTOR pathway activation in the brain and the abnormal behaviours observed in MIR offspring.
- Therefore, we used the CSFR1 inhibitor, Plexxikon5622 (PLX5622), to deplete brain microglia in order to test this hypothesis.
- We found that ablation of microglia in young adult mice partially rescues repetitive, social, and sensory abnormalities, suggesting that microglia do play a role in the pathophysiology of MIR exposure.
- However, microglia ablation does not significantly rescue these behaviours in old adult MIR mice even though rapamycin treatment does rescue them at this age, suggesting that while microglia may play a role in the development and evolution of behavioural abnormalities, they are unlikely to be the primary mediator of ongoing behavioural alterations.
- Rapamycin treatment reduced this seizure susceptibility in MIR mice, lowering the seizure score of mice but not eliminating the seizure-inducing effect of PTZ on the mice
- Adult MIR mice display abnormal neuronal hyper-excitability in cortical and striatal neurons that is normalized by acute rapamycin treatment, suggesting that one mechanism by which rapamycin is acting acutely on the brain is via the rapid normalization of inhibitory/excitatory balance in the brain.
[1] Orthostatic intolerance is the umbrella term for a range of different conditions that result in difficulty with the upright posture, particularly standing.
[2] SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting and have been widely used.
[3] A stereotypy is a repetitive or ritualistic movement, posture, or utterance. Stereotypies may be simple movements such as body rocking, or complex, such as self-caressing, crossing and uncrossing of legs, and marching in place. They are found especially in people with autism spectrum disorder.
[4] Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD)
[5] Pentylenetetrazol (PTZ) is a seizure-inducing drug
If you wanted to follow my Substack: Beneficial Social Behaviour Modulating Effects of Rapamycin
This was a subject I was researching for a while since I noticed some interesting social effects from Rapamycin usage myself. I was going to refine this a bit more before posting but someone asked for evidence of claims so I figure Iâd just post it now so people could discuss it.
