There is an unmet treatment need for people at clinical high risk (CHR) for psychosis¹. As only a minority of them go on to develop a psychotic disorder, interventions need to be particularly safe and well tolerated.

Cannabidiol (CBD), a non-intoxicating constituent of cannabis, has potential anxiolytic and antipsychotic properties² and a good safety profile. In two out of three clinical trials in patients with established psychosis, evidence of its antipsychotic efficacy has been reported^3-5. However, there have not been trials of a period of treatment with CBD in CHR individuals. We assessed the clinical effects of a course of CBD treatment in people with a CHR state following a protocol approved by the National Research Ethics Service Committee London (Camberwell, St. Giles) (ISRCTN46322781).

The study was conducted on antipsychotic-naïve subjects attending early detection services in the UK who met one or more criteria for CHR state for psychosis: a) attenuated psychotic symptoms; b) brief limited intermittent psychosis (i.e., a psychotic episode lasting <1 week which remitted without treatment); c) recent functional decline and either schizotypal personality disorder or first-degree relative with psychosis. Key exclusion criteria were history of previous psychotic disorder or manic episode, neurological disorder, or current DSM-IV diagnosis of substance dependence.

Thirty-three subjects were recruited after they provided written informed consent. They were advised to refrain from using cannabis for 96 hours, alcohol for a minimum of 24 hours, nicotine for 6 hours, and any other recreational drugs for 2 weeks before entering the study, and to continue to refrain from using cannabis or other recreational drugs during the course of the study. Baseline assessments included the Comprehensive Assessment of At-Risk Mental States (CAARMS)⁶; the Spielberger State-Trait Anxiety Inventory, State Subscale (STAI-S)⁷; and the Positive and Negative Syndrome Scale (PANSS)⁸.

Using a parallel group, double-blind, placebo-controlled design, participants were randomly allocated to either CBD (N=16) or placebo (N=17). They received either a CBD capsule or an identical-looking placebo capsule as a single daily oral dose, which they continued for 21 days. The dose of CBD (99.9% pure) was 600 mg/day, found to be effective and well-tolerated previously^{4, 9}. All clinical assessments were repeated after 7 and 21 days of treatment, except for the CAARMS, which was administered at baseline and at the end of treatment. Blood samples were collected before and after taking the study drug on days 1 and 21 to assay CBD plasma levels. The effects of treatment on symptoms were examined using analyses of variance with treatment (CBD vs. placebo) as the between-subject factor after controlling for baseline scores.

At baseline, the two treatment groups were comparable in demographic and clinical variables (see supplementary information). None of the participants received any psychotropic medication other than CBD or placebo during the course of the study. Two participants dropped out from the placebo arm. Following 21-day treatment (intention-to-treat, last observation carried forward analysis), CBD-treated participants had a lower total CAARMS score (F_1,30=7.168, p=0.012) than those receiving placebo, after controlling for baseline score. There were no significant differences between the treatment groups in the incidence of treatment-emergent side effects (see also supplementary information).

The CBD group also reported less distress associated with psychotic symptoms (F_1,30=4.66, p=0.039) and had a lower PANSS total score (p=0.042), after controlling for the respective baseline values. There was a greater reduction in the CAARMS negative symptoms (p=0.045), but not in the CAARMS positive symptoms (p=0.144), in CBD-treated patients. State anxiety levels following treatment were not different between the two groups (p=0.862).

When the analyses were restricted to participants with complete data for the respective measures, the CBD-treated group again had a lower total CAARMS score (p=0.033), with a trend for less distress associated with psychotic symptoms (p=0.072) and a lower total PANSS score (p=0.056). There were no group differences in the mean number of pills missed (p=0.85) or the proportion of patients who missed at least one pill (p=1.00). CBD levels were detectable in all except one out of 15 CBD participants with available data (see also supplementary information).

These data provide the first evidence that CBD can ameliorate symptoms in the CHR population. We found that treatment with CBD for three weeks was accompanied by a reduction in the severity of CHR symptoms and the distress associated with psychotic ex-periences. As we did not find an effect of CBD on the STAI-S score, these effects were unlikely to be driven by a reduction in state anxiety.

Recent meta-analyses suggest that existing pharmacological and psychological treatments have little effect on symptoms or the incidence of psychosis in CHR subjects¹, and there is currently no licensed treatment for this population. Consistent with previous evidence^3-5, the incidence of adverse effects in the CBD-treated group was not different from the placebo-treated group, making CBD a good candidate treatment for CHR subjects. No subject dropped out of the CBD arm.

A limitation of the study is the small sample size, underscoring the preliminary nature of the evidence. Because treatment was limited to 21 days, we were not able to examine the effect of treatment on the risk of later transition to psychosis. As some clinical outcome data were missing, we analyzed effects on clinical outcomes using a last observation carried forward method of imputation. However, when we subsequently repeated the analyses but restricted inclusion to participants with complete data for the respective measures, the main results remained unchanged.

Our findings indicate that short-term treatment with CBD can ameliorate the symptoms of CHR state for psychosis, and is well tolerated. These results highlight the potential of CBD as a novel treatment for psychosis, and the need for large-scale efficacy studies to further evaluate its clinical utility.

精神病临床高危 (CHR) 人群的治疗需求尚未得到满足¹ 。由于只有少数人会继续发展为精神障碍，因此干预措施必须特别安全且具有良好的耐受性。

大麻二酚 (CBD) 是大麻的一种非中毒成分，具有潜在的抗焦虑和抗精神病特性²且安全性良好。在对已确诊精神病患者进行的三分之二的临床试验中，报告了其抗精神病功效的证据^3-5 。然而，尚未在 CHR 个体中进行 CBD 治疗一段时间的试验。我们按照伦敦国家研究伦理服务委员会（坎伯韦尔，圣吉尔斯）批准的方案（ISRCTN46322781）评估了 CBD 治疗过程对 CHR 状态患者的临床效果。

这项研究是在英国参加早期检测服务的未接受过抗精神病药物治疗的受试者中进行的，这些受试者符合 CHR 精神病状态的一项或多项标准：a) 精神病症状减轻； b) 短暂的有限间歇性精神病（即持续<1周的精神病发作，无需治疗即可缓解）； c) 近期功能衰退和精神分裂型人格障碍或一级亲属患有精神病。主要排除标准是既往精神病史或躁狂发作史、神经系统疾病或当前 DSM-IV 诊断的物质依赖。

在提供书面知情同意书后，招募了 33 名受试者。建议他们在进入研究前 2 周内不要使用大麻，至少 24 小时不要饮酒，6 小时不要使用尼古丁，不要使用任何其他娱乐性药物，并继续不要使用大麻或其他娱乐性药物在学习过程中。基线评估包括高危心理状态综合评估 (CAARMS) ⁶ ；斯皮尔伯格状态特质焦虑量表，状态分量表 (STAI-S) ⁷ ；以及阳性和阴性症状量表 (PANSS) ⁸ 。

采用平行组、双盲、安慰剂对照设计，参与者被随机分配到 CBD (N=16) 或安慰剂 (N=17)。他们每天口服 CBD 胶囊或外观相同的安慰剂胶囊，持续 21 天。 CBD（99.9% 纯度）的剂量为 600 毫克/天，之前发现有效且耐受性良好^{4, 9} 。除 CAARMS 外，所有临床评估均在治疗 7 天和 21 天后重复进行，CAARMS 是在基线和治疗结束时进行的。在第 1 天和第 21 天服用研究药物之前和之后收集血样，以测定 CBD 血浆水平。在控制基线分数后，使用治疗方差分析（CBD 与安慰剂）作为受试者间因素来检查治疗对症状的影响。

在基线时，两个治疗组在人口统计学和临床​​变量方面具有可比性（参见补充信息）。在研究过程中，没有参与者接受除 CBD 或安慰剂以外的任何精神药物。两名参与者从安慰剂组中退出。经过 21 天的治疗（意向治疗，最后观察进行分析）后，在控制基线后，接受 CBD 治疗的参与者的 CAARMS 总评分（F _1,30 = 7.168，p = 0.012）低于接受安慰剂的参与者分数。治疗组之间治疗引起的副作用的发生率没有显着差异（另见补充信息）。

在控制各自的基线值后，CBD 组还报告与精神病症状相关的痛苦较少（F _1,30 = 4.66，p = 0.039），并且 PANSS 总分较低（p = 0.042）。在 CBD 治疗的患者中，CAARMS 阴性症状有更大的减少（p = 0.045），但 CAARMS 阳性症状没有减少（p = 0.144）。治疗后的状态焦虑水平在两组之间没有差异（p=0.862）。

当分析仅限于具有各自测量的完整数据的参与者时，CBD治疗组的CAARMS总分再次较低（p = 0.033），与精神病症状相关的痛苦有减少的趋势（p = 0.072）和PANSS 总分较低 (p=0.056)。漏服药的平均数量 (p=0.85) 或漏服至少一颗药的患者比例 (p=1.00) 没有组间差异。除了有可用数据的 15 名 CBD 参与者中的一名外，所有人都可检测到 CBD 水平（另请参阅补充信息）。

这些数据首次证明 CBD 可以改善 CHR 人群的症状。我们发现，用 CBD 治疗三周可以减轻 CHR 症状的严重程度以及与精神病经历相关的痛苦。由于我们没有发现 CBD 对 STAI-S 评分有影响，因此这些影响不太可能是由状态焦虑的减少引起的。

最近的荟萃分析表明，现有的药物和心理治疗对 CHR 受试者的症状或精神病的发生率影响不大¹ ，并且目前没有针对该人群的许可治疗。与之前的证据一致^3-5 ，CBD 治疗组的不良反应发生率与安慰剂治疗组没有差异，这使得 CBD 成为 CHR 受试者的良好候选治疗方法。没有受试者从 CBD 分支中退出。

该研究的一个局限性是样本量较小，强调了证据的初步性质。由于治疗仅限 21 天，因此我们无法检查治疗对以后转变为精神病的风险的影响。由于缺少一些临床结果数据，我们使用最后观察的推算方法分析了对临床结果的影响。然而，当我们随后重复分析但限制纳入具有各自措施的完整数据的参与者时，主要结果保持不变。

我们的研究结果表明，短期 CBD 治疗可以改善精神病的 CHR 状态症状，并且耐受性良好。这些结果凸显了 CBD 作为一种新型精神病治疗方法的潜力，以及需要进行大规模疗效研究以进一步评估其临床效用。