cbd mthfr mutationDecember 15, 2021
There can be one abnormal variant (heterozygous) or two (homozygous), which are passed down from parent to child. The more variations you have, the more issues your body will have with methylating.
MTHFR is a gene that provides the body with instructions for making a certain enzyme called methylenetetrahydrofolate reductase (MTHFR). When you eat foods that contain folic acid, MTHFR converts it into methyl-folate (folate’s active form).
Those with an MTHFR mutation are also at higher risk of being low in Vitamin B12 . Vitamin B12 can be supplemented easily without a prescription, whether as isolated B12 or present in multivitamins and B complex vitamins. Always check with your provider what is best for you. Foods high in vitamin B12 include pastured eggs, nuts, beans, and nutritional yeast. Additional foods that support healthy methylation include asparagus, avocado, broccoli, and legumes.
Symptoms of an MTHFR gene mutation.
Having the MTHFR mutation is an opportunity to make changes to your diet and lifestyle to maximize your methylation, manage symptoms, and optimize your overall health.
Humans have an estimated 20,000 genes, and one of those is the MTHFR gene, a gene that helps your body process folate. Unfortunately, 30-60 percent of all people carry an MTHFR gene variant which may lead to low levels of folate and b vitamins and high levels of homocysteine in the blood. Over time, these downstream effects of mutations in the MTHFR gene can put people at higher risk for many common health problems such as preventable heart disease, colon cancer, stroke, Alzheimer’s disease, and more.
Consuming more folate in your diet may aid with methylation. Some of the best whole-food sources of folate include dark leafy greens, avocado, and lentils.
MTHFR mutations affect everyone differently, and symptoms can vary from long-term health issues to hardly noticeable changes in overall health. Research has shown an association between MTHFR mutations and several health problems including:
Those with MTHFR genetic variations are more likely to have an imbalance of neurotransmitter levels, which can affect mood and irritability, especially when stressed. In fact, high levels of stress can exacerbate MTHFR mutation symptoms. Tips for decreasing overall stress include starting a regular meditation practice , journaling, spending time in nature, and volunteering but ultimately, uncovering the specific activities that help you to unwind, stay grounded, and decompress are the most important tools to help manage personal stress levels on a daily basis.
Methyl-folate is critical to methylation, which helps to optimize a huge number of processes in your body including the production of DNA, metabolism of hormones, and proper detoxification.
What exactly is an MTHFR mutation?
Alcohol intake can make symptoms worse by inhibiting DNA methylation and increasing the demands of detoxification on the liver. Limiting your consumption of alcohol can support less interference in already stunted methylation processes in those with MTHFR genetic mutations. If you do decide to drink alcohol, it should be consumed in moderation—up to one drink per day for women and two drinks per day for men—and preferably in the forms of tequila, vodka, and mezcal, rather than wine and beer. Read about some of our best biohacks to help you cut back on your alcohol intake .
People with MTHFR mutations might have more difficulty converting folic acid into its usable form, and this may cause symptoms to worsen. Check if your current supplements contain folic acid and if they do, stop taking them or switch to another brand. It’s important to opt for a supplement that contains the most bioavailable form of folate—methyl-folate—which can help your body absorb the vitamin more efficiently. Additional supplements that help support this genetic variant include magnesium, vitamin D , and vitamin B6.
An MTHFR gene mutation may change the way you metabolize and convert nutrients from your diet into active vitamins, minerals, and proteins your body can use. This genetic mutation may also affect hormone and neurotransmitter levels, brain function, digestion, cholesterol levels, and more.
So how do you know if you have a MTHFR variant and what can you do about it? This article will outline the most common symptoms, testing available, and the best natural treatments to help you manage symptoms for the long term.
3. Minimize alcohol intake.
Your body is made up of trillions of cells, each containing your genes—the set of instructions for making you who you are. Genes are segments of DNA, and each gene provides a particular set of instructions, usually coding for a specific protein or a particular function.
Research has even found an association with an MTHFR mutation and depression, anxiety, and other mental health disorders . MTHFR produces an essential enzyme that converts folate into a form that plays a role in mood-regulating neurotransmitter production.
A genetic test can determine if you have an MTHFR gene mutation or other genetic SNP (single nucleotide polymorphism) variations that may be affecting you. This can be done with any of our Parsley Health physicians and often is covered by insurance. Other tests that can help confirm an MTHFR mutation include homocysteine levels, hormone level testing , and microbiome labs —all of which can also be ordered and interpreted by your Parsley Health clinician.
Because reduced methylation contributes to poor detoxification, it’s important to support your body’s natural elimination pathways.
Having an MTHFR mutation doesn’t automatically mean you will experience the symptoms or health issues outlined above. MTHFR mutation symptoms also depend on which variant of the mutation you have and whether the variations affect both of your MTHFR genes.
Discovery sample. Using SCID-I, current and past depressive episodes were assessed at baseline, and at 5 follow-up measurements at 3, 12, 24, 36 and 66 months after baseline. With these follow-up assessments, we diagnosed relapses (<6 months after a previous major depressive episode) or recurrences during follow-up, both further addressed as ‘recurrence’ for clarity reasons. The trained SCID evaluators were blind to treatment condition and subjects were instructed not to reveal their treatment condition to the interviewers (psychologist/research assistants). All interviews were audio taped. Two independent experienced psychiatrists, also blinded to treatment condition, evaluated all occasions of participants meeting the DSM-IV criteria for MDD. In cases of disagreement, we used the ratings of the psychiatrists. The κ-value for inter-rater agreement between the interviewers and psychiatrist on categorization of a relapse/recurrence or no relapse/recurrence was 0.96, indicating high agreement. 40.
The extent of the effect modification can be seen by comparing the risk for recurrence between the four MTHFR C677T by TCE combination groups (T+ and TCE+ N =26; T+ and TCE− N =38; T− and TCE+ N =28; T− and TCE− N =32). We found a significantly higher hazard for the T+ and TCE+ groups as compared with the T− and TCE− groups (hazard ratio 3.55; Wald 17.7, d.f.=1, P <0.001). For patients who experienced TCEs, the hazard for recurrence in T-allele carriers was 2.4 times higher than in non-T-allele carriers ( P =0.002; Figure 1 ). This corresponds to the observed differences in median time till recurrence that were respectively 191 days for T+ and TCEs+ patients; 461 days for T− and TCE+ patients; 773 days for T+ and TCE− patients and 866 days for T− and TCE− patients.
TCE: experienced TCE yes/no, with no TCE as the reference category.
Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase ( MTHFR ) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence ( P =0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T− and TCE+ patients; 773 days for T+ and TCE− patients and 866 days for T− and TCE− patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology ( P =0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma.
Group comparisons were calculated using Student’s t -tests, χ 2 tests or Fisher’s exact tests.
MTHFR: T-allele carrying patients versus non-T-allele carrying patients, with non-T-allele carriers as the reference category.
Cox regression analysis.
Replication sample. All participants were of Dutch ancestry. Genotype data were generated on three different array platforms: the Illumina (San Diego, CA, USA) Human Omni Express ( N =576), the Illumina Human610-Quad Beadchip ( N =768) and the Illumina HumanHap550 array ( N =34). For each SNP platform, quality control procedures were initially performed separately using PLINK V1.07. 53 Subjects were excluded based on >5% missing genotypes and gender errors. We used linkage disequilibrium-based SNP pruning to select the most informative SNPs ( R 2 <0.2) only for the subsequent quality control step. This resulted in ∼67k SNPs for the sets to assess heterozygosity (F <3 s.d.), homozygosity (F>3 s.d.) and relatedness by pairwise identity-by-descent values (PIHAT >0.15). Data sets were merged with Hapmap Phase 3 individuals to check ethnicity. After these quality control procedures on subjects (excluding in total 101 individuals), quality control on SNPs was performed as follows. All SNPs were filtered on missingness (>2%) and Hardy–Weinberg ( P >1e −6 ) before merging the three data sets. Four duplicates and three related sample pairs were detected in the merged data sets (according to criteria described above) and one outlier after clustering the merged data set. From these data, the MTHFR genotype (rs1801133) was extracted.
Childhood maltreatment is associated with substantial and long-lasting cognitive and biological effects on the brain including heightened stress sensitivity. Therefore, individuals who have been exposed to childhood maltreatment are predisposed to an unfavorable course of major depressive disorder (MDD) and treatment outcome, as indicated by a recent meta-analysis. 1 However, not all individuals exposed to traumatic stress develop a depression. Therefore, it is important to characterize the gene–environment interplay underlying the effects of traumatic childhood events (TCEs) on depression outcomes.
In spite of these limitations, our study is unique in providing the opportunity to investigate the role of the interaction between genes and environment on prospectively assessed recurrence over 5.5 years. In addition, this was investigated in a specific sample of highly recurrent depressed patients, which can be considered characteristic for those patients particularly causing the large MDD-associated burden of disease. 63 By including specific recurrently depressed patients, we were able to investigate a clinically highly relevant sample. Our replication of the interaction in a population sample supports the robustness of our findings and suggests that this genetic vulnerability is relevant in the broader context of depression.
Participants in the discovery sample were recruited using a project website launched in 2006 targeted at Dutch young adults and adolescents from age 18 to 25 years (www.cannabisquest.nl). 44 Strategies to generate traffic on the project website included collaboration with over a hundred colleges, universities and youth centers, as well as the use of online commercial advertisement products (that is, banners and text links). 44 The chance to win an Apple iPod or a Nintendo Wii was used as an incentive. Double entries were prevented by exclusion of subjects with an identical e-mail address, surname and date of birth. Anonymous submission of data was not possible. The online assessment included verification questions to protect against random answers, and participants failing to correctly complete the verification questions were subsequently excluded. From the online data ( N =17 698), 1259 participants were included for subsequent genetic assessment in two waves. First, in order to increase power for gene × environment interactions, 45 in the context of cannabis and psychosis, we prioritized a sample of 719 participants who belonged to the top or bottom quintile of total scores of psychotic experiences as measured by the Community Assessment of Psychic Experiences (CAPE) score who were either cannabis naive (that is, a lifetime cannabis exposure frequency of <6 times) or were heavy cannabis users (that is, current expenditure for personal cannabis use exceeded 3€ weekly). Second, an unselected sample of 540 individuals was included. As ascertained with the validated Dutch version of either the SCID 42 or the MINI International Neuropsychiatric Interview, 46 healthy controls had no history of any psychotic disorder. For 84 participants, no interview data were available, and for these cases the presence of a psychotic disorder was excluded by the absence of antipsychotic drug use or a history of psychiatric treatment. The possible concomitant use of recreational drugs was assessed with the substance abuse module of the Composite International Diagnostic Interview. 47 Of the 1259 participants who completed comprehensive assessments and provided blood samples for genetic testing, complete data were available for 665 subjects because of a later implementation of the Childhood Trauma Questionnaire (CTQ) 48 assessment in the study. All participants provided a urine sample to screen for the presence of recreational drugs in order to verify recent self-reported cannabis use. The study was approved by the ethical review board of the University Medical Center Utrecht and all participants gave written informed consent.
Of the 172 patients of the original trial, 137 provided DNA. Of these 35 patients, 15 (8.7%) were lost to follow-up and the remaining patients (11.6%) did not participate because of a diversity of reasons (for example, being afraid of needles, ethical issues concerning genetic study). Five patients could not be analyzed because of MTHFR C677T genotyping failure (genotyping success rate=96.3%). Of the remaining 132 patients, 1 was non-Caucasian, 2 were lost to follow-up and we could not obtain TCEs data for 4 patients. All analyses pertain to the resulting 124 patients. These 124 patients were comparable to the other 48 patients on gender, age, educational level, number of previous episodes and age of onset of first depression, but differed on marital status and antidepressant use. Compared with the 48 excluded patients, the 124 remaining patients comprised fewer singles (37% vs 54% χ 2 =4.14, d.f.=1, P =0.042), and more users of antidepressants (57% vs 35% χ 2 =6.61, d.f.=1, P =0.010).
Abbreviations: AD, antidepressant, BMI, body mass index, F, female; HDRS 17 , 17-item Hamilton Depression Rating Scale; M, male; TCE, traumatic childhood event.
This impact of the combination of early childhood trauma and C677T MTHFR polymorphism on onset of depressive symptomatology and recurrences in MDD gives rise to hypotheses about the underlying pathophysiological pathways. The thermolabile variant of the MTHFR gene may represent a genetic vulnerability factor for limited defense against (oxidative) stress, because it results in a reduction of methyl donors for essential methylation processes, for example, glutathione production and synthesis of neurotransmitters. 18 This vulnerability becomes exposed when triggered by enhanced environmental stress such as childhood trauma. 37 This could be the result of long-lasting trauma-induced epigenetic changes. These changes include DNA methylation and chromatin modifications, patterns that are inherited but responsive to environmental shifts such as stress, and especially vulnerable during development. 58 McGowan et al. 59 showed altered methylation of the promoter region of the glucocorticoid receptor gene in hippocampus tissue from suicide victims with a history of childhood abuse. Interestingly, Shalev et al. 60 recently reported stress-related accelerated telomere erosion already in childhood; compared with their counterparts, children who experienced two or more kinds of violence exposure showed significantly more telomere erosion. The authors suggest that these effects are mediated by oxidative stress. Heim et al. 61 proposed that many of the biological changes thought to be characteristic of MDD might, in fact, be secondary to early-life trauma and represent the risk of developing MDD. Moreover, Nanni et al. 1 revealed that childhood maltreatment was associated with lack of response (or remission) during treatment for MDD. Hypothetically, TCEs disrupt the physiological response to stress, the overactivation of which may lead to detrimental consequences in stress-sensitive systems, namely the nervous, immune, metabolic and endocrine systems. 61, 62 The resulting cumulative biological ‘weight’ might determine poor prognosis in terms of recurrences in MDD. However, thus far, prospective studies in recurrent MDD were lacking.
Although significantly different enzymatic activity and thermolability were reported, overlapping profiles for the TT and CT genotypes have been described, with CC remaining as a distinct genotype. 55 Therefore, and for power reasons, the MTHFR C677T polymorphism variable was dichotomized into T-allele carriers (TT and CT combined) and non-T carriers (the wild-type genotype CC) groups in the discovery sample. In the replication sample, genotypes were coded 0, 1, or 2 and modeled as a linear effect (additive genetic model) to account for different genotype distributions because it avoids small subgroup stratification. 57 Deviation from Hardy–Weinberg equilibrium was tested by allele counting and χ 2 analysis.
Discovery sample. We collected 20 ml blood samples at patients’ homes by venipuncture. DNA was isolated from blood using a filter-based method (QIAamp DNA Mini Kit, Qiagen, Manchester, UK). The PCR primers were designed using Primer 3 (http://frodo.wi.mit.edu/primer3/input.htm). The PCR primer sequence was 5′-GGCAGGTTACCCCAAAGGC-3′ and 5′-TGGGGTGGAGGGAGCTTATG-3′, and the PEX primer sequence was 5′-GAGAAGGTGTCTLCGGGAG-3′. Genotyping was done using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer from Bruker Daltonics (Wormer, The Netherlands). All samples were genotyped in duplicate to increase reliability. 52 Genotyping error rate based on these duplicates was 3.7%.
After a first episode of MDD, ∼50% of patients will experience recurrences, which are responsible for considerable disability and impairment. 2, 3, 4, 5 Burcusa and Iacono 6 stated as an explanation for recurrence in MDD that ‘individuals at high risk for multiple episodes possess the necessary characteristics to make them prone to recurrent depression, and such characteristics exist even before their first episode’. The recurrent type of MDD has a higher heritability than a single episode of MDD. 7 Furthermore, biological studies in individuals at risk for MDD, or remitted from MDD, as well as their nondepressed family members, showed that pathophysiological disturbances also precede the development of MDD and remain present after remission, suggestive of stable heritable vulnerability traits, that is, endophenotypes. 8, 9, 10, 11, 12 However, a direct identification of candidate genes with recurrence of MDD has proven to be difficult, presumably as a result of complex interactions between genes and environmental stressors. 13, 14.
The gene–environment interaction between methylenetetrahydrofolate reductase ( MTHFR ) genotype and traumatic childhood events (TCEs) on depressive symptoms in 665 individuals from the general population ( P =0.0027). 0, T/T genotype; 1, C/T genotype; and 2, C/C genotype.